Academiejaar 2013 – 2014
Postoperative sleep disturbances:
a review and an observational study
Mies CRIVITS
Promotor: Prof. dr. Jan Mulier
Co-promotor: Prof. dr. Luc De Baerdemaeker
Masterproef voorgedragen in de master in de specialistische geneeskunde
Anesthesie & Reanimatie
Academiejaar 2013 – 2014
Postoperative sleep disturbances:
a review and an observational study
Mies CRIVITS
Promotor: Prof. dr. Jan Mulier
Co-promotor: Prof. dr. Luc De Baerdemaeker
Masterproef voorgedragen in de master in de specialistische geneeskunde
Anesthesie & Reanimatie
De auteur en de promotor geven de toelating deze masterproef voor consultatie beschikbaar te stellen
en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperkingen van
het auteursrecht, in het bijzonder met betrekking tot de verplichting uitdrukkelijk de bron te vermelden
bij het aanhalen van resultaten uit deze masterproef.
Datum: 11/7/2014
(handtekening ASO)
(handtekening promotor)
Mies Crivits
Prof. dr. Jan Mulier
Inhoudstafel – Table of contents
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Abstract English
……………………………………………………………………………..……..
Abstract Nederlands ……………………………………………………………………………..……..
Introduction
……………………………………………………………………………..……..
Methodology
……………………………………………………………………………..……..
Results literature review
……………………………………………..…………………………
 Normal sleep architecture
..............................................................
 Assessment of sleep ……………………………………………..…………………………
i. Subjectively ……………………………………………..…………………………
ii. Objectively
……………………………………………..…………………………
 Physiology of sleep
……………………………………………..…………………………
 Pathophysiology of sleep
..............................................................
 Postoperative sleep
……………………………………………..…………………………
i. Effect of pain on sleep ..............................................................
ii. Effect of opioids on sleep
……………………………………………….
iii. Effect of non-opioid Anaesthesia on sleep
………………………
- Dexmedetomidine
……………………………………………….
- Inhalation anaesthetics
…………………………………..
- Local anaesthetics
……………………………………………….
- Paracetamol and non-steroidal anti-inflammatory drugs
iv. Effect of surgery on sleep
……………………………………………….
v. Miscellaneous
..............................................................
Results observational study
……………………………………………..…………………………
Discussion
……………………………………………………………………………..……..
Conclusion
……………………………………………………………………………..……..
References
……………………………………………………………………………..……..
Appendix A
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English abstract
Introduction: Different studies have shown that sleep disturbances in the first postoperative
nights are common. We will first review the relevance of these sleep disturbances and explore
the possible contributing factors in detail. Next, the observational study we conducted
comparing opioid anaesthesia (OA) versus opioid free anaesthesia (OFA) on sleep quality is
discussed.
Methodology: First, we conducted a thorough literature study using Pubmed, ISI web of
science, Google Scholar and the Cochrane Library. Articles were selected according to their
relevance, using different combinations of following MESH terms: postoperative, opioids,
opioid free anaesthesia, sleep architecture, sleep disturbance and sleep physiology.
Next we conducted a single centre retrospective observational study comparing opioid free
anaesthesia to opioid anaesthesia in adult patients after standard or revision gastric bypass
surgery on their wellbeing and subjective quality of sleep. After the first postoperative night,
sleep quality was assessed using the validated quality of recovery score (QoR-40). This
questionnaire covers different postoperative aspects - the five relevant to the sleep quality
were analysed. The results were statistically processed using the Pearson's chi-squared test.
Results: The aetiology of a disturbed sleep architecture is multifactorial. We explored the
relative contribution of different perioperative factors such as the impact of anaesthesia,
surgical stress, postoperative pain and especially of opioids on sleep architecture. The
observational study included a total of 292 patients. The patients treated in the OFA group
experienced less bad dreams (p = 0.017), felt more comfortable (p = 0.001), reported better
sleep (p = 0.011) and felt better rested (p = 0.012) than patients in the OA group. On the other
hand, we found no impact of the extend of surgery (primary or revision) on the five different
aspects of sleep measured by the QoR-40 scale.
Conclusion: It is well established that the postoperative sleep pattern is severely disturbed.
We conclude that this cannot be solely explained by opioid use alone, which favours the
assumption that the biggest impact on sleep is seen as a result of surgical trauma and
environmental factors. Opioid free anesthesia did result in increased patient sleep quality.
Nederlandstalig abstract
Inleiding: Verschillende studies hebben aangetoond dat patiënten de eerste postoperatieve
nachten ernstige slaapstoornissen ervaren. In deze scriptie wordt de relevantie van deze
slaapstoornissen besproken alsook de mogelijke oorzaken. Verder bespreken we onze
observationele studie waarin de impact op slaapkwaliteit wordt vergeleken na opioïde en
opioïdvrije anesthesie.
Methodologie: Eerst werd een grondige literatuurstudie verricht met behulp van Pubmed, ISI
Web of Science, Google Scholar en de Cochrane Library. Artikelen werden geselecteerd op
basis van hun relevantie, met behulp van verschillende combinaties van volgende MESH
termen: postoperatief, opioïden, opioïdvrije anesthesie, slaaparchitectuur, slaapverstoring en
slaapfysiologie. Vervolgens voerden we een retrospectieve observationele studie uit waarbij
patiënten bevraagd werden naar hun algemeen welzijn en subjectieve slaapkwaliteit. We
gingen hierbij na of er een impact is van opioïde of opoïdvrije anesthesie. Daarenboven
bekeken we de potentiële impact van de uitgebreidheid van heelkunde, waarbij we de
patiënten na standaard of na een revisie gastric bypass met elkaar vergelijken. Na de eerste
postoperatieve nacht werd de slaapkwaliteit gemeten met de gevalideerde ‘Quality of
recovery score’ (QOR-40). Deze vragenlijst heeft betrekking op verschillende postoperatieve
aspecten - vijf relevant voor de kwaliteit van slaap werden geanalyseerd. De resultaten
werden statistisch verwerkt met behulp van de Pearson chi-kwadraat test.
Resultaten: De etiologie van een verstoorde slaaparchitectuur is multifactorieel. We
verkenden de relatieve bijdrage van de verschillende perioperatieve factoren zoals de effecten
van anesthesie, chirurgische stress, postoperatieve pijn en vooral opioïden op de
slaaparchitectuur. De observationele studie omvatte 292 patiënten. De patiënten in de
opioidvrije groep ondervonden minder slechte dromen (p = 0,017), meer comfort (p = 0,001),
betere nachtrust (p = 0,011) en voelden zich beter uitgerust (p = 0,012) dan patiënten in de
opioïde groep. Daarentegen vonden we geen invloed van de uitgebreidheid van chirurgie
(primair of revisie) op de vijf verschillende aspecten van de slaap gemeten door de QOR-40
schaal
Conclusie: Het is bekend dat het postoperatieve slaappatroon ernstig verstoord is. We
concluderen dat dit niet alleen door het gebruik van opioïden kan verklaard worden. Dit
ondersteunt de veronderstelling dat het grootste effect op slaap een gevolg is van chirurgisch
trauma en omgevingsfactoren. Opioïd vrije anesthesie resulteerde wel in een verbeterde
slaapkwaliteit.
Introduction
Although the perioperative risks related to anaesthesia and surgery have greatly diminished
over the years, surgery is still beset with postoperative complications. The in-hospital
mortality and morbidity the first two postoperative months is still high as recently measured
by Pearse.1 Different types of complications including pulmonary, cardiac, thrombo-embolic
and cerebral dysfunctions, are likely not solely explained by inadequate surgical or
anaesthetic techniques.
The major disturbances seen after surgery are not merely discomfort. One of the observations
is that sleep quality is frequently disturbed the first postoperative days. The changes in sleep
architecture include sleep fragmentation, reduced total sleep time and loss of time spend in
slow wave sleep (SWS) and rapid eye movement (REM) sleep.2
We will first discuss the relevance of sleep disturbances. After which we will explore in more
detail the possible contributing factors. We also include an observational study comparing
opioid anaesthesia versus opioid free anaesthesia on sleep quality.
Disturbed and rebound REM sleep
Rapid eye movement (REM) sleep is a short moment of high autonomic nervous system
activity, which could be stressful for the body, especially after surgery. This REM sleep
accounts for 25% of total sleep time during a normal night. Interestingly, if suppressed for one
or more nights, rebound REM sleep occurs the following nights, which resembles REM sleep
but with an increased intensity and duration.
Various studies have been able to show that REM sleep is diminished or even completely
abolished in the first postoperative nights and thus is followed by rebound REM sleep the
consecutive
nights.3 During REM sleep and its coupled episodes of apnea, ventricular
tachycardia and severe bradycardia are common and this may impose additional stress on
underlying heart disease, especially after major surgery where important fluid and electrolyte
shifts have taken place. This is even more so as the effects of REM are intensified during
rebound REM sleep.3
As reported by Kaw3, rebound REM sleep is associated with a threefold increase in hypoxic
episodes. This may account for the observation made by Hung et al.4 where in a group of
unselected male survivors of acute myocardial infarction, an apnoea index of more than 5,3 is
an independent predictive factor for the development of a myocardial infarction. This
hypothesis is further supported by the fact that the majority of unexplained postoperative
deaths occur at night in the first postoperative week. The highest incidence of postoperative
cardiac complications occurs during the first three postoperative days, with a peak on the third
day. This coincides with the time window where there is a state of rebound REM sleep.5
Rebound REM sleep has also been linked with obstructive sleep apnoea syndrome, stroke,
myocardial infarction, mental confusion, delirium, and haemodynamic instability and wound
breakdown.3
Disturbed sleep and pain
Despite the presence of effective analgesics, acute postoperative pain control is insufficient in
about 30% of the patients. Importantly, of those patients 2-10% develop severe chronic pain.2
Sleep and pain interact bidirectional: sleep deprivation has a hyperalgesic effect and pain
disturbs the sleep architecture.6 In the postoperative setting there are additional factors that
may disturb sleep architecture, including suboptimal sleep environment, medication
interaction and the biochemical response to the surgical insult.
To exclude these confounding factors, Roerhs et al.7 conducted a study in healthy, pain free
volunteers. As a measure of the subjects pain threshold, the finger withdrawal latency to a
thermal stimulus was recorded after normal and reduced total sleep time. A reduction from
eight to four hours of sleep resulted in a reduction of the finger withdrawal latency with 25%.
Secondly they confirmed that a loss of REM sleep also decreased the pain threshold with a
32% loss of latency. Roerhs showed a clear effect on the pain threshold of reduced total sleep
time and reduced REM sleep. However according to Lauterbacher it remains unclear whether
it is the sleep continuity disturbance per se or the loss of sleep-specific stages that is
responsible for the decreased pain threshold.6 Neither are all types of noxious stimuli in the
same way affected. It seems that pressure pain tolerance is more easily affected than heat pain
tolerance.8
There are multiple causal factors that may partially explain this phenomenon:7
- REM sleep deprivation decreases cholinergic activity, and acetylcholine (ACh) is known to
promote both analgesia and REM sleep
- REM sleep deprivation depletes brain stem levels of serotonin and some data show that
serotonerg cells are active in the brainstem inhibition of nociception
- a stimulation of excitatory amino acids like glutamate which have a influence through
descending pain control pathways
- an impact on the endogenous opioid system with a reduced binding to mu and delta
receptors
- an inflammatory process is also proposed. Haack showed increased amount of interleukin-6
(IL-6) after prolonged sleep deprivation.9 IL-6 is associated with pain related discomfort.6
- there is also a psychological factor that can influence pain perception as sleep deprivation
has an impact on attention, anxiety and the emotional state.6
Methodology
This paper is divided into two parts, a literature and an observational study.
Articles for the literature study were gathered using Pubmed, ISI web of science, Google
Scholar and the Cochrane Library. Articles were selected according to their relevance, using
different combinations of following MESH terms: postoperative,
opioids, opioid free
anaesthesia, anaesthesia, surgery, sleep stages, sleep architecture, sleep disturbance and sleep
physiology. Inclusion criteria for the literature search were limited to the English language.
Human and animal studies were included. Editorials, case reports, and duplicates were
excluded. Narrative reviews were reviewed to confirm an exhaustive review of the scientific
literature. All references were evaluated from the manuscripts to confirm inclusion of all
pertinent studies. Two investigators independently screened the identified article titles and
abstracts, and independently assessed the risk of bias.
Next we conducted a single centre retrospective observational study comparing opioid free
anaesthesia to opioid anaesthesia in adult patients. In this study we questioned all patients
over a period of two months who had a standard or revision gastric bypass surgery on their
wellbeing and subjective quality of sleep on the first postoperative day. Patients received
opioid free anaesthesia (OFA group) by half of the anaesthesiologists while the other
anaesthesiologists gave traditional opioid anaesthesia (OA group) with sufentanil. Patients
who got an opioid sparing method, consisting of a combination of maximum 10 µg sufentanil
with dexmedetomidine were excluded. Urgent surgery was also excluded. In the opioid
group, the dose of sufentanil was between 15 and 50 µg according to the anaesthesiologists
discretion. The opioid free group received dexmedetomidine at maximum 1 µg.kg-1.h-1,
lidocaine at maximum 1,5 mg.kg-1.h-1, magnesium at 5 mg.kg-1.h-1, a low dose ketamine of 25
mg and inhalation anaesthesia below 1 MAC. Postoperative pain was treated using a
predetermined flowchart, until VAS < 3. Non opioid drugs (paracetamol and diclofenac) were
used first and opioids (piritramide and morphine) were added if pain treatment was
insufficient. After the first postoperative night, sleep quality was assessed using the validated
quality of recovery score (QoR-40 score – see appendix A).10 This questionnaire covers
different postoperative aspects, but only the five relevant to the sleep quality were analysed.
Following topics were covered: having a good sleep, difficulty in falling asleep, bad dreams,
feeling rested and feeling comfortable. Three other questions have been added to control the
impact of moderate pain, nausea and feeling too cold on the effect of sleep quality. The results
were statistically processed using the Pearson's chi-squared test.
Literature
Normal sleep architecture
There are two standards for the analysis of sleep, one published in 1968 by Rechtschaffen and
Kales, the other in 2007 by the American Academy of Sleep Medicine. In the literature both
standards are still used. In this paper we will describe the stages and architecture of sleep
according to the most recent standard.
Sleep is analysed in 30 second phases which can be divided into rapid eye movement (REM)
sleep and non-rapid eye movement (NREM) sleep based on their electrophysiological
patterns.
Figure 1 - Normal adult hypnogram demonstrating usual sleep stage transitions. REM
indicates rapid eye movement sleep, N1 through N3 are the three different NREM sleep
stages according to the American Academy of Sleep Medicine. (Kamdar et al. 11)
REM sleep covers 20 to 25 percent of the total sleep time and is characterized by three main
features:
-
a low voltage, fast frequency electroencephalogram (EEG) pattern that resembles an
active, awake EEG pattern
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rapid eye movements
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an atonic electromyogram (EMG) indicating inactivity of all voluntary muscles,
except the extraocular muscles. The atonia is the result of direct inhibition of the
alpha motor neurons.
REM sleep is further divided into phasic REM sleep and tonic REM sleep. During phasic
REM sleep there are bursts of rapid eye movements associated with brief burst of muscle
activity, seen on EMG. Tonic REM sleep is the sleep between the phasic bursts. Although
REM sleep is typically a parasympathetic state, there is sympathetic activity during phasic
REM sleep. The sudden increase in sympathetic activity gives rise to an increase in arterial
blood pressure, heart rate and/or respiratory rate with an increased risk of cardiac ischemia,
cerebral ischemia and cardiac arrhythmias. Short central apnoea’s, hypopnoeas and long
cardiac systoles have also been reported.12
NREM sleep is subdivided into different stages. The original standard of Rechtschaffen and
Kales recognized four stages (N1 to N4), however the newer standards fused stages N3 and
N4 so that only three stages of NREM sleep are described.
Stage N1 is the transition from wakefulness to sleep and is the lightest sleep stage. It is
characterised by low amplitude, relative fast EEG frequencies in the theta range (4 to 7 Hz)
and accounts for 2 to 5 percent of the total sleep time. Stage N2 sleep is called intermediate
sleep and shows on EEG a slowing of the frequency and an increase of the amplitude. This
stage accounts for 40 to 50 percent of the total sleep time. Stage N3 is referred to as the deep
sleep or slow wave sleep (SWS), is characterised by low frequency, high amplitude delta EEG
waves and accounts for 20 percent of the total sleep time.
The sleep stages occur in 90 to 120 minute cycles, with four to five cycles in a normal night.
The first cycle starts with a briefly passing from wakefulness to N1 sleep and then to stages
N2 and N3. Subsequent cycles consist of N2, N3 and REM sleep. During the second half of
the night N2 and REM sleep alternate. N1 and N3 are usually absent.
Assessment of sleep
To study and compare the quality of sleep, validated systems are indispensable. Sleep can be
measured subjectively and objectively. Although validation between both is sometimes
assumed13, this assumption has not been definitively proven.
Subjectively
According to Rosenberg it is possible to evaluate the subjective sleep quality simply by
asking the patient how he perceived his sleep. It shows to be related to total sleep duration and
the number of awakenings.14
However more accurate questionnaires have also been designed to obtain information about
different aspects of sleep.8 The Stanford sleepiness scale is an eight-item questionnaire used
to assess sleep deprivation. The Epworth sleepiness scale is also an eight-item questionnaire
measuring subjective daytime sleepiness. It has been evaluated in sleep apnoea. The Leeds
sleep evaluation questionnaire uses ten 100mm line analogue scales to measure the perceived
changes to sleep caused by medication. The Pittsburgh sleep quality index probes about the
sleep habits during the previous month, and also includes information from the sleeping
partner. The St Mary’s sleep questionnaire is designed for hospitalized patients to evaluate the
state of sleep and wakefulness during the preceding 24 hours.
Objectively
Objective measurement is a must to study sleep disturbances since they may reveal and
quantify more subtleties than a questionnaire. Also, it has been shown that subjective
observation by a third person, such as the nursing staff, strongly overestimates the actual
sleeping time of the patients.15
The laboratory polysomnography (PSG) is considered to be the golden standard. PSG
continuously and simultaneously records physiological variables during sleep. For an analysis
of sleep states and sleep architecture the PSG must record, as a minimum, the
electroencephalogram, the electro-oculogram and the chin electromyogram. Routinely the
electrocardiogram and respiratory variables such as nasobuccal airflow, thoracoabdominal
respiratory movements, pulse-oxymetry and snoring are also recorded.
Actigraphy is a more flexible technique that monitors periods of rest and activity. Sleep is
detected by asking the patient to maintain a sleep journal. This tool is used to study disorders
in sleep-wake rhythm as well as tremor, periodic leg movement and insomnia but cannot be
used in bedridden patients.
Physiology of sleep
Two processes that keep each other balanced regulate the sleep-wake cycle. The process S
defines the drive to sleep and is primarily regulated by adenosine, the end product of the
adenosine triphosphate metabolism, and by melatonin, secreted by the pineal gland.
The opposite, the wakefulness, is regulated by the process C, which is the circadian
pacemaker, situated in the suprachiasmatic nucleus. Neural pathways that inhibit melatonin
secretion when exposed to light and a mixture of different neurotransmitters including orexin,
acetylcholine, serotonin, norepinephrine, dopamine and histamine modulate this process.11
During sleep the body experiences a lot of physiological changes, important for growth and
homeostasis:11
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respiratory physiology
Voluntary control is lost during sleep with a decreased response to hypoxia and hypercarbia.
During REM sleep respiration is very variable with changes in minute ventilation, respiratory
rate and tidal volumes. This variability is most pronounced during bursts of phasic REM.
-
cardiovascular physiology
During NREM sleep there is autonomic stability with a parasympathetic overtone. On the
contrary, during REM sleep there is a marked variability. Tonic REM sleep is characterized
by vagal bursts leading to brady arrhythmias and sinus pauses. Phasic REM is dominated by
increased autonomic activity with transient increases of 35% in heart rate and blood pressure.
-
gastrointestinal physiology
Throughout sleep oesophageal motility decreases while gastrointestinal motility remains
constant. Gastric acid secretion follows a circadian rhythm with a peak in early sleep.
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thermoregulation
Temperature sensitivity decreases during NREM and is completely abolished during REM
sleep. Body temperature is at its lowest during the end of sleep, followed by a rise in
temperature preceding awakening.
-
endocrine physiology
Some anabolic hormones, like growth hormone and prolactin follow a sleep-wake cycle and
the secretion is suppressed when sleep is restricted. Other hormones, like cortisol and thyroid
stimulating hormone, have a circadian pattern. Secretion of thyroid stimulating hormone is
inhibited by SWS sleep and rises when sleep deprived.11
There is no agreement on the exact function of sleep. Several theories exist, none of which
have been proven to this point. The most widely accepted is the restorative sleep theory,
which states that the process of sleep restores tissues and prepares the body and brain for the
next day.14 Total or selective sleep deprivation affects particularly the brain, with
psychological and neurological dysfunction as an impaired behavioural and psychological
performance, sleepiness and an impaired concentration and performance on psychometric
tests. Mood is also affected with increased sadness and irritability. The adaptive theory of
sleep is an evolutionary theory and proposes that sleep increases survival as it immobilises the
body during the most dangerous time of the day. Finally the energy conservation theory states
that the function of sleep is to provide an interval during which there is a reduced metabolism
and the possibility to conserve energy.
Likewise the purposes of REM and NREM sleep remain uncertain. REM sleep appears to be
an essential part of sleep since animals with REM sleep deprivation die after several weeks. 16
Furthermore the need to compensate for lost REM sleep with rebound REM sleep also
suggests that insufficient REM sleep is detrimental.17It has been proposed that REM sleep has
an important role in memory consolidation.18 During SWS there is a homeostatic process for
mind and body in which there seems to be a release of anabolic hormones and an increase in
immune activity.8
Pathophysiology of sleep
In sleep deprived patients, different physiologic changes have been described:11
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respiratory changes
In healthy volunteers 24 to 30 hours of sleep deprivations leads to respiratory muscle
weakness and a decreased ventilatory response to hypercapnia.
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cardiovascular changes
Sleep deprivation leads to an increased sympathetic and decreased parasympathetic tone and a
state of increased catecholamine release resulting in high blood pressure and heart rate and as
such an increased risk of acute myocardial infarction. Furthermore endothelial disruptions are
caused by the release of inflammatory cytokines.
-
immunologic changes
In animal settings the necessity of sleep for an adequate immune response has been shown.
Prolonged sleep deprivation onsets a catabolic state with opportunistic infections followed by
septicaemia and death in 27 days. In humans the relationship between sleep deprivation and
immunology is less clear. Data suggest that it affects cellular immunity and cytokine function
but the exact mechanism and clinical implications are not known.
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hormonal and metabolic changes
There is a rise in cortisol levels and catecholamine release, reflected by the increased
metabolic indices as oxygen consumption and carbon dioxide production. The same
circumstances are present in patients with sepsis, which may suggest that sleep deprivation
intensifies the stress response. Also glucose metabolism is changed with a decreased
sensitivity to insulin and impaired glucose tolerance.
-
psychological changes
Delirium is the best know psychologic postoperative complication. It can also be present in
critically ill patients. Although the exact contribution of sleep deprivation to the development
of delirium is not clear, both conditions share important mechanisms, risk factors and
symptoms.11
Postoperative sleep
Multiple observations show intense postoperative sleep disturbances with a complete
abolishment of REM sleep the first postoperative night, a reduced amount of SWS, an
increase in light NREM sleep, a reduced total sleep time and an increased amount of
awakenings.8 Typically the REM sleep reduction is compensated in the next postoperative
nights by a rebound REM sleep occurring on the second and third postoperative night.
In 1985 Aurell and Elmqvist15 studied 9 patients after non-cardiac surgery. All were sleep
deprived afterwards. The cumulative sleep time over the first 48 hours postoperative was less
than 2 hours a day. REM sleep and SWS were completely suppressed. Several factors may
contribute to this disturbed sleep pattern postoperatively.
Figure 2 - Schematic diagram of the relationship between sleep disruptions, opioid use,
and postoperative pain, and respective contributing factors. Filled arrows represent the
relationship and clear arrows represent contributing factors. (Chouchou et al. 2)
Effect of pain on sleep
As mentioned earlier, sleep deprivation can lead to an increased pain perception the next day.2
Reciprocally, pain itself can alter sleep and sleep architecture. It is often assumed that
effective pain relief is enough to restore sleep architecture. However, most medications used
to treat pain, also affect the sleep process.
Effect of opioids on sleep
Opioids have been suggested as a causal factor in the postoperative sleep disturbances. We
have to consider the intrinsic bias, considering the inverse relationship between opioids and
pain. To rule out the factor of postoperative pain, we will first review the studies on healthy,
pain free subjects.
In 1969 Kay et al.19 concluded that morphine increases the wakefulness and inhibits the REM
sleep and SWS in a dose dependent manner. Administration of 0.22mg/kg morphine reduced
REM by 50%; 0.43mg/kg abolished REM sleep completely. In 1987 Moote also confirmed a
REM sleep and SWS suppression with doses of morphine ≥ 0,2mg/kg.20
It has to be noted that a lot of the earlier studies were conducted on opioid addicted patients.
In experiments on catsthey also measured a dose dependent inhibition of REM sleep by
opioids, which was reversible by naloxone and hence receptor subtype specific.21,22 Cronin et
al. injected synthetic opioid agonists selective for mu, delta and kappa subtypes of opioid
receptors into the medial pontine reticular formation (mPRF) in awake cats and studied the
polysomnographic recordings. The results support the hypothesis that inhibition of REM sleep
is at least partially caused by a direct effect on mu receptors in the mPRF22. More studies23,24
have demonstrated a cholinergic control of REM sleep. Injection of atropine into the mPRF
inhibits natural REM sleep.22 Opioids have the ability to inhibit the release of acetylcholine
and this pathway accounts for an indirect negative effect on REM sleep.
Cronin et al.25 tested the hypothesis that opioids disturb postoperative sleep independently of
pain by conducting a study in 2001 on nine people undergoing a gynaecological procedure
requiring a low abdominal incision. Five of them received postoperative pain control by
patient controlled epidural anaesthesia (PCEA) with solely opioids (fentanyl), the other four
patients received a PCEA with local anaesthetics (bupivacaine). Polysomnographic control
was performed on the preoperative night and the first three postoperative nights. In both
groups there was a complete abolishment of the REM sleep on the first postoperative night,
compensated by an increase in light NREM sleep. In the second night there was already an
increase in REM sleep. The only significant difference between both groups was the SWS. On
the second postoperative night SWS was lower in the group on opioids, compared to the
group on local anaesthetics.
In 2005 Shaw conducted a study on opioid naive patients.13 Seven patients underwent a PSG
in a crossover design with 3 different data points: at baseline, after administration saline and
after morphine 0,1mg/kg. They concluded an overall shift to lighter sleep with a 75%
reduction in SWS, 5% reduction in REM sleep and an increase of 15% in NREM sleep. The
total sleep time did not alter. There was a reduction of total sleep time between baseline and
morphine but there was no difference between morphine and placebo suggesting that injection
on its own caused more stress and therefore less total sleep time. Although they saw
significantly more arousals in the morphine group, they were still in the physiologic range.
Furthermore, subjectively the patients didn't notice a difference in sleep quality between the
three different settings and the changes in sleep architecture measured in the study are less
pronounced than the typical changes seen postoperatively. Bonafide argues that, since
previous studies always applied opioids before the start of the data recording, it is possible
that the increased awakenings are caused by the agitation of opioid withdrawal. 28 To reduce
this bias Bonafide et al. used a continuous infusion of remifentanil. They noted a significant
reduction in REM sleep with a 72% decrease even at low concentration of remifentanil (0,010,04ug.kg-1.h-1). There was a decrease in SWS of 53% and an increase of wake time of 58%
but this was not significant.
Another plausible explanation for the reduction in REM sleep and SWS after opioids could be
that they derange the circadian pacemaker. To test this hypothesis they measured the
melatonin concentration at different times during the night, which remained normal. Then
they administered exogenous melatonin in the assumption that it would restore REM sleep
and SWS, but it did not. Furthermore although remifentanil decreases REM sleep, the REM
sleep distribution, with a predominance in the second half of the night, remains. Therefore
they could confirm that opioids do change sleep architecture and that it is not because of
withdrawal nor because of a disturbance of the circadian pacemaker.
Effect of non-opioid anaesthesia on sleep
-
Dexmedetomidine:
Functional MRI shows a change in local brain activity in patients sedated with
dexmedetomidine similar to the activity seen in natural occurring sleep. Binding of
dexmedetomidine to the α2-a adrenoreceptor in the pontine locus ceruleus hyperpolarizes the
noradrenergic fibres decreasing their firing rate.22 Nelson et al. postulate that the loss of
consciousness seen with dexmedetomidine is via the activation of an endogenous sleep
promoting pathway through an inhibition of the release of norepinephrine in the locus
ceruleus. This mimics NREM sleep and enhances SWS, but at the same time it inhibits REM
sleep since norepinephrine has a REM sleep permissive role.27 Oto et al. tested the hypothesis
that dexmedetomidine favours NREM sleep.28 They did this in a population of mechanically
ventilated patients on intensive care unit (ICU). Although this isn't quite the typical
postoperative setting, it has been shown that there are similar sleep architectural changes on
the ICU with a loss of REM sleep and SWS.29 Additionally they see a scattered sleep pattern
where half of the sleep is during the day and the other half during the night.30 In this study
they administered a continuous infusion of dexmedetomidine only during the night. All types
of sedation were interrupted during the day, within comfort limits of the patient. Twenty-four
hour PSG recordings were taken in 10 patients.28 They found a remarkable shift of sleep to the
night-time versus daytime and the arousal index was within normal limits. However the sleep
measured during the night existed mostly of NREM stage 2 sleep with an almost complete
absence of REM sleep and SWS. There may be a lot of confounding factors in this study and
even though they saw a clear improvement of the circadian pattern, it is plausible that the
daytime interruption of sedation is at least partially responsible for this result since it has been
shown that continuous sedation reduces melatonin secretion.31
-
Inhalation anaesthetics
In 1988 Moote saw a reduced amount of SWS after the use of isoflurane, without an effect on
REM sleep.32 Nonsurgical volunteers were kept under anaesthesia using isoflurane for three
hours. They only noticed a modest reduction in SWS for one hour, with no effect on REM
sleep.
In 2007 Steinmetz conducted a prospective study in 39 children comparing postoperative
sleep in two therapeutic and one control group.33 The effects of anaesthesia conducted with
sevoflurane and those conducted with propofol-remifentanil were observed with attention to
subjective sleep quality, measured by a questionnaires completed by the parents. The
hypothesis was that children would have more disturbed sleep after sevoflurane because
emergence agitation is more common after inhalation anaesthesia. However the longest
continuous sleep was significantly longer in the sevoflurane group. In both groups there was
an significantly impaired sleep pattern, returning back to normal after 10 days, with no
difference between groups.
-
Local anaesthetics
A recent study by Dette et al. looked at the sleep phases after surgery under regional
anaesthesia.34 There were no opioids administered the first three postoperative days. PSG
recordings were made the night preoperative and the first and fifth postoperative night. The
same sleep disturbances were seen as after general anaesthesia with a decrease in REM sleep,
SWS and total sleep time the first postoperative night and a -almost- normalisation on the fifth
night. It must be stated that this study was performed on 12 patients and couldn’t attain
sufficient power.
-
Paracetamol and non-steroidal anti-inflammatory drugs
Smith stated in 1985 that paracetamol has a positive effect on sleep, even in individuals
without pain.35 Murphy could not confirm the positive effect, but could not detect a negative
effect either in his study in 1994.36
It used to be presumed, after a study by Lavie in 199137, that non-steroidal anti-inflammatory
drugs (NSAID) had a negative impact on sleep architecture with an increase in arousals and
light NREM sleep, and a decrease in SWS and overall sleep efficiency. More recently
however Gengo et al.38 refuted this in their study a PSG was recorded at baseline and after a
total of 1200 mg ibuprofen. They could not detect any effect on sleep architecture.
Effect of surgery on sleep
The fact that similar sleep patterns are observed after regional anaesthesia and in the ICU, as
compared to after general anaesthesia, suggests that sleep changes aren’t merely caused by
general anaesthesia. Critically ill patients show a fragmented, light sleep with lack of SWS
and REM sleep. This observation supports the hypothesis that stress, illness and possibly also
environmental factors play an important role.11
Knill et al. measured the sleep quality after open cholecystectomy (CCE) with gastroplasty
and found the typical strong sleep deviations.39 Rosenberg observed in 1994 similar findings
after extensive abdominal surgery.40 On the contrary, two years later Rosenberg observed the
sleep architecture following laparoscopic CCE was found a postoperative undisturbed REM
sleep and only a slight reduction in SWS with a compensatory rise in light NREM sleep.41
Already in 1976 Ellis stated that the extend of surgery might correlate with the magnitude of
sleep deviations.42
Surgical stress and trauma on its own may be the main factor in the postoperative sleep
disturbance due to a endocrine, autonomic and inflammatory stress response to surgery.2
Tissue trauma and surgical stress cause a release of cytokines like interleukin-1, tumor
necrosis factor alfa and IL-6, known to have a negative effect on REM sleep and SWS.2,25
Another effect of surgery is the rise of cortisol. Cortisol reduces REM sleep, but to a lesser
extend as seen postoperatively. Furthermore cortisol even increases SWS.2,25
Miscellaneous
Many other non medical factors, like circadian rhythm, sleep environment, chronic sleeping
problems, ... can also influence sleep and might be even more important. However this is
beyond the scope of this review.
Observational study
We conducted an observational study comparing sleep quality in patients receiving opioid
anaesthesia (group OA) to patients undergoing opioid free anaesthesia (group OFA). A
second analysis was done to assess the possible impact of the extend of surgery on sleep
quality comparing first time to revision Roux en-Y (RNY). The methodology of this study
was explained earlier in the chapter Methodology (p5).
We included 292 patients in a time period of 2 months. Eight patients were lost in follow-up
because two patients were already dismissed out of the hospital, five patients were not
available on two different occasions and one patient wasn’t able to answer the questions
because she was being scheduled for an urgent revision. There were no significant differences
first RNY
105
revision RNY 40
first RNY
102
147
revision RNY 45
group OA 145
group
OFA
type of
surgery
patients
total
patients
found between the different groups in number, age, length and weight. (table 1)
age
mean
41.72
41.41
40.47
49.07
SD
13.97
11.94
13.44
12.09
length in cm
mean
168.82
168.17
167.52
167.63
SD
9.38
9.65
9.62
10.86
weight in kg
mean
113.15
116.79
111.04
116.74
SD
14.89
23.47
17.58
30.56
table 1 – Demographic data on the patients. SD: standard deviation
The QoR40 questionnaire includes five questions relevant to sleep. Table 2 gives the number
of positive answers for the OFA versus OA and table 3 states the number of positive answers
for the first bariatric surgery versus the revision bariatric surgery. Three other questions of the
Qo40 on nausea, feeling cold and experiencing moderate pain were included. This was done
because they could have an effect on sleep quality. Statistical analysis was performed using
the Pearson’s Chi-square test with a α type 1 error of 0.05.
feeling comfortable
bad dreams
difficulty falling asleep
having a good sleep
feeling rested
nausea
feeling too cold
moderate pain
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
OA
103/42
71.0
8/137
5.5
59/86
40.7
41/104
28.3
68/77
46.9
58/87
40.0
35/110
24.2
95/50
65.5
OFA
128/18
89.5
1/145
0.7
62/83
42.8
62/84
42.5
90/54
62.5
39/107
26.7
13/133
8.9
70/76
47.9
P-values
0.001
0.017
0.759
0.011
0.012
0.016
0.001
0.002
Table 2 - Result of Chi square analysis Group OA compared to Group OFA.
Statistical significant P-values are represented in bold.
feeling comfortable
bad dreams
difficulty falling asleep
having a good sleep
feeling rested
nausea
feeling too cold
moderate pain
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
Y/N
%
first RNY
162/44
78.6
7/199
3.4
91/114
44.4
66/140
32.0
117/87
57.4
63/143
30.6
30/176
14.6
120/86
58.2
revision RNY
69/16
81.2
2/83
2.3
30/55
35.3
37/48
43.5
41/44
48.2
34/51
40
18/67
21.2
45/40
52.9
P-value
0.627
0.64
0.162
0.062
0.183
0.121
0.167
0.406
Table 3 - Result of Chi square analysis first RNY compared to revision RNY.
The patients treated in the OFA group experienced less bad dreams(p = 0.017), more feelings
of comfort (p = 0.001), had more reports of good sleep (p = 0.011) and felt better rested (p =
0.012) than patients in the OA group. However we could not detect a difference in ease of
falling asleep between both groups (p = 0.759). On the other hand, we found no impact of the
extend of surgery (primary or revision) on the five different aspects of sleep measured by the
QoR-40 scale. Patients felt that the primary cause of not being able to fall asleep was the fact
that they weren’t home in their own bed, followed by noise and nursing activity during the
night.
Furthermore patients receiving OFA felt less nausea (p = 0.016), less cold (p = 0.001) and less
moderate pain (p = 0.002) compared to those in the OA group. The postoperative necessity
for opioids was also recorded. There was a significant lower use of piritramide (dipidolor®)
in the OFA (6 +/- 9 mg) group than in the OA group (16 +/- 10 mg) with a p-value of 0.001.
So these results suggest that type of anaesthesia and not type of surgery has an impact on the
sleep quality. Nausea, feeling too cold and moderate pain are also related to type of
anaesthesia and not to type of surgery.
Discussion
As we review the literature some inconsistencies become apparent. Shaw 13 couldn’t measure
the same profound impact on sleep architecture as Kay19 did. A valid reason could off course
be the limited amount of subjects studied (n=7). Although the opiate doses used by Shaw et
al. were relatively small at 0.1 mg/kg of morphine, it could also imply that non dependent
opioid addicts, the test population in Kay's study, have a different arousal response to
additional opioid administration than opioid naive people do.
Possible mechanisms are found that explain the effects of opioids on sleep. Osman conducted
two sets of experiments on rats to test and confirm the role of Ach.43 They found that opioids
cause a concentration dependent and naloxone-sensitive decrease in ACh release in the
prefrontal cortex. This most anterior part of the cortical region has different major functions
as the regulation of arousal, autonomic control and cognitive processing.
Also the higher incidence of delirium can be explained by this mu receptor specific decrease
in ACh since the cortical ACh is essential for normal cognition and sleep.43 There are some
limitations to this study though. First of all it is a study on rats and the relevance for humans
is not known. Although there is much information about the prefrontal cortex in primates and
similar results has been found in mice so this suggests the results are generalizable, rather
than species specific. The study also doesn’t exclude the possibility that other
neurotransmitters can have an additional role as well.
The study by Cronin et al. compared sleep disturbances in two groups, where the only
difference was the administration of opioids or local anaesthetics.25 This study confirms the
profound sleep disturbances postoperative and found it to be independent of the anaesthetic
technique used. They concluded that this should be viewed as evidence for additional
unidentified and more powerful REM sleep inhibiting influences in postoperative patients.
Concerning the observational study we can comment that there was no randomization and
therefore patients receiving opioid free anaesthesia could have been selected on basis of
obesity, obstructive sleep apnoea syndrome, metabolic syndrome or other comorbidities in
request for special attention. This means that difficult, longer and high risk patients could
have got more OFA than OA. Nevertheless there was no significant difference in age, body
weight or procedure type between OFA and OA groups.
The revision bariatric surgery normally, but not always, takes longer and induces more
surgical and peritoneal trauma. Nevertheless type of surgery had no impact on sleep quality
questions, in contrast to what has been seen in other studies. It can be assumed that the
difference in surgical stress of a open versus laparoscopic CCE is much more pronounced
than the difference of a first versus a revision RNY.
OFA gives less nausea, less cold feeling and less pain postoperative while the total dose of
opioids postoperative is also significant lower. It is possible that this better outcome allows
patients to have a better first night sleep and that the opioids are not directly responsible for a
sleep disorder.
Sleep is however not perfect in the OFA group either. Difficulty falling asleep is even very
bad and not different between both groups. And again, environmental factors were reported
as major reason why patients could not fall asleep
In contrast to Cronin25, we could detect a difference in postoperative sleep quality depending
on the anaesthetic technique used. An important bias in Cronins study is the fact that they
were only partially successful in separating the influences of opioids and pain since the
bupivacaine group tended to have slightly more pain than the opioid group.
Furthermore, only 5 aspects of sleep were observed with this questionnaire. It is very well
possible that there is a difference on PSG. An important bias is that both groups received
opioids in the postoperative setting. The OFA group got significant less piritramide and had
less moderate or severe pain postoperative. During laparoscopy the pneumoperitoneum with
CO2 causes also peritoneal ischemia and inflammation on areas without any surgical activity.
This peritoneal damage is dependent on surgical time, insufflation pressure and several other
factors. OFA could be also protective here and explain the lower inflammation and reduced
pain.
Sleep improvement after surgery requires therefore a multimodal approach in which reducing
the surgical trauma and peritoneal ischemia is probably the most important aspect.
Anaesthesia can have an impact on it and therefore it is important to study its effects more in
detail.
Conclusion
In the postoperative setting there are many different factors accountable for a disturbed sleep.
For one, pain is a very important cause of disturbed sleep. Although assumed that pain relief
is the most effective way to resolve this problem, thought must be given that pain medication
on its own also disturbs the sleep architecture. The commonly used opioids have an irrefutable
role in the postoperative changes in sleep architecture as proven by multiple independent
studies. Also the question of how these changes are caused is more and more answered.
Additionally, the postoperative sleep pattern is more severely disturbed than can be explained
by opioids alone. And even when opioids are completely avoided postoperatively, sleep
disturbances remain. This favours the assumption that the biggest impact on sleep is seen as a
result of surgical stress, tissue trauma and environmental factors.
Due to the multitude of possible confounders during the postoperative setting it remains
difficult to separate the impact of each of these factors on the sleep.
References
1. Pearse RM, Moreno RP, Bauer P, Pelosi P, Metnitz P, Spies C, et al. Mortality after
surgery in Europe: a 7 day cohort study. Lancet. 2012 Sep 22;380(9847):1059–65.
2. Chouchou F, Khoury S, Chauny J-M, Denis R, Lavigne GJ. Postoperative sleep
disruptions: A potential catalyst of acute pain? Sleep Med Rev 2014 Jun;18(3):273-82.
3. Kaw R, Michota F, Jaffer A, Ghamande S, Auckley D, Golish J. Unrecognized sleep apnea
in the surgical patient: implications for the perioperative setting. Chest. 2006 Jan;129(1):198–
205.
4. Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with
myocardial infarction in men. Lancet. 1990 Aug 4;336(8710):261–4.
5. Gögenur I, Wildschiøtz G, Rosenberg J. Circadian distribution of sleep phases after major
abdominal surgery. Br J Anaesth. 2008 Jan;100(1):45–9.
6. Lautenbacher S, Kundermann B, Krieg J-C. Sleep deprivation and pain perception. Sleep
Med Rev. 2006 Oct;10(5):357–69.
7. Roehrs T, Hyde M, Blaisdell B, Greenwald M, Roth T. Sleep loss and REM sleep loss are
hyperalgesic. Sleep. 2006 Feb;29(2):145–51.
8. Onen SH, Onen F, Courpron P, Dubray C. How pain and analgesics disturb sleep. Clin J
Pain. 2005 Oct;21(5):422–31.
9. Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to
prolonged sleep restriction are associated with increased pain experience in healthy
volunteers. Sleep. 2007 Sep;30(9):1145–52.
10. Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability of a
postoperative quality of recovery score: the QoR-40. Br J Anaesth. 2000 Jan 1;84(1):11–5.
11. Kamdar BB, Needham DM, Collop NA. Sleep deprivation in critical illness: its role in
physical and psychological recovery. J Intensive Care Med. 2012 Apr;27(2):97–111.
12. Pressman M. Stages and architecture of normal sleep. In: UpToDate, Post TW (Ed),
UpToDate, Waltham, MA. (Accessed on November 11, 2013.)
13. Shaw IR, Lavigne G, Mayer P, Choinière M. Acute intravenous administration of
morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study.
Sleep. 2005 Jun;28(6):677–82.
14. Rosenberg-Adamsen S, Kehlet H, Dodds C, Rosenberg J. Postoperative sleep
disturbances: mechanisms and clinical implications. Br J Anaesth. 1996 Apr;76(4):552–9.
15. Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic
recording of sleep in nine patients receiving postoperative care. Br Med J (Clin Res Ed). 1985
Apr 6;290(6474):1029–32.
16. Rechtschaffen A, Bergmann BM, Everson CA, Kushida CA, Gilliland MA. Sleep
deprivation in the rat: X. Integration and discussion of the findings. Sleep. 1989
Feb;12(1):68–87.
17. Endo T, Roth C, Landolt HP, Werth E, Aeschbach D, Achermann P, et al. Selective REM
sleep deprivation in humans: effects on sleep and sleep EEG. Am J Physiol. 1998 Apr;274(4
Pt 2):R1186–1194.
18. Hobson JA. REM sleep and dreaming: towards a theory of protoconsciousness. Nat Rev
Neurosci. 2009 Nov;10(11):803–13.
19. Kay DC, Eisenstein RB, Jasinski DR. Morphine effects on human REM state, waking
state and NREM sleep. Psychopharmacologia. 1969;14(5):404–16.
20. Moote CA, Knill RL, Skinner MI, Rose EA, Lok PY. Morphine produces a profound
disruption of nocturnal sleep in humans. Can J Anaesth 1987;34:S100–1.
21. Keifer JC, Baghdoyan HA, Lydic R. Sleep disruption and increased apneas after pontine
microinjection of morphine. Anesthesiology. 1992 Nov;77(5):973–82.
22. Cronin A, Keifer JC, Baghdoyan HA, Lydic R. Opioid inhibition of rapid eye movement
sleep by a specific mu receptor agonist. Br J Anaesth. 1995 Feb;74(2):188–92.
23. Lydic R, Baghdoyan HA. The neurobiology of rapid-eye-movement sleep. In: Saunders
NA, Sullivan CE, eds. Sleep and Breathing. New York: Marcel-Dekker, 1994;47-77.
24. Lydic R, Baghdoyan HA. Cholinergic pontine mechanisms causing state-dependent
respiratory depression. News in Psychological Sciences 1992; 7: 220-24.
25. Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO. Postoperative sleep disturbance:
influences of opioids and pain in humans. Sleep. 2001 Feb 1;24(1):39–44.
26. Bonafide CP, Aucutt-Walter N, Divittore N, King T, Bixler EO, Cronin AJ. Remifentanil
inhibits rapid eye movement sleep but not the nocturnal melatonin surge in humans.
Anesthesiology. 2008 Apr;108(4):627–33.
27. Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor
agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its
sedative effects. Anesthesiology. 2003 Feb;98(2):428–36.
28. Oto J, Yamamoto K, Koike S, Onodera M, Imanaka H, Nishimura M. Sleep quality of
mechanically ventilated patients sedated with dexmedetomidine. Intensive Care Med. 2012
Dec;38(12):1982–9.
29. Weinhouse GL, Watson PL. Sedation and sleep disturbances in the ICU. Crit Care Clin.
2009 Jul;25(3):539–549, ix.
30. Cooper AB, Thornley KS, Young GB, Slutsky AS, Stewart TE, Hanly PJ. Sleep in
critically ill patients requiring mechanical ventilation. Chest. 2000 Mar;117(3):809–18.
31. Olofsson K, Alling C, Lundberg D, Malmros C. Abolished circadian rhythm of melatonin
secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol
Scand. 2004 Jul;48(6):679–84.
32. Moote CA, Knill RL. Isoflurane anesthesia causes a transient alteration in nocturnal
sleep. Anesthesiology. 1988 Sep;69(3):327–31.
33. Steinmetz J, Holm-Knudsen R, Eriksen K, Marxen D, Rasmussen LS. Quality differences
in postoperative sleep between propofol-remifentanil and sevoflurane anesthesia in infants.
Anesth Analg. 2007 Apr;104(4):779–83.
34. Dette F, Cassel W, Urban F, Zoremba M, Koehler U, Wulf H, et al. Occurrence of rapid
eye movement sleep deprivation after surgery under regional anesthesia. Anesth Analg. 2013
Apr;116(4):939–43.
35. Smith GM, Smith PH. Effects of doxylamine and acetaminophen on postoperative sleep.
Clin Pharmacol Ther. 1985 May;37(5):549–57.
36. Murphy PJ, Badia P, Myers BL, Boecker MR, Wright KP. Nonsteroidal antiinflammatory drugs affect normal sleep patterns in humans. Physiol Behav. 1994
Jun;55(6):1063–6.
37. Lavie P, Nahir M, Lorber M, Scharf Y. Nonsteroidal antiinflammatory drug therapy in
rheumatoid arthritis patients. Lack of association between clinical improvement and effects on
sleep. Arthritis Rheum. 1991 Jun;34(6):655–9.
38. Gengo F. Effects of ibuprofen on sleep quality as measured using polysomnography and
subjective measures in healthy adults. Clin Ther. 2006 Nov;28(11):1820–6.
39. Knill RL, Moote CA, Skinner MI, Rose EA. Anesthesia with abdominal surgery leads to
intense REM sleep during the first postoperative week. Anesthesiology. 1990 Jul;73(1):52–
61.
40. Rosenberg J, Wildschiødtz G, Pedersen MH, von Jessen F, Kehlet H. Late postoperative
nocturnal episodic hypoxaemia and associated sleep pattern. Br J Anaesth. 1994
Feb;72(2):145–50.
41. Rosenberg-Adamsen S, Skarbye M, Wildschiødtz G, Kehlet H, Rosenberg J. Sleep after
laparoscopic cholecystectomy. Br J Anaesth. 1996 Nov;77(5):572–5.
42. Ellis BW, Dudley HA. Some aspects of sleep research in surgical stress. J Psychosom
Res. 1976;20(4):303–8.
43. Osman NI, Baghdoyan HA, Lydic R. Morphine inhibits acetylcholine release in rat
prefrontal cortex when delivered systemically or by microdialysis to basal forebrain.
Anesthesiology. 2005 Oct;103(4):779–87.
Appendix A