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ARTICLE IN PRESS
Sleep Medicine Reviews (2007) 11,35–46
CLINICAL REVIEW
Opioids, sleep architecture and
sleep-disordered breathing
David Wang
a,c,d,
, Harry Teichtahl
a,b
a
Department of Medicine, Royal Melbourne Hospital and Western Hospital, The University of Melbourne,
Gordon Street, Footscray, Vic. 3011, Australia
b
Department of Respiratory & Sleep Disorders Medicine, Western Hospital, Gordon Street, Footscray,
Vic. 3011, Australia
c
Woolcock Institute of Medical Research, The university of Sydney, Missenden Road, Camperdown,
Sydney 2050, Australia
d
Department of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road,
Camperdown, Sydney 2050, Australia
KEYWORDS
Opiates;
Narcotic;
Endogenous opioid;
Opioid receptor;
Sleep architecture;
Central sleep
apnoea;
OSA;
Hypercapnic;
Hypoxic;
Ventilatory response
Summary Opioid use whether acute or chronic, illicit or therapeutic is prevalent
in Western societies. Opioid receptors are located in the same nuclei that are active
in sleep regulation and opioid peptides are suggested to be involved in the induction
and maintenance of the sleep state. m-Opioids are the most commonly used opioids
and are recognized respiratory depressants that cause abnormal awake ventilatory
responses to hypercapnia and hypoxia. Abnormal sleep architecture has been
reported during the process of opioids induction, maintenance and withdrawal.
During induction and maintenance of opioid use there is reduction of rapid eye
movement (REM) sleep and slow wave sleep. More recently, central sleep apnoea
(CSA) has been reported with chronic opioid use and 30% of stable methadone
maintenance treatment patients have CSA. Given these facts, it is sobering to note
the paucity of human data available regarding the effects of short and long-term
opioid use on sleep architecture and respiration during sleep. In this manuscript, we
review the current knowledge regarding the effects of m-opioids on sleep and
respiration during sleep and suggest research pathways to advance our knowledge
and to explore the possible responsible mechanisms related to these effects.
&2006 Elsevier Ltd. All rights reserved.
www.elsevier.com/locate/smrv
1087-0792/$ - see front matter &2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.smrv.2006.03.006
Corresponding author. Department of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown,
Sydney 2050, Australia. Tel.: +61 2 9515 5048; fax: +61 2 9515 7196.
E-mail addresses: dwang@med.usyd.edu.au (D. Wang),harry.teichtahl@wh.org.au (H. Teichtahl).
Introduction
Opioid use whether therapeutic or illicit is common
worldwide. In year 2000, approximately 1.2% of the
American population reported heroin use at least
once in their lifetime.
1
In Australia, the estimate of
recent illicit opioid users was 0.6% of the 14 yrs and
older population in 2001 compared to 1% in 1998.
2
More than 140,000 patients were receiving metha-
done maintenance treatment (MMT) in 1998 in the
United States,
3
and in Australia 30,000 were
receiving MMT in year 2000.
4
Opioids are also
commonly used for acute and chronic pain manage-
ment and as an adjunct to anaesthesia and
occasionally for the restless legs syndrome.
5,6
An
American study reported that 80% of 2118 cancer
patients referred to a pain service were prescribed
opioids.
6
In year 2004, there were more than
410,000 registrants for opioid use in American
pharmacies compared to around 390,000 in 1997.
7
The average gram weight per registrant increased
7.3 fold for oxycodone, 5 fold for methadone, 4.6
fold for fentanyl base and 3 fold for hydrocodone
from 1997 to 2004.
7
Prescribed opioids related
deaths account for most of non-illicit drug poison-
ing deaths in America and the problem has been
increasing in the past decade.
8
Abuse of opioid
analgesics is very common and in 2005, 9.5% of
American 12th graders reported using Vicodin and
5.5% of these students reported using OxyContin in
the past year.
9
Many opioid receptors are located in the same
nuclei that are active in sleep regulation
10
and it
has been suggested opioid peptides are involved in
the induction and maintenance of the sleep state.
11
Chronic opioid use has been hypothesized to cause
disturbed sleep as well as excessive day-time
sleepiness and fatigue.
12
A few studies have
reported abnormal sleep architecture in opioid
users but most were performed prior to 1990 and
few tested breathing during sleep though opioids
are well-known respiratory depressants.
5
In recent
studies, central sleep apnoea (CSA) has been found
in stable MMT patients and in patients prescribed
time-release opioid analgesic management.
13–15
Abnormal ventilatory responses to hypercapnia
(HCVR) and hypoxia (HVR) have also been noted in
stable MMT patients.
16
Infants born to substance-
abusing mothers have a higher prevalence of
periodic breathing during sleep and a 5–10 times
increased risk of sudden infant death syndrome
(SIDS) compared to normal infants.
17,18
The poten-
tial symptoms and other sequelae related to CSA
and periodic breathing have not been discussed
in reviews of opioid use for chronic pain or in
methadone substitution programs.
6
Morphine-like m-opioids are clinically the most
commonly used opioids and this review focuses on
their effects on sleep and respiration during sleep
in humans. Where evidence is available, we will
discuss the pathogenesis of abnormalities described
and will also discuss future research directions
given the considerable lack of knowledge in this
important area of medicine. The scope of this
review includes sleep and respiration during sleep
in acute and chronic opioid analgesic use, opioid
abuse and in MMT programs.
Opioids and control of sleep
There are four major classes of endogenous opioid
receptors in the central nervous system: m,d,kand
nociceptin/orphanin FQ (N/OFQ) receptor.
5
Each of
these receptor subtypes has a distinct profile in
terms of its pharmacology as well as its distribution
within the brain and spinal cord. Most of the
clinically used opioids are relatively selective for m
receptors, such as morphine and methadone.
5
It appears that REM suppression is associated
ARTICLE IN PRESS
Nomenclature
ACTH adrenocorticotropic hormone
a-MSH melanocyte-stimulating hormone
b-LPH b-lipotropin
BMI body mass index
CSA central sleep apnoea
ESS Epworth Sleepiness Score
HCVR ventilatory responses to hypercapnia
HVR ventilatory responses to hypoxia
MMT methadone maintenance treatment
N/OFQ nociceptin/orphanin FQ receptor
OSA obstructive sleep apnoea
POMC prepro-opiomelanocortin
PSG polysomnography
R&K Rechtschaffen and Kales criteria for
sleep stages
REM rapid eye movement
REMS REM sleep
SCN suprachiasmatic nuclei
SE sleep efficiency
SIDS sudden infant death syndrome
SL sleep latency
SWS slow wave sleep
TST total sleep time
D. Wang, H. Teichtahl36
primarily with the actions of m-opioid receptor
agonists.
19
Three classes of opioid peptides have
been identified: the enkephalins, endorphins and
dynorphins.
5
These have been shown to have a role
in sensory modulation and analgesia and may be
important in the onset and maintenance of sleep,
and therefore be involved in attenuation of arousal
and waking.
20
Enkephalin is contained in neurons
that are widely distributed through the brain and
regions involved in slow wave sleep (SWS) such as
the solitary tract nucleus, the preoptic area and
the raphe, where it is colocalized with serotonin
receptors.
20
Enkephalin containing fibres innervate
the locus coeruleus noradrenergic neurons which
are inhibited by locally delivered opioids and
produce decreased awakenings and increased
SWS.
20
b-Endorphin is derived from prepro-opiome-
lanocortin (POMC) which is also processed into the
non-opioid peptides adrenocorticotropic hormone
(ACTH), melanocyte-stimulating hormone (a-MSH)
and b-lipotropin (b-LPH).
5
ACTH is the hormone
closely related to stress and a-MSH has been
suggested to induce sleep and increase SWS. The
association of sharing the same precursors implies a
close physiological linkage between stress, sleep
and the opioid systems.
5
The mechanism of opioid peptide action on sleep
control remains unclear. It has been hypothesized
that opioid peptides in conjunction with the
peptide neurohormone vasopressin are involved in
the induction and maintenance of the sleep state
through a complex and modifiable circadian me-
chanism driven by the suprachiasmatic nuclei
(SCN).
11
Vasopressin, one of the neurohormones in
the circadian pacemaker SCN, has been shown to
have a close relationship to circadian rhythms.
21
Vasopressin causes the secretion of endorphins into
the cerebro–spinal fluid (CSF), while pain and
opioids stimulate the secretion of vasopressin from
the pituitary.
22
In the supraoptic and paraventri-
cular nuclei, vasopressin is stored with the opioid
peptide dynorphin which also shows circadian
variability of its blood levels.
23
It is possible that
both vasopressin and the opioids are part of the
neurochemical mechanism driven by SCN to main-
tain the daily sleep and wake rhythm.
11
Exogenous opioids may affect the activity of
opioid receptors by binding to the same sites as
those of endogenous opioid peptides.
24
Endogenous
enkephalin production is linked by a negative feed-
back mechanism to the serum level of opioids which
are high in chronic opioid users.
25
Given the possible
links between endogenous opioids and control of
sleep previously discussed, it is reasonable to
suggest that acute and chronic opioid use may have
an effect on sleep hygiene and sleep architecture.
Opioids and control of respiration when
awake and during anaesthesia
In humans, the primary opioid receptors involved in
control of respiration are assumed to be m-receptor
type.
5
d-Receptors may exert modest respiratory
depressant effects, whereas k-receptors have little
respiratory depressant activity.
26
Acute use of
m-receptor stimulating opioids can cause dose
dependant depression of respiration.
5
Opioid recep-
tors in brain stem (medulla, pons, nucleus tractus
solitarius, and nucleus ambiguous), spinal cord, and
peripheral sites such as lung tissue are involved in
the respiratory depression. However, the brain stem
respiratory centres predominate with regard to this
effect.
5,26,27
Both HCVR and HVR can be significantly
reduced by acute use of opioids.
26,28
Opioids can
also blunt the increase in respiratory drive normally
associated with increased loads such as increased
airway resistance.
27
Acute opioid use may cause
increased respiratory pauses, delays in expiration,
irregular and/or periodic breathing and decreased/
normal tidal volume.
27
The prolonged expiratory
time in the respiratory cycle induced by opioids
often results in greater reductions in respiratory
rate than in tidal volume.
26
Increased tidal volume
variability was reported to be a better predictor
of respiratory depression than a fall in respiratory
rate when remifentanil was infused during dental
anaesthesia.
29
Waters et al. studied 13 children with OSA and 24
normal subjects undergoing tonsillectomy.
30
They
found that under inhalational anaesthetic and
spontaneous ventilation, the OSA group hypoventi-
lated and tended to have higher end tidal CO
2
levels than the normal group. Following fentanyl
injection, 6 of the OSA group exhibited central
apnoea compared with one of the normal subjects.
The production of central apnoea post opioid
injection in both groups was related to end tidal
CO
2
higher than 50 Torr.
30
Though this study has
methodological flaws, the data suggests that at
least in children, subjects prone to hypoventilation
may progress to central apnoea when given a m-
opioid, however, whether this equates to CSA in
these children is unknown.
With long-term use of opioids, subjects have
reduced HCVR although tolerance appears to
develop.
16,31
An early study assessing HVR in MMT
patients suggested blunting of HVR in both the
acute and chronic stages of methadone use.
31
However, this study should be interpreted with
caution as there was no baseline data from normal
subjects available for comparison.
31
In contrast, in
our study of stable MMT patients, HVR appears to
be increased (Fig. 1).
16
The causes for this finding
ARTICLE IN PRESS
Opioids, sleep architecture and sleep-disordered breathing 37
are not clearly known and may relate to long-term
stimulation of the hypoxic response by long-term
intermittent hypoxia.
16
The high HVR and low HCVR
we found in the stable MMT patients related to
changes in respiratory rate and not tidal volume
response.
16
To our knowledge there are no studies assessing
HCVR and HVR during sleep in subjects with acute
or chronic opioid use.
Opioid use, sleep and respiration during
sleep
Given the large opioid using population and the
possible close link between endogenous opioids and
control of sleep, there is a scarcity of studies
investigating sleep in human adult subjects using
opioids.
12
There are studies assessing sleep in
animals that show changes in sleep architecture
with acute and chronic m-opioid use.
32,33
We were
unable to find data related to effects of chronic use
of m-opioids on respiration during sleep in animals.
Breathing during sleep in human subjects using
opioids has been poorly studied despite the fact
that the commonly used m-opioids are known to
depress respiration and sleep-disordered breathing
in its own right can significantly affect sleep
architecture.
5
Table 1 shows the findings and methodologies of
18 human studies available on PUBMED published
between 1966 and 2005 investigating sleep and
respiration during sleep in adult humans using
opioids. We cite only those studies using objective
measurements and reported in English. Studies
assessing the effects of opioids on sleep and
respiration during sleep in post-operative surgical
patients and restless legs syndrome patients are not
included in the table. Restless legs syndrome itself
can significantly disturb sleep and the studies in the
anaesthetic literature are often confounded by
poor patient selection, use of concomitant anaes-
thetic agents, analgesics and post-operative pain.
In addition, natural sleep is clearly different to
anaesthesia which is a state of unrousable uncon-
sciousness.
34
During anaesthesia, there is dose-
dependant depression to most of the vital functions
including respiration.
34
Abnormal breathing pat-
terns in anaesthesia are different to sleep-disor-
dered breathing although the tendency to upper
airway obstruction during sleep and during anaes-
thesia are probably related.
35
Of the studies listed
in Table 1, 16 used morphine like m-opioids and 3
used opioid antagonists.
Methodological review of publications
Only four (22%) of the studies had sample size
410.
Subject selection is skewed to male preponder-
ance as only 47 (24%) females were studied from
a total of 192 subjects.
Only 6 studies (33%) had normal subjects as
control group for comparison. However, the
normal subjects and patients were matched for
age and BMI in only two studies.
13,14
10 out of 18 studies used the commonly accepted
sleep scoring criteria of Rechtschaffen and Kales
(R & K), although all the studies were reported
after the introduction of the R & K criteria.
Only 5 studies (28%) investigated respiration
during sleep.
The above review suggests that the findings from
the 18 studies need to be interpreted with caution.
For example, ‘‘delta burst’’ could be either stage 2
or 3 sleep in R & K criteria.
36,37
‘‘Delta sleep’’ is
equivalent to stage 4 sleep in R & K criteria rather
than SWS (including both stage 3 and 4 sleep).
36,37
ARTICLE IN PRESS
HCVR
0
1
2
3
mean+SE (L/min/%fall in SpO2)
0
1
2
3
MMT
Control
mean+SE (L/min/mmHg Pco2)
HVR
p = 0.01 p = 0.008
Figure 1 HCVR and HVR in stable MMT patients and control subjects. The figure is cited from Ref. 16
HCVR ¼hypercapnic ventilatory response; HVR ¼hypoxic ventilatory response; SE ¼standard error.
D. Wang, H. Teichtahl38
ARTICLE IN PRESS
Table 1 Summary of studies objectively evaluating the effects of opioids on human adult sleep and respiration during sleep.
Reference Subjects Drug Control
subjects
Study design, acute/chronic
dosing
R & K criteria Respiration
during sleep
Major findings in sleep
Kay et al.
61
8M, prisoners Morphine or
Placebo
No Single-blind cross-over;
Acute
No No kREMS number and duration, mREMS
latency, mwaking, mStages 1&2, kStages 3
and 4.
Lewis et al.
39
4M, authors of
the paper
Heroin No 3 Phase (3 nights each):
Control, induction and
withdrawal; acute
Yes No k%REMS during induction and rebound
m%REMS during withdrawal. mSL and
%Stage 1 during induction, back to normal
during withdrawal. %Stage 2 and %SWS no
change.
Martin et al.
40
6M, prisoners Methadone No 4 Phase: 2 weeks control, 5
weeks ascending, 8 weeks
stabilization and 24 weeks
protracted abstinence 46
weeks withdrawal
No No Addiction: Slower EEG, mdelta burst,
vocalization during REMS, mday-time
sleepiness. Withdrawal: mREM and delta
sleep after 10 weeks.
Kay
36
6M, prisoners Morphine No 5 nights baseline, 1 night
induction and 5 nights stable
phase
No No Chronic morphine: Delta sleep shifted later
in the night, kREMS, partial tolerance
develops to sleep disturbance.
Kay
41
6M, prisoners Methadone 37 addicts 4 Phase: 12 weeks control, 6
weeks induction, 8 weeks
stabilization and 22 weeks
protracted abstinence (no
acute withdrawalo6 weeks
recorded)
No No mwaking state initially, improved during
stabilization and further reduced during
withdrawal. kREMS initially, plateau REMS
during stabilization phase and rebound
mREMS during withdrawal. kdelta sleep
during initial and stabilization phase and
rebound mdelta sleep during withdrawal.
During stabilization, mday-time sleepiness,
mdelta burst and 30% subjects vocalized
during REMS.
Orr and Stahl
62
5M, MMT Methadone 5M 2 groups comparison;
chronic
Yes No m%Stage 1, k%SWS, kREMS latency, No
change in %REM, %Stage 2, TST, SL and
awakenings.
Kay et al.
42
7M, prisoners Morphine,
Methadone
Heroin or
Placebo
No Randomized cross-over;
Acute
No No All opioids: marousals and waking state,
kREM and spindle sleep. Heroin is twice as
potent as morphine or methadone on EEG
changes.
Howe et al.
38
14M, army staff Heroin 5M 5–7 days acute withdrawal
phase
Yes No kTST, mawake, k%REMS, %SWS no change,
m%Stage 1 and m%Stage 2 sleep.
Pickworth et al.
43
7M, prisoners Morphine,
methadone or
placebo
No Double-blind, randomized
cross-over; acute
No No Methadone & morphine have comparable
effects: mwake time, m%spindle sleep,
kdelta sleep, kREMS, mREMS onset
latency.
Kay et al.
63
7M, prisoners Heroin,
morphine or
placebo
No Double-blind, cross-over;
acute
No No Heroin: mwake time, kTST, kSE, no change
in SL, m%spindle sleep, k%delta sleep,
k%REMS. Morphine: mwakefulness, kTST
comparable to that of heroin
Opioids, sleep architecture and sleep-disordered breathing 39
ARTICLE IN PRESS
Table 1 (continued )
Reference Subjects Drug Control
subjects
Study design, acute/chronic
dosing
R & K criteria Respiration
during sleep
Major findings in sleep
Sitaram and Gillin
64
8M, 5F normal
volunteers
Naloxone (opioid
antagonist) or
placebo
No Double-blind, repeated-
measure counterbalanced
design; acute
Yes N o mREMS onset latency, kNumber of REMS
periods, No significant change in %REMS,
TST, SE
Pickworth et al.
65
7M, prisoners Cyclazocine
(opioid
antagonist) or
placebo
No Double-blind, cross-over;
acute
No No kTST, kREMS, mREMS onset latency,
m%spindle sleep, k%delta sleep,
mdrowsiness and arousal
Robinson et al.
44
10M, 2F healthy
subjects
2 & 4 mg oral
hydromorphone
or placebo
No Placebo controlled
comparison study; acute
Yes No significant
change in
sleep-
disordered
breathing
N/A
Staedt et al.
66
3F, 7M MMT; 10M
Naltrexone
Methadone,
Naltrexone
10M students 3 groups comparison;
chronic
Yes No SL(MMT4naltrexone4control),
TST(MMTonaltrexone ocontrol),
SWS(MMTonaltrexone ocontrol), REMS
(MMTonaltrexone ¼control),
Wake(MMT4naltrexone 4control). MMT
patients are more depressed and
psychophysiologically more impaired than
naltrexone users.
Teichtahl et al.
13
6M, 4F MMT Methadone 6M, 3F Cross-sectional, 2 group
comparison; chronic
Yes CSA in 6/10
stable MMT
patients
mwake time, kSE, m%Stage 2, k%SWS,
kREMS mins & periods
Farney et al.
15
3F with time-
release opioids
Morphine,
methadone,
fentanyl
No Case study; chronic N/A CSA, ataxic
breathing,
obstructive
hypopnea,
hypoxemia
N/A
Shaw et al.
45
2M, 5F healthy
subjects
i.v. Morphine or
placebo
No Placebo controlled
comparison study; acute
Yes No sleep-
disordered
breathing
found
kSWS, kREMS, m%Stage 2
Wang et al.
14
25M, 25F MMT Methadone 10M, 10F Cross-sectional, 2 group
comparison; chronic
Yes CSA in 30% of
stable MMT
patients, OSA
no different
to controls
k%Stage 1, m%Stage 2, kREMS. No change
in TST, SE, %SWS, SL and REMS onset
latency, mESS
Annotation:REMS¼REM sleep, SL ¼sleep latency, TST ¼total sleep time, SE ¼sleep efficiency, CSA ¼central sleep apnea, OSA ¼obstructive sleep apnoea; R&K ¼Rechtschaffen
and Kales criteria for sleep stages, ESS ¼Epworth Sleepiness Score, MMT ¼methadone maintenance treatment, SWS ¼slow wave sleep, N/A ¼sleep not assessed.
D. Wang, H. Teichtahl40
‘‘Spindle sleep’’ is only part of stage 2 sleep in
R & K criteria.
36,37
Most of the studies (81%) did not
measure breathing during sleep although sleep-
disordered breathing itself may have significant
impact on sleep architecture, especially with the
recent finding of significant CSA in subjects using
opioids chronically.
13,14
Summary of opioid effects on sleep
Despite the inherent methodological limitations
discussed above, the studies provide useful infor-
mation about the effects of opioids on sleep. There
are four basic phases of opioid dependence and
withdrawal: drug induction phase, drug mainte-
nance phase, acute abstinence phase and pro-
tracted abstinence phase.
38
Sleep architecture
changes are different for each of the 4 phases. In
general, during the induction phase, the use of
morphine-like opioids significantly disrupts sleep
with reduced REM sleep and SWS and increased
wakefulness and arousals from sleep. TST and SE
are usually reduced while percentage stage 2 sleep
and REM sleep latency are often increased. During
the maintenance phase of m-opioid use, the
decreases in SWS and REM sleep tend to normal as
do the increases of wakefulness, arousal and REM
sleep latency. Vocalization during REM sleep,
significant delta burst and increased daytime
sleepiness may commonly appear in this phase.
Limited evidence is available regarding sleep
during acute withdrawal from chronic opioid
use.
38
Changes in sleep from withdrawal of short-
term opioid administration
39
may be different to
the changes seen in withdrawal from chronic opioid
use. Significant insomnia is the major complaint
during chronic opioid withdrawal, accompanied by
frequent arousals and decreased REM sleep. During
the protracted abstinence phase, TST significantly
increases with rebound of SWS and REM sleep. After
chronic methadone use, the rebound of SWS and
REM sleep usually occurs between 13 and 22 weeks
following withdrawal of the opioid.
40,41
Chronic opioid use is associated with symptoms
of fatigue and excessive daytime sleepiness.
12,14
The abnormal sleep architecture discussed above
can affect daytime functioning in its own right.
However, it is difficult to know how much the
abnormal sleep architecture noted in these studies
impacts on daytime function and excess daytime
sleepiness.
Within the opioid class, morphine and methadone
have comparable effects on sleep and are half as
potent as heroin with regard to EEG measures.
42
The difference between morphine and methadone
on sleep is that chronic morphine use gives
measures of persistent sleep architecture distur-
bances which are not found with chronic metha-
done use.
40,41,43
Further studies employing larger
subject numbers and improved methodology are
necessary to gain a clearer and more comprehen-
sive understanding of opioid effects on sleep and to
explore the long-term affects of sleep architecture
changes on the subjects’ daytime function.
Respiration during sleep with acute opioid
use
There are only two human studies assessing
respiration during sleep with acute m–opioid use.
Robinson et al. assessed awake pharyngeal resis-
tance, HCVR, HVR and respiration during sleep in 12
healthy adult humans after ingestion of 2 and 4 mg
of oral hydromorphone.
44
Awake pharyngeal resis-
tance, HCVR and breathing during sleep did not
change significantly following either dose of the
drug, although there is a trend toward increased
apneas (more than doubled) and decreased hypop-
neas with the 4 mg dose. Awake HVR was signifi-
cantly reduced after 4 mg of the drug.
44
Similarly,
Shaw et al. measured breathing during sleep on
7 healthy adults after injection of morphine
(0.1 mg/kg) and did not find an increase in sleep-
disordered breathing compared to either baseline
or placebo use.
45
Further studies with larger
sample size are needed to test the effects of acute
opioid use on respiration during sleep.
Respiration during sleep with chronic opioid
use
Few studies have investigated respiration during
sleep in subjects using opioids long term.
13–15,46
The studies include two that assessed stable MMT
subjects;
13,14
one assessed 3 subjects using chronic
time release opioid analgesics;
15
and one assessed
subjects with restless legs syndrome.
46
The stable
MMT subject studies were the only studies that
matched patients and normal subjects for age, sex
and BMI.
13,14
CSA was noted in 20 of 60 subjects in
the MMT cohort and no CSA was noted in the normal
subjects.
13,14
In the largest cohort study assessing respiration
during sleep in subjects using opioids chronically,
CSA was found in 30% of 50 stable MMT patients
while obstructive sleep-disordered breathing was
similar in the MMT cohort and normal subjects.
14
The CSA in the MMT patients is more prominent in
NREM sleep than in REM sleep and did not cause
increased arousals compared to normal control
ARTICLE IN PRESS
Opioids, sleep architecture and sleep-disordered breathing 41
subjects.
14
The CSA described in stable MMT
patients is of periodic and non-periodic type.
13,14
During sleep, MMT patients have only mildly
reduced arterial oxygen saturation and mildly
increased transcutaneous arterial carbon dioxide
tension.
14
CSA, periodic breathing and Biot’s breathing
pattern (i.e. ‘‘ataxic breathing’’ with unpredict-
able irregular pattern) was reported in 3 females
using opioids chronically for pain relief.
15
This
report lacks data regarding a clear definition of
‘‘ataxic breathing’’ and whether the irregular
breathing was or was not related to arousals or
transitional sleep.
15
This breathing pattern appears
to be similar to sub-criteria CSA or the non periodic
breathing CSA we describe in the stable MMT
patients
14
(Fig. 2). Opioids have been suggested
to interfere with pontine and medullary respiratory
centres that regulate respiratory rhytmicity based
on various cats studies.
27
To date there is however
no evidence regarding the prevalence and possible
mechanisms of the ataxic/Biot’s breathing pattern
during human sleep in chronic opioid use.
Seven patients with restless legs syndrome were
studied with PSG before and after long-term opioid
monotherapy over an average of 7 years.
46
Tw o o f
ARTICLE IN PRESS
Figure 2 Two examples of central sleep apnoea (CSA) found in stable MMT patients. The graph is cited from Ref. 14 (A)
Example of non-periodic breathing type of CSA. (B) periodic breathing type but without crescendo–decrescendo
breathing typical of Cheyne–Stokes respiration. The periodic breathing cycle time is shorter than seen in Cheyne–Stokes
respiration associated with congestive heart failure. The time base is 30 sec for upper epoch and 5 min for lower epoch
for each example. NASAL ¼Nasal pressure; THERM ¼thermister; THOR ¼thoracic movements; ABDO ¼abdominal
movement; SaO
2
¼arterial oxygen saturation; patients were in stage 2 sleep in both examples.
D. Wang, H. Teichtahl42
the seven patients developed sleep apnoea with
respiratory disturbance index of 10 and 15 and a
third patient developed worsening of pre-existing
sleep apnoea. The type of sleep apnoea found in
the 3 patients was not reported.
46
It therefore
appears that further studies with larger sample size
and improved methodology are needed to elucidate
if the CSA noted in stable MMT patients also exists
in the patients using opioids chronically for pain
relief and restless legs syndrome.
The outcome of the CSA observed in these groups
of patients is unknown. For example, we do not
know if these patients with CSA have higher
morbidity or mortality than those patients using
long-term opioids but without CSA. We also do not
know whether the CSA noted in these patients
contributes to daytime dysfunction, though it is
clear that stable MMT patients are more depressed
and sleepier during the day, and have poorer
general health than normal subjects.
14,47
What we
do know is that CSA is not the sole cause of excess
daytime sleepiness in the MMT patients.
14
Potential mechanisms for CSA with chronic
opioid use
Though the human studies showing CSA with
chronic opioid use are of interest, only 2 have
assessed potential mechanisms related to this
finding.
14,16
One of the major problems with using
human subjects for investigating the pathogenesis
of CSA in these populations is that chronic opioid
use is usually associated with a number of other
medical and psychiatric conditions.
47
Therefore,
these subjects often use concomitant therapy such
as benzodiazapines and antidepressants, and many
have a history of cigarette abuse.
47
These con-
founders make it difficult to reach conclusions
regarding pathogenetic mechanisms for CSA with-
out testing large numbers of subjects and this can
be difficult in these patient populations. We
therefore suggest that future research be targeted
at further developing animal models to better
assess the mechanisms involved in CSA with chronic
opioid use. However, even with the above caveats,
the data obtained from our previous studies can
give direction for further animal and human
research and we will in detail discuss some of the
information we have obtained in a cohort of stable
MMT patients.
14
These MMT patients were on stable
doses of methadone and had been in the treatment
program for a minimum of 2 months.
The CSA noted in the MMT patients appears to be
different to the Cheyne–Stokes respiration seen in
congestive heart failure patients.
14
For example,
the CSA of MMT patients shown in Fig. 2 are not of
the crescendo–decrescendo type and have much
shorter cycle time than the Cheyne–Stokes respira-
tion of congestive heart failure.
14,48
In addition
these MMT patients had normal cardiac function.
49
The CSA in the MMT patients is not of the idiopathic
type as these subjects lacked the typical charac-
teristics of idiopathic CSA, such as male preponder-
ance and significant arousals during sleep.
14,50
Hypercapnia alone does not seem to explain the
CSA in these stable MMT patients as their lung
function tests were only mildly abnormal and their
awake arterial CO
2
tension was marginally raised in
only 10 of the 50 patients.
48
We currently believe that no simple cause and
effect relationship can explain CSA with chronic
opioid use. An important clue is that methadone
blood concentration is the best predicting variable
for CSA in stable MMT patients.
14
Another impor-
tant lead is that stable MMT patients have blunted
central chemosensitivity but elevated peripheral
chemosensitivity.
16
We therefore believe that the
pathogenesis for CSA in this group is most likely
multifactorial in nature and related to a variable
interplay of abnormalities of central controller
function and central and peripheral chemoreceptor
sensitivity. m-Opioids are well known central re-
spiratory depressants.
5
The significant association
between CSA and methadone blood concentration
suggests that depressed central controller plays a
critical role in the genesis of CSA.
14
Structural brain
damage has been reported to occur secondary to
cerebrovascular accidents associated with prior
illicit drug use.
51
This brain damage particularly if
it occurs in the midbrain or brainstem would lead to
central respiratory controller dysfunction in these
MMT patients. Functional and structural MRI studies
are required in this group of patients to assess this
hypothesis.
As shown in Fig. 1, stable MMT patients have
significantly reduced HCVR but increased HVR,
which may suggest blunted central chemosensitiv-
ity but elevated peripheral chemosensitivity.
16
An
imbalance of central and peripheral chemosensi-
tivity has been suggested to pose a greater risk for
periodic breathing.
52
When carotid chemoreceptor
stimulation becomes the dominant sensory input to
the respiratory controller relative to the input of
the medullary chemoreceptors, the breathing
pattern tends to become instable.
52
The combina-
tion of antidepressant and methadone use may
further reduce the already blunted HCVR
16
and lead
to an increased risk of CSA.
14
We have shown that
of the stable MMT patients with CSA, 57% of those
receiving both antidepressant and methadone had
central apnoea index 410.
14
These patients had
ARTICLE IN PRESS
Opioids, sleep architecture and sleep-disordered breathing 43
significantly reduced central chemosensitivity com-
pared to the patients taking methadone alone.
16
This mechanism is therefore similar to that of
hypercapnic-type CSA.
50
Acute opioids use can
significantly reduce HVR, however, long-term ap-
plication of opioids may lead to recurrent episodic
hypoxia which may continuously stimulate periph-
eral chemosensitivity and lead to an increased
HVR.
14,28
It has been reported that exposing
subjects to very mild and short-term hypoxia can
cause an increase in HVR.
53
High peripheral
chemosensitivity itself is a predisposing factor for
sleep-disordered breathing
54
and has been shown
to occur in high altitude periodic breathing
55
and in
CSA of congestive heart failure.
48
The above mechanisms may contribute to the
CSA seen in chronic opioid use. Each mechanism
may occur in isolation or in variable combinations
with other mechanisms.
Opioid use and SIDS
The SIDS is acknowledged as a major cause of death
in infancy.
56
In Australia in the late 1990s’, SIDS killed
approximately one in every 1200 infants. Neonatal
life of infants born to substance abusing mothers or
born to those using opioids chronically is similar to
that of chronic opioid use followed by a natural
opioid abstinence period. Following birth there is an
acute withdrawal of supply of exogenous opioids
through placental circulation while endogenous
opioids production is low. This may cause functional
impairment in the CNS and altered sleep patterns.
57
In pregnant MMT patients, foetal breathing move-
ments and the response to carbon dioxide are
significantly less than in normal subjects, and are
further decreased after receiving methadone.
58
Infants born to substance-abusing mothers have been
shown to have an impaired repertoire of protective
responses to hypoxia and hypercapnia during sleep.
59
They have higher prevalence of periodic breathing
during sleep and a 5–10 times increased risk of SIDS
compared to normal infants.
17,18,59
In a population-
based study, more than 1.2 million infants born in
New York City between 1979 and 1989 were
investigated and infants born to mothers in MMT
were found to have 3.6 times increased chance of
having SIDS compared to infants born to mothers not
using methadone.
60
Practice points
There is increasing acute and chronic use of
illicit and prescribed opioids in Western
societies.
Sleep architecture is abnormal with opioid
use and the abnormalities of sleep archi-
tecture are different across the four basic
phases of opioid dependence and with-
drawal.
CSA including periodic and non-periodic
breathing pattern have been reported with
chronic opioid use and 30% of stable MMT
patients have CSA. The potential impacts on
patient outcomes of these findings are
unknown.
The mechanisms producing CSA with chronic
opioid use probably involve changes in
central and peripheral ventilatory control
mechanisms.
Infants born to substance abusing mothers
have a higher prevalence of periodic
breathing during sleep than normal infants
and a 5–10 times increased risk of SIDS
compared to infants born to non-substance
abusing mothers.
Research agenda
Assess the prevalence of sleep-disordered
breathing in patients using opioids long-
term.
Animal and human studies are required
to explore the pathogenesis of sleep-
disordered breathing noted with chronic
opioid use.
Assess the short and long-term effects of
sleep architecture changes and sleep-
disordered breathing with chronic opioid
use and investigate strategies to prevent
the complications.
Data is required regarding the acute
and chronic interactions of opioids, anti-
depressants and benzodiazapines on
sleep architecture and respiration during
sleep.
Animal and human studies with improved
methodology are needed to assess the
effects of acute opioid use on respiration
during sleep.
Data is required for patients with OSA
undergoing surgery to assess the effects of
opioid anaesthesia and of opioid analgesia
on post-operative respiration both awake
and during sleep.
Develop clinical guidelines as to when
patients using opioids should be investi-
gated for sleep disorders including sleep-
disordered breathing.
ARTICLE IN PRESS
D. Wang, H. Teichtahl44
Acknowledgements
The authors wish to acknowledge Dr. John Loads-
man for his constructive help in reviewing this
manuscript and for guidance with regard to the
effects on respiration of opioid anesthesia.
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D. Wang, H. Teichtahl46
