ARTICLE IN PRESS

Sleep Medicine Reviews (2007) 11, 35–46

1087-0792/$ - sdoi:10.1016/j.s

�CorrespondiSydney 2050, A

E-mail addr

www.elsevier.com/locate/smrv

CLINICAL REVIEW

Opioids, sleep architecture andsleep-disordered breathing

David Wanga,c,d,�, Harry Teichtahla,b

aDepartment of Medicine, Royal Melbourne Hospital and Western Hospital, The University of Melbourne,Gordon Street, Footscray, Vic. 3011, AustraliabDepartment of Respiratory & Sleep Disorders Medicine, Western Hospital, Gordon Street, Footscray,Vic. 3011, AustraliacWoolcock Institute of Medical Research, The university of Sydney, Missenden Road, Camperdown,Sydney 2050, AustraliadDepartment of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road,Camperdown, Sydney 2050, Australia

KEYWORDSOpiates;Narcotic;Endogenous opioid;Opioid receptor;Sleep architecture;Central sleepapnoea;OSA;Hypercapnic;Hypoxic;Ventilatory response

ee front matter & 2006mrv.2006.03.006

ng author. Departmentustralia. Tel.: +61 2 951esses: dwang@med.usy

Summary Opioid use whether acute or chronic, illicit or therapeutic is prevalentin Western societies. Opioid receptors are located in the same nuclei that are activein sleep regulation and opioid peptides are suggested to be involved in the inductionand maintenance of the sleep state. m-Opioids are the most commonly used opioidsand are recognized respiratory depressants that cause abnormal awake ventilatoryresponses to hypercapnia and hypoxia. Abnormal sleep architecture has beenreported during the process of opioids induction, maintenance and withdrawal.During induction and maintenance of opioid use there is reduction of rapid eyemovement (REM) sleep and slow wave sleep. More recently, central sleep apnoea(CSA) has been reported with chronic opioid use and 30% of stable methadonemaintenance treatment patients have CSA. Given these facts, it is sobering to notethe paucity of human data available regarding the effects of short and long-termopioid use on sleep architecture and respiration during sleep. In this manuscript, wereview the current knowledge regarding the effects of m-opioids on sleep andrespiration during sleep and suggest research pathways to advance our knowledgeand to explore the possible responsible mechanisms related to these effects.& 2006 Elsevier Ltd. All rights reserved.

Elsevier Ltd. All rights reserved.

of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown,5 5048; fax: +61 2 9515 7196.d.edu.au (D. Wang), harry.teichtahl@wh.org.au (H. Teichtahl).

ARTICLE IN PRESS

Nomenclature

ACTH adrenocorticotropic hormonea-MSH melanocyte-stimulating hormoneb-LPH b-lipotropinBMI body mass indexCSA central sleep apnoeaESS Epworth Sleepiness ScoreHCVR ventilatory responses to hypercapniaHVR ventilatory responses to hypoxiaMMT methadone maintenance treatmentN/OFQ nociceptin/orphanin FQ receptorOSA obstructive sleep apnoea

POMC prepro-opiomelanocortinPSG polysomnographyR&K Rechtschaffen and Kales criteria for

sleep stagesREM rapid eye movementREMS REM sleepSCN suprachiasmatic nucleiSE sleep efficiencySIDS sudden infant death syndromeSL sleep latencySWS slow wave sleepTST total sleep time

D. Wang, H. Teichtahl36

Introduction

Opioid use whether therapeutic or illicit is commonworldwide. In year 2000, approximately 1.2% of theAmerican population reported heroin use at leastonce in their lifetime.1 In Australia, the estimate ofrecent illicit opioid users was 0.6% of the 14 yrs andolder population in 2001 compared to 1% in 1998.2

More than 140,000 patients were receiving metha-done maintenance treatment (MMT) in 1998 in theUnited States,3 and in Australia 30,000 werereceiving MMT in year 2000.4 Opioids are alsocommonly used for acute and chronic pain manage-ment and as an adjunct to anaesthesia andoccasionally for the restless legs syndrome.5,6 AnAmerican study reported that 80% of 2118 cancerpatients referred to a pain service were prescribedopioids.6 In year 2004, there were more than410,000 registrants for opioid use in Americanpharmacies compared to around 390,000 in 1997.7

The average gram weight per registrant increased7.3 fold for oxycodone, 5 fold for methadone, 4.6fold for fentanyl base and 3 fold for hydrocodonefrom 1997 to 2004.7 Prescribed opioids relateddeaths account for most of non-illicit drug poison-ing deaths in America and the problem has beenincreasing in the past decade.8 Abuse of opioidanalgesics is very common and in 2005, 9.5% ofAmerican 12th graders reported using Vicodin and5.5% of these students reported using OxyContin inthe past year.9

Many opioid receptors are located in the samenuclei that are active in sleep regulation10 and ithas been suggested opioid peptides are involved inthe induction and maintenance of the sleep state.11

Chronic opioid use has been hypothesized to causedisturbed sleep as well as excessive day-timesleepiness and fatigue.12 A few studies havereported abnormal sleep architecture in opioidusers but most were performed prior to 1990 and

few tested breathing during sleep though opioidsare well-known respiratory depressants.5 In recentstudies, central sleep apnoea (CSA) has been foundin stable MMT patients and in patients prescribedtime-release opioid analgesic management.13–15

Abnormal ventilatory responses to hypercapnia(HCVR) and hypoxia (HVR) have also been noted instable MMT patients.16 Infants born to substance-abusing mothers have a higher prevalence ofperiodic breathing during sleep and a 5–10 timesincreased risk of sudden infant death syndrome(SIDS) compared to normal infants.17,18 The poten-tial symptoms and other sequelae related to CSAand periodic breathing have not been discussedin reviews of opioid use for chronic pain or inmethadone substitution programs.6

Morphine-like m-opioids are clinically the mostcommonly used opioids and this review focuses ontheir effects on sleep and respiration during sleepin humans. Where evidence is available, we willdiscuss the pathogenesis of abnormalities describedand will also discuss future research directionsgiven the considerable lack of knowledge in thisimportant area of medicine. The scope of thisreview includes sleep and respiration during sleepin acute and chronic opioid analgesic use, opioidabuse and in MMT programs.

Opioids and control of sleep

There are four major classes of endogenous opioidreceptors in the central nervous system: m, d, k andnociceptin/orphanin FQ (N/OFQ) receptor.5 Each ofthese receptor subtypes has a distinct profile interms of its pharmacology as well as its distributionwithin the brain and spinal cord. Most of theclinically used opioids are relatively selective for mreceptors, such as morphine and methadone.5

It appears that REM suppression is associated

ARTICLE IN PRESS

Opioids, sleep architecture and sleep-disordered breathing 37

primarily with the actions of m-opioid receptoragonists.19 Three classes of opioid peptides havebeen identified: the enkephalins, endorphins anddynorphins.5 These have been shown to have a rolein sensory modulation and analgesia and may beimportant in the onset and maintenance of sleep,and therefore be involved in attenuation of arousaland waking.20 Enkephalin is contained in neuronsthat are widely distributed through the brain andregions involved in slow wave sleep (SWS) such asthe solitary tract nucleus, the preoptic area andthe raphe, where it is colocalized with serotoninreceptors.20 Enkephalin containing fibres innervatethe locus coeruleus noradrenergic neurons whichare inhibited by locally delivered opioids andproduce decreased awakenings and increasedSWS.20 b-Endorphin is derived from prepro-opiome-lanocortin (POMC) which is also processed into thenon-opioid peptides adrenocorticotropic hormone(ACTH), melanocyte-stimulating hormone (a-MSH)and b-lipotropin (b-LPH).5 ACTH is the hormoneclosely related to stress and a-MSH has beensuggested to induce sleep and increase SWS. Theassociation of sharing the same precursors implies aclose physiological linkage between stress, sleepand the opioid systems.5

The mechanism of opioid peptide action on sleepcontrol remains unclear. It has been hypothesizedthat opioid peptides in conjunction with thepeptide neurohormone vasopressin are involved inthe induction and maintenance of the sleep statethrough a complex and modifiable circadian me-chanism driven by the suprachiasmatic nuclei(SCN).11 Vasopressin, one of the neurohormones inthe circadian pacemaker SCN, has been shown tohave a close relationship to circadian rhythms.21

Vasopressin causes the secretion of endorphins intothe cerebro–spinal fluid (CSF), while pain andopioids stimulate the secretion of vasopressin fromthe pituitary.22 In the supraoptic and paraventri-cular nuclei, vasopressin is stored with the opioidpeptide dynorphin which also shows circadianvariability of its blood levels.23 It is possible thatboth vasopressin and the opioids are part of theneurochemical mechanism driven by SCN to main-tain the daily sleep and wake rhythm.11

Exogenous opioids may affect the activity ofopioid receptors by binding to the same sites asthose of endogenous opioid peptides.24 Endogenousenkephalin production is linked by a negative feed-back mechanism to the serum level of opioids whichare high in chronic opioid users.25 Given the possiblelinks between endogenous opioids and control ofsleep previously discussed, it is reasonable tosuggest that acute and chronic opioid use may havean effect on sleep hygiene and sleep architecture.

Opioids and control of respiration whenawake and during anaesthesia

In humans, the primary opioid receptors involved incontrol of respiration are assumed to be m-receptortype.5 d-Receptors may exert modest respiratorydepressant effects, whereas k-receptors have littlerespiratory depressant activity.26 Acute use ofm-receptor stimulating opioids can cause dosedependant depression of respiration.5 Opioid recep-tors in brain stem (medulla, pons, nucleus tractussolitarius, and nucleus ambiguous), spinal cord, andperipheral sites such as lung tissue are involved inthe respiratory depression. However, the brain stemrespiratory centres predominate with regard to thiseffect.5,26,27 Both HCVR and HVR can be significantlyreduced by acute use of opioids.26,28 Opioids canalso blunt the increase in respiratory drive normallyassociated with increased loads such as increasedairway resistance.27 Acute opioid use may causeincreased respiratory pauses, delays in expiration,irregular and/or periodic breathing and decreased/normal tidal volume.27 The prolonged expiratorytime in the respiratory cycle induced by opioidsoften results in greater reductions in respiratoryrate than in tidal volume.26 Increased tidal volumevariability was reported to be a better predictorof respiratory depression than a fall in respiratoryrate when remifentanil was infused during dentalanaesthesia.29

Waters et al. studied 13 children with OSA and 24normal subjects undergoing tonsillectomy.30 Theyfound that under inhalational anaesthetic andspontaneous ventilation, the OSA group hypoventi-lated and tended to have higher end tidal CO2

levels than the normal group. Following fentanylinjection, 6 of the OSA group exhibited centralapnoea compared with one of the normal subjects.The production of central apnoea post opioidinjection in both groups was related to end tidalCO2 higher than 50 Torr.30 Though this study hasmethodological flaws, the data suggests that atleast in children, subjects prone to hypoventilationmay progress to central apnoea when given a m-opioid, however, whether this equates to CSA inthese children is unknown.

With long-term use of opioids, subjects havereduced HCVR although tolerance appears todevelop.16,31 An early study assessing HVR in MMTpatients suggested blunting of HVR in both theacute and chronic stages of methadone use.31

However, this study should be interpreted withcaution as there was no baseline data from normalsubjects available for comparison.31 In contrast, inour study of stable MMT patients, HVR appears tobe increased (Fig. 1).16 The causes for this finding

ARTICLE IN PRESS

HCVR

0

1

2

3

mea

n+S

E (

L/m

in/%

fall

in S

pO2)

0

1

2

3MMTControl

mea

n+S

E (

L/m

in/m

mH

g P

co2)

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. 16HCVR ¼ hypercapnic ventilatory response; HVR ¼ hypoxic ventilatory response; SE ¼ standard error.

D. Wang, H. Teichtahl38

are not clearly known and may relate to long-termstimulation of the hypoxic response by long-termintermittent hypoxia.16 The high HVR and low HCVRwe found in the stable MMT patients related tochanges in respiratory rate and not tidal volumeresponse.16

To our knowledge there are no studies assessingHCVR and HVR during sleep in subjects with acuteor chronic opioid use.

Opioid use, sleep and respiration duringsleep

Given the large opioid using population and thepossible close link between endogenous opioids andcontrol of sleep, there is a scarcity of studiesinvestigating sleep in human adult subjects usingopioids.12 There are studies assessing sleep inanimals that show changes in sleep architecturewith acute and chronic m-opioid use.32,33 We wereunable to find data related to effects of chronic useof m-opioids on respiration during sleep in animals.Breathing during sleep in human subjects usingopioids has been poorly studied despite the factthat the commonly used m-opioids are known todepress respiration and sleep-disordered breathingin its own right can significantly affect sleeparchitecture.5

Table 1 shows the findings and methodologies of18 human studies available on PUBMED publishedbetween 1966 and 2005 investigating sleep andrespiration during sleep in adult humans usingopioids. We cite only those studies using objectivemeasurements and reported in English. Studiesassessing the effects of opioids on sleep andrespiration during sleep in post-operative surgicalpatients and restless legs syndrome patients are notincluded in the table. Restless legs syndrome itselfcan significantly disturb sleep and the studies in the

anaesthetic literature are often confounded bypoor patient selection, use of concomitant anaes-thetic agents, analgesics and post-operative pain.In addition, natural sleep is clearly different toanaesthesia which is a state of unrousable uncon-sciousness.34 During anaesthesia, there is dose-dependant depression to most of the vital functionsincluding respiration.34 Abnormal breathing pat-terns in anaesthesia are different to sleep-disor-dered breathing although the tendency to upperairway obstruction during sleep and during anaes-thesia are probably related.35 Of the studies listedin Table 1, 16 used morphine like m-opioids and 3used opioid antagonists.

Methodological review of publications

�

Only four (22%) of the studies had sample size410. � Subject selection is skewed to male preponder-

ance as only 47 (24%) females were studied froma total of 192 subjects.

� Only 6 studies (33%) had normal subjects as

control group for comparison. However, thenormal subjects and patients were matched forage and BMI in only two studies.13,14

�

10 out of 18 studies used the commonly acceptedsleep scoring criteria of Rechtschaffen and Kales(R & K), although all the studies were reportedafter the introduction of the R & K criteria. � Only 5 studies (28%) investigated respiration

during sleep.

The above review suggests that the findings fromthe 18 studies need to be interpreted with caution.For example, ‘‘delta burst’’ could be either stage 2or 3 sleep in R & K criteria.36,37 ‘‘Delta sleep’’ isequivalent to stage 4 sleep in R & K criteria ratherthan SWS (including both stage 3 and 4 sleep).36,37

ARTICLE IN PRESS

Table

1Su

mmaryof

stud

iesob

jectivelyev

alua

ting

theeffectsof

opioidson

human

adultslee

pan

drespirationduringslee

p.

Referenc

eSu

bjects

Drug

Con

trol

subjects

Stud

ydesign,

acute/

chronic

dosing

R&

Kcriteria

Respiration

duringslee

pMajor

find

ings

inslee

p

Kay

etal.6

18M

,prisone

rsMorphine

orPlace

bo

No

Sing

le-blind

cross-ov

er;

Acu

teNo

No

kREM

Snu

mber

andduration,

mREM

Slatenc

y,mwak

ing,

mStag

es1&

2,kStag

es3

and4.

Lewis

etal.3

94M

,au

thorsof

thepap

erHeroin

No

3Ph

ase(3

nigh

tsea

ch):

Con

trol,induc

tion

and

withd

rawal;ac

ute

Yes

No

k%REM

Sduringinduc

tion

andrebou

ndm%REM

Sduringwithd

rawal.mSL

and

%Stag

e1duringinduc

tion

,bac

kto

norm

alduringwithd

rawal.%Stag

e2an

d%SW

Sno

chan

ge.

Martinet

al.4

06M

,prisone

rsMetha

don

eNo

4Ph

ase:

2wee

ksco

ntrol,5

wee

ksasce

nding,

8wee

ksstab

ilizationan

d24

wee

ksprotrac

tedab

stinen

ce4

6wee

kswithd

rawal

No

No

Addiction

:Slow

erEE

G,mdelta

burst,

voca

lization

duringREM

S,mday

-tim

eslee

piness.

Withd

rawal:mREM

anddelta

slee

pafter10

wee

ks.

Kay

36

6M,prisone

rsMorphine

No

5nigh

tsbaseline,

1nigh

tinduc

tion

and5nigh

tsstab

lepha

se

No

No

Chron

icmorphine

:Delta

slee

pshiftedlater

inthenigh

t,kREM

S,partial

toleranc

edev

elop

sto

slee

pdisturban

ce.

Kay

41

6M,prisone

rsMetha

don

e37

addicts

4Ph

ase:

12wee

ksco

ntrol,6

wee

ksinduc

tion

,8wee

ksstab

ilizationan

d22

wee

ksprotrac

tedab

stinen

ce(no

acutewithd

rawalo6wee

ksreco

rded

)

No

No

mwak

ingstateinitially,

improve

dduring

stab

ilizationan

dfurthe

rreduc

edduring

withd

rawal.kREM

Sinitially,

plateau

REM

Sduringstab

ilizationpha

sean

drebou

ndmREM

Sduringwithd

rawal.kdelta

slee

pduringinitialan

dstab

ilizationpha

sean

drebou

ndmdelta

slee

pduringwithd

rawal.

Duringstab

ilization,

mday

-tim

eslee

piness,

mdelta

burst

and30

%subjectsvo

calize

dduringREM

S.Orr

andStah

l62

5M,MMT

Metha

don

e5M

2grou

psco

mparison

;ch

ronic

Yes

No

m%Stag

e1,

k%SW

S,kREM

Slatenc

y,No

chan

gein

%REM

,%Stag

e2,

TST,SL

and

awak

enings.

Kay

etal.4

27M

,prisone

rsMorphine

,Metha

don

eHeroinor

Place

bo

No

Ran

dom

ized

cross-ov

er;

Acu

teNo

No

Allop

ioids:

marou

sals

andwak

ingstate,

kREM

andspindle

slee

p.Heroinistw

iceas

poten

tas

morphine

ormetha

don

eon

EEG

chan

ges.

How

eet

al.3

814

M,armystaff

Heroin

5M5–

7day

sac

utewithd

rawal

pha

seYes

No

kTST,maw

ake,

k%REM

S,%SW

Sno

chan

ge,

m%Stag

e1an

dm%Stag

e2slee

p.

Pickworth

etal.4

37M

,prisone

rsMorphine

,metha

don

eor

place

bo

No

Dou

ble-blind

,rand

omized

cross-ov

er;ac

ute

No

No

Metha

don

e&

morphine

have

comparab

leeffects:

mwak

etime,

m%spindle

slee

p,

kdelta

slee

p,kREM

S,mREM

Son

set

latenc

y.Kay

etal.6

37M

,prisone

rsHeroin,

morphine

orplace

bo

No

Dou

ble-blind

,cross-ov

er;

acute

No

No

Heroin:

mwak

etime,

kTST,kSE

,no

chan

gein

SL,m%spindle

slee

p,k%delta

slee

p,

k%REM

S.Morphine

:mwak

efulne

ss,kTST

comparab

leto

that

ofhe

roin

Opioids, sleep architecture and sleep-disordered breathing 39

ARTICLE IN PRESS

Table

1(con

tinu

ed)

Referenc

eSu

bjects

Drug

Con

trol

subjects

Stud

ydesign,

acute/

chronic

dosing

R&

Kcriteria

Respiration

duringslee

pMajor

find

ings

inslee

p

Sitaram

andGillin6

48M

,5F

norm

alvo

luntee

rsNalox

one(opioid

antago

nist)or

place

bo

No

Dou

ble-blind

,repea

ted-

mea

sure

coun

terbalan

ced

design;

acute

Yes

No

mREM

Son

setlatenc

y,kNum

ber

ofREM

Speriods,

Nosign

ifica

ntch

ange

in%REM

S,TST,SE

Pickworth

etal.6

57M

,prisone

rsCyclazocine

(opioid

antago

nist)or

place

bo

No

Dou

ble-blind

,cross-ov

er;

acute

No

No

kTST,kREM

S,mREM

Son

setlatenc

y,m%spindle

slee

p,k%delta

slee

p,

mdrowsine

ssan

darou

sal

Robinsonet

al.4

410

M,2F

healthy

subjects

2&

4mgoral

hydromorpho

neor

place

bo

No

Place

boco

ntrolled

comparison

stud

y;ac

ute

Yes

Nosign

ifica

ntch

ange

inslee

p-

disordered

breathing

N/A

Stae

dtet

al.6

63F,7M

MMT;

10M

Naltrex

one

Metha

don

e,Naltrex

one

10M

stud

ents

3grou

psco

mparison

;ch

ronic

Yes

No

SL(M

MT4

naltrexo

ne4

control),

TST

(MMTo

naltrexo

neoco

ntrol),

SWS(MMTo

naltrexo

neoco

ntrol),REM

S(M

MTo

naltrexo

ne¼

control),

Wak

e(MMT4

naltrexo

ne4

control).MMT

patientsaremoredep

ressed

and

psych

ophy

siolog

ically

moreim

pairedthan

naltrexo

neusers.

Teichtah

let

al.1

36M

,4F

MMT

Metha

don

e6M

,3F

Cross-sec

tion

al,2grou

pco

mparison

;ch

ronic

Yes

CSA

in6/

10stab

leMMT

patients

mwak

etime,

kSE

,m%Stag

e2,

k%SW

S,kREM

Smins&

periods

Farney

etal.1

53F

withtime-

releaseop

ioids

Morphine

,metha

don

e,fentan

yl

No

Casestud

y;ch

ronic

N/A

CSA

,atax

icbreathing

,ob

structive

hypop

nea,

hypox

emia

N/A

Shaw

etal.4

52M

,5F

healthy

subjects

i.v.

Morphine

orplace

bo

No

Place

boco

ntrolled

comparison

stud

y;ac

ute

Yes

Noslee

p-

disordered

breathing

foun

d

kSW

S,kREM

S,m%Stag

e2

Wan

get

al.1

425

M,25

FMMT

Metha

don

e10

M,10

FCross-sec

tion

al,2grou

pco

mparison

;ch

ronic

Yes

CSA

in30

%of

stab

leMMT

patients,

OSA

nodifferent

toco

ntrols

k%Stag

e1,

m%Stag

e2,

kREM

S.Noch

ange

inTST,SE

,%SW

S,SL

andREM

Son

set

latenc

y,mES

S

Ann

otation:

REM

S¼

REM

slee

p,SL¼

slee

platenc

y,TST¼

totalslee

ptime,

SE¼

slee

pefficien

cy,CSA¼

centralslee

pap

nea,

OSA¼

obstructiveslee

pap

noea

;R&K¼

Rech

tsch

affen

andKales

criteria

forslee

pstag

es,ES

S¼

Epworth

Slee

pine

ssScore,

MMT¼

metha

done

mainten

ance

trea

tmen

t,SW

S¼

slow

wav

eslee

p,N/A¼

slee

pno

tassessed

.

D. Wang, H. Teichtahl40

ARTICLE IN PRESS

Opioids, sleep architecture and sleep-disordered breathing 41

‘‘Spindle sleep’’ is only part of stage 2 sleep inR & K criteria.36,37 Most of the studies (81%) did notmeasure breathing during sleep although sleep-disordered breathing itself may have significantimpact on sleep architecture, especially with therecent finding of significant CSA in subjects usingopioids chronically.13,14

Summary of opioid effects on sleep

Despite the inherent methodological limitationsdiscussed above, the studies provide useful infor-mation about the effects of opioids on sleep. Thereare four basic phases of opioid dependence andwithdrawal: drug induction phase, drug mainte-nance phase, acute abstinence phase and pro-tracted abstinence phase.38 Sleep architecturechanges are different for each of the 4 phases. Ingeneral, during the induction phase, the use ofmorphine-like opioids significantly disrupts sleepwith reduced REM sleep and SWS and increasedwakefulness and arousals from sleep. TST and SEare usually reduced while percentage stage 2 sleepand REM sleep latency are often increased. Duringthe maintenance phase of m-opioid use, thedecreases in SWS and REM sleep tend to normal asdo the increases of wakefulness, arousal and REMsleep latency. Vocalization during REM sleep,significant delta burst and increased daytimesleepiness may commonly appear in this phase.Limited evidence is available regarding sleepduring acute withdrawal from chronic opioiduse.38 Changes in sleep from withdrawal of short-term opioid administration39 may be different tothe changes seen in withdrawal from chronic opioiduse. Significant insomnia is the major complaintduring chronic opioid withdrawal, accompanied byfrequent arousals and decreased REM sleep. Duringthe protracted abstinence phase, TST significantlyincreases with rebound of SWS and REM sleep. Afterchronic methadone use, the rebound of SWS andREM sleep usually occurs between 13 and 22 weeksfollowing withdrawal of the opioid.40,41

Chronic opioid use is associated with symptomsof fatigue and excessive daytime sleepiness.12,14

The abnormal sleep architecture discussed abovecan affect daytime functioning in its own right.However, it is difficult to know how much theabnormal sleep architecture noted in these studiesimpacts on daytime function and excess daytimesleepiness.

Within the opioid class, morphine and methadonehave comparable effects on sleep and are half aspotent as heroin with regard to EEG measures.42

The difference between morphine and methadone

on sleep is that chronic morphine use givesmeasures of persistent sleep architecture distur-bances which are not found with chronic metha-done use.40,41,43 Further studies employing largersubject numbers and improved methodology arenecessary to gain a clearer and more comprehen-sive understanding of opioid effects on sleep and toexplore the long-term affects of sleep architecturechanges on the subjects’ daytime function.

Respiration during sleep with acute opioiduse

There are only two human studies assessingrespiration during sleep with acute m–opioid use.Robinson et al. assessed awake pharyngeal resis-tance, HCVR, HVR and respiration during sleep in 12healthy adult humans after ingestion of 2 and 4mgof oral hydromorphone.44 Awake pharyngeal resis-tance, HCVR and breathing during sleep did notchange significantly following either dose of thedrug, although there is a trend toward increasedapneas (more than doubled) and decreased hypop-neas with the 4mg dose. Awake HVR was signifi-cantly reduced after 4mg of the drug.44 Similarly,Shaw et al. measured breathing during sleep on7 healthy adults after injection of morphine(0.1mg/kg) and did not find an increase in sleep-disordered breathing compared to either baselineor placebo use.45 Further studies with largersample size are needed to test the effects of acuteopioid use on respiration during sleep.

Respiration during sleep with chronic opioiduse

Few studies have investigated respiration duringsleep in subjects using opioids long term.13–15,46

The studies include two that assessed stable MMTsubjects;13,14 one assessed 3 subjects using chronictime release opioid analgesics;15 and one assessedsubjects with restless legs syndrome.46 The stableMMT subject studies were the only studies thatmatched patients and normal subjects for age, sexand BMI.13,14 CSA was noted in 20 of 60 subjects inthe MMTcohort and no CSA was noted in the normalsubjects.13,14

In the largest cohort study assessing respirationduring sleep in subjects using opioids chronically,CSA was found in 30% of 50 stable MMT patientswhile obstructive sleep-disordered breathing wassimilar in the MMT cohort and normal subjects.14

The CSA in the MMT patients is more prominent inNREM sleep than in REM sleep and did not causeincreased arousals compared to normal control

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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–decrescendobreathing typical of Cheyne–Stokes respiration. The periodic breathing cycle time is shorter than seen in Cheyne–Stokesrespiration associated with congestive heart failure. The time base is 30 sec for upper epoch and 5min for lower epochfor each example. NASAL ¼ Nasal pressure; THERM ¼ thermister; THOR ¼ thoracic movements; ABDO ¼ abdominalmovement; SaO2 ¼ arterial oxygen saturation; patients were in stage 2 sleep in both examples.

D. Wang, H. Teichtahl42

subjects.14 The CSA described in stable MMTpatients is of periodic and non-periodic type.13,14

During sleep, MMT patients have only mildlyreduced arterial oxygen saturation and mildlyincreased transcutaneous arterial carbon dioxidetension.14

CSA, periodic breathing and Biot’s breathingpattern (i.e. ‘‘ataxic breathing’’ with unpredict-able irregular pattern) was reported in 3 femalesusing opioids chronically for pain relief.15 Thisreport lacks data regarding a clear definition of‘‘ataxic breathing’’ and whether the irregularbreathing was or was not related to arousals or

transitional sleep.15 This breathing pattern appearsto be similar to sub-criteria CSA or the non periodicbreathing CSA we describe in the stable MMTpatients14 (Fig. 2). Opioids have been suggestedto interfere with pontine and medullary respiratorycentres that regulate respiratory rhytmicity basedon various cats studies.27 To date there is howeverno evidence regarding the prevalence and possiblemechanisms of the ataxic/Biot’s breathing patternduring human sleep in chronic opioid use.

Seven patients with restless legs syndrome werestudied with PSG before and after long-term opioidmonotherapy over an average of 7 years.46 Two of

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Opioids, sleep architecture and sleep-disordered breathing 43

the seven patients developed sleep apnoea withrespiratory disturbance index of 10 and 15 and athird patient developed worsening of pre-existingsleep apnoea. The type of sleep apnoea found inthe 3 patients was not reported.46 It thereforeappears that further studies with larger sample sizeand improved methodology are needed to elucidateif the CSA noted in stable MMT patients also existsin the patients using opioids chronically for painrelief and restless legs syndrome.

The outcome of the CSA observed in these groupsof patients is unknown. For example, we do notknow if these patients with CSA have highermorbidity or mortality than those patients usinglong-term opioids but without CSA. We also do notknow whether the CSA noted in these patientscontributes to daytime dysfunction, though it isclear that stable MMT patients are more depressedand sleepier during the day, and have poorergeneral health than normal subjects.14,47 What wedo know is that CSA is not the sole cause of excessdaytime sleepiness in the MMT patients.14

Potential mechanisms for CSA with chronicopioid use

Though the human studies showing CSA withchronic opioid use are of interest, only 2 haveassessed potential mechanisms related to thisfinding.14,16 One of the major problems with usinghuman subjects for investigating the pathogenesisof CSA in these populations is that chronic opioiduse is usually associated with a number of othermedical and psychiatric conditions.47 Therefore,these subjects often use concomitant therapy suchas benzodiazapines and antidepressants, and manyhave a history of cigarette abuse.47 These con-founders make it difficult to reach conclusionsregarding pathogenetic mechanisms for CSA with-out testing large numbers of subjects and this canbe difficult in these patient populations. Wetherefore suggest that future research be targetedat further developing animal models to betterassess the mechanisms involved in CSA with chronicopioid use. However, even with the above caveats,the data obtained from our previous studies cangive direction for further animal and humanresearch and we will in detail discuss some of theinformation we have obtained in a cohort of stableMMT patients.14 These MMT patients were on stabledoses of methadone and had been in the treatmentprogram for a minimum of 2 months.

The CSA noted in the MMT patients appears to bedifferent to the Cheyne–Stokes respiration seen incongestive heart failure patients.14 For example,

the CSA of MMT patients shown in Fig. 2 are not ofthe crescendo–decrescendo type and have muchshorter cycle time than the Cheyne–Stokes respira-tion of congestive heart failure.14,48 In additionthese MMT patients had normal cardiac function.49

The CSA in the MMT patients is not of the idiopathictype 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 theCSA in these stable MMT patients as their lungfunction tests were only mildly abnormal and theirawake arterial CO2 tension was marginally raised inonly 10 of the 50 patients.48

We currently believe that no simple cause andeffect relationship can explain CSA with chronicopioid use. An important clue is that methadoneblood concentration is the best predicting variablefor CSA in stable MMT patients.14 Another impor-tant lead is that stable MMT patients have bluntedcentral chemosensitivity but elevated peripheralchemosensitivity.16 We therefore believe that thepathogenesis for CSA in this group is most likelymultifactorial in nature and related to a variableinterplay of abnormalities of central controllerfunction and central and peripheral chemoreceptorsensitivity. m-Opioids are well known central re-spiratory depressants.5 The significant associationbetween CSA and methadone blood concentrationsuggests that depressed central controller plays acritical role in the genesis of CSA.14 Structural braindamage has been reported to occur secondary tocerebrovascular accidents associated with priorillicit drug use.51 This brain damage particularly ifit occurs in the midbrain or brainstem would lead tocentral respiratory controller dysfunction in theseMMT patients. Functional and structural MRI studiesare required in this group of patients to assess thishypothesis.

As shown in Fig. 1, stable MMT patients havesignificantly reduced HCVR but increased HVR,which may suggest blunted central chemosensitiv-ity but elevated peripheral chemosensitivity.16 Animbalance of central and peripheral chemosensi-tivity has been suggested to pose a greater risk forperiodic breathing.52 When carotid chemoreceptorstimulation becomes the dominant sensory input tothe respiratory controller relative to the input ofthe medullary chemoreceptors, the breathingpattern tends to become instable.52 The combina-tion of antidepressant and methadone use mayfurther reduce the already blunted HCVR16 and leadto an increased risk of CSA.14 We have shown thatof the stable MMT patients with CSA, 57% of thosereceiving both antidepressant and methadone hadcentral apnoea index 410.14 These patients had

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D. Wang, H. Teichtahl44

significantly reduced central chemosensitivity com-pared to the patients taking methadone alone.16

This mechanism is therefore similar to that ofhypercapnic-type CSA.50 Acute opioids use cansignificantly reduce HVR, however, long-term ap-plication of opioids may lead to recurrent episodichypoxia which may continuously stimulate periph-eral chemosensitivity and lead to an increasedHVR.14,28 It has been reported that exposingsubjects to very mild and short-term hypoxia cancause an increase in HVR.53 High peripheralchemosensitivity itself is a predisposing factor forsleep-disordered breathing54 and has been shownto occur in high altitude periodic breathing55 and inCSA of congestive heart failure.48

The above mechanisms may contribute to theCSA seen in chronic opioid use. Each mechanismmay occur in isolation or in variable combinationswith other mechanisms.

Opioid use and SIDS

The SIDS is acknowledged as a major cause of deathin infancy.56 In Australia in the late 1990s’, SIDS killedapproximately one in every 1200 infants. Neonatallife of infants born to substance abusing mothers orborn to those using opioids chronically is similar tothat of chronic opioid use followed by a naturalopioid abstinence period. Following birth there is anacute withdrawal of supply of exogenous opioidsthrough placental circulation while endogenousopioids production is low. This may cause functionalimpairment in the CNS and altered sleep patterns.57

In pregnant MMT patients, foetal breathing move-ments and the response to carbon dioxide aresignificantly less than in normal subjects, and arefurther decreased after receiving methadone.58

Infants born to substance-abusing mothers have beenshown to have an impaired repertoire of protectiveresponses to hypoxia and hypercapnia during sleep.59

They have higher prevalence of periodic breathingduring sleep and a 5–10 times increased risk of SIDScompared to normal infants.17,18,59 In a population-based study, more than 1.2 million infants born inNew York City between 1979 and 1989 wereinvestigated and infants born to mothers in MMTwere found to have 3.6 times increased chance ofhaving SIDS compared to infants born to mothers notusing methadone.60

Practice points

� There is increasing acute and chronic use ofillicit and prescribed opioids in Westernsocieties.

� Sleep architecture is abnormal with opioiduse and the abnormalities of sleep archi-tecture are different across the four basicphases of opioid dependence and with-drawal.� CSA including periodic and non-periodic

breathing pattern have been reported withchronic opioid use and 30% of stable MMTpatients have CSA. The potential impacts onpatient outcomes of these findings areunknown.� The mechanisms producing CSA with chronic

opioid use probably involve changes incentral and peripheral ventilatory controlmechanisms.� Infants born to substance abusing mothers

have a higher prevalence of periodicbreathing during sleep than normal infantsand a 5–10 times increased risk of SIDScompared to infants born to non-substanceabusing mothers.

Research agenda

� Assess the prevalence of sleep-disorderedbreathing in patients using opioids long-term.� Animal and human studies are required

to explore the pathogenesis of sleep-disordered breathing noted with chronicopioid use.� Assess the short and long-term effects of

sleep architecture changes and sleep-disordered breathing with chronic opioiduse and investigate strategies to preventthe complications.� Data is required regarding the acute

and chronic interactions of opioids, anti-depressants and benzodiazapines onsleep architecture and respiration duringsleep.� Animal and human studies with improved

methodology are needed to assess theeffects of acute opioid use on respirationduring sleep.� Data is required for patients with OSA

undergoing surgery to assess the effects ofopioid anaesthesia and of opioid analgesiaon post-operative respiration both awakeand during sleep.� Develop clinical guidelines as to when

patients using opioids should be investi-gated for sleep disorders including sleep-disordered breathing.

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Opioids, sleep architecture and sleep-disordered breathing 45

Acknowledgements

The authors wish to acknowledge Dr. John Loads-man for his constructive help in reviewing thismanuscript and for guidance with regard to theeffects on respiration of opioid anesthesia.

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