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Analgscs and pan l n pgnancy andbastdngDebra Kennedy , Director, MotherSafe, Royal Hospital for Women, and Conjoint Lecturer,

School of Women's and Children's Health, University of New South Wales, Sydney 

Summay

wmn shuld b assud that pan can b

tatd dung pgnancy and lactatn and

that thy nd nt su unncssaly. ovall,

apppat thaputc dss th cmmnly

usd analgscs ncludng paactaml, aspn

and pds hav nt bn asscatd th anncasd ncdnc bth dcts. Th us

nn-stdal ant-nlammaty dugs n th

thd tmst s nt cmmndd. Untatd

psstnt pan can hav advs cts th

mth and h pgnancy and mn th

psstnt pan shuld dally hav ptmsatn

th pan managmnt b pgnancy.

Key wrds: cdeine, nn-steridal anti-inflammatry drugs,

piids, paracetaml.

(Aust Prescr 2011;34:8–10) 

intductn

Pain during pregnancy may be due t acute cnditins such as

injury r infectin, r secndary t underlying medical disrders

such as rheumatid arthritis. Pain related t pregnancy can als

ccur.

Inadequately managed persistent pain can result in depressin

and anxiety. These may impact n a wman's physical and

psychlgical wellbeing and can ptentially have an adverse

effect n her pregnancy.

Wmen shuld nt suffer unnecessarily frm pain during

pregnancy and lactatin. If used apprpriately, cmmn

analgesics such as paracetaml, aspirin, nn-steridal anti-

inflammatry drugs (NSAIDs) and piids are relatively safe.

In cunselling wmen abut taking medicines during pregnancy

it is always imprtant t emphasise that all cuples have a

backgrund risk f arund 3% f having a baby with a majr

birth defect and that apprximately 15% f all recgnised

pregnancies end in miscarriage, regardless f any drug

expsures. over 85% f wmen use sme medicatin during

pregnancy and analgesics are the mst cmmn preparatinsused, after vitamins, in all trimesters f pregnancy, with ver

50% f wmen using analgesics during their pregnancy.1

The risks r therwise f drug expsures need t be put int

the cntext f this backgrund risk. Wmen and their health

prfessinals can then make infrmed decisins and weigh up

the ptential risks f treating versus nt treating pain during

pregnancy and breastfeeding.

Paactaml

Paracetaml is the analgesic and antipyretic drug mst widely

used in Australia, particularly by pregnant wmen. Althugh

it readily crsses the placenta in its uncnjugated frm, in

therapeutic dses it des nt appear t increase the risk f 

birth defects r ther adverse pregnancy utcmes. Despite

paracetaml's widespread use there are, smewhat surprisingly,

n prspective cntrlled studies abut its use in pregnancy.

The drug is nt cnsidered t be teratgenic althugh sme

retrspective studies including the US Cllabrative Perinatal

Prject fund an increased risk f any cngenital abnrmality

and specifically an increase in cngenital dislcatin f the hip

in expsed infants. A registry-based study frm Denmark f 

26 424 children wh were expsed t paracetaml in utero during

the first trimester fund n increase in either the specific r the

verall rate f birth defects cmpared with unexpsed cntrls.2

Aspn

Aspirin is used t treat mild pain and fever, and lw-dse aspirin

is als prescribed by sme bstetricians (ften with heparin)

t reduce the risk f adverse utcmes in pregnant wmen

with antiphsphlipid syndrme and recurrent miscarriages.3 

overall, aspirin is nt assciated with an increased risk

f cngenital malfrmatins, althugh ne meta-analysis

suggested an assciatin between first trimester aspirin use and

increased risk f gastrschisis*.4 

NSAiDs

NSAIDs including ibuprfen, naprxen, indmethacin and

diclfenac are widely used t treat mild t mderate pain and

fever. They are inhibitrs f cycl-xygenase. In the fetus and

newbrn, cycl-xygenase is a ptent dilatr f the ductus

arterisus and pulmnary resistance vessels. Its inhibitin culd

ptentially cause premature clsure f these vessels. These

* an abdminal wall defect resulting frm rupture f theamnitic membrane during gut-lp herniatin r, later, due t

delayed umbilical ring clsure

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drugs have nt been shwn t increase the risk f structural

birth defects r ther adverse utcmes such as preterm

delivery r lw birth weight. Hwever, a case-cntrl and

ppulatin-based bservatinal chrt study frm Scandinavia

demnstrated an increased risk f spntaneus abrtin

with first trimester use f NSAIDs but with n evidence f 

ther adverse pregnancy utcmes. Majr flaws in this study,

hwever, were that it was prescriptin-based and retrspective

and did nt cntrl fr the indicatins f use f NSAIDs (such as

underlying fever r viral illness).5 

A Califrnian study als shwed an 80% increase in the risk f 

miscarriage assciated with first trimester use

f bth aspirin and NSAIDs. This assciatin

was nt seen with paracetaml.6 

A suggested mechanism t explain the

increased risk f miscarriage is interference

with implantatin as a result f effects n

the prstaglandin pathway. Wmen wh have used NSAIDs

inadvertently during the first trimester shuld be reassured

abut the use, but ther analgesics such as paracetaml shuld

be recmmended as preferable ptins fr subsequent use.

Use f NSAIDs after 30 weeks gestatin is cntraindicated

because f their ptential t cause premature clsure f the

fetal ductus arterisus and persistent pulmnary hypertensin.

High dses f NSAIDs in the third trimester may als reduce

perfusin f the fetal kidneys and decrease fetal urine utput.

This is why NSAIDs are ccasinally used as an interventin

t try and reduce liqur vlume and the chances f crd

entanglement in cases f mn-amnitic twin pregnancy. Mst

f the cases f reduced utput are reversible, but there have

been reprts f nly partial reslutin and even f death due t

anuric renal failure.7,8

As with the lder NSAIDs, the main cncerns with the CoX-2

inhibitrs are effects n the ductus arterisus as well as perfusin

f the fetal/nenatal kidney and intestine. Tpical NSAIDs generally

result in negligible bld levels and wuld be cnsidered t be

relatively safe in pregnancy althugh absrptin is increased by

use ver a large surface area r the applicatin f heat.

opds

opiids such as cdeine, xycdne, hydrmrphne,

hydrcdne and mrphine, as well as drugs such as

pethidine and tramadl, are used t treat mderate t severe

pain. Cdeine is als widely used in varius ver-the-cunter

preparatins. overall, piid analgesics have nt been

assciated with an increase in birth defects r ther adverse

utcmes such as miscarriage. There are als reassuring data n

lnger-term neurdevelpmental fllw-up in expsed infants.

The main cncern abut these drugs is that persistent use maylead t dependence and tlerance in the mther with resultant

withdrawal (nenatal abstinence syndrme) in the nenate.

Wmen with persistent pain wh may require high dses f 

piids during pregnancy shuld seek advice abut ptimising

their pain management befre pregnancy. Smetimes

alternative drugs including tricyclic antidepressants may help

t cntrl persistent pain and reduce piid expsure. Tricyclic

antidepressants have nt been assciated with an increased rate

f birth defects r lng-term neurdevelpmental effects.9 

Bastdng

Paracetaml is cnsidered t be safe fr use during lactatin.

The estimated dse received via breast milk is 6% f the

maternal dse. It shuld be remembered that

paracetaml is widely used at dses far greater

than this fr children.

NSAIDs, such as ibuprfen and diclfenac,

are cnsidered t be cmpatible with

breastfeeding. The infant dses relative t thematernal dses are 0.65% and 1% respectively, even in wmen

taking high dses – fr example diclfenac suppsitries 75 mg.10 

The advantage f using these drugs, especially in the immediate

pstpartum perid, is a reduced need fr piids and the

ptential risks assciated with them.

Aspirin is generally nt recmmended fr treatment f pain during

breastfeeding mainly because there may be significant adverse

effects in infants (the relative infant dse may be as high as 10%)

and safer alternatives are available. There is als the theretical

cncern that aspirin can cause Reye's syndrme in infants.10

Genetic polymorphisms and opioids 

Cytchrme P450 2D6 catalyses the o-demethylatin f 

cdeine t mrphine and genetic plymrphisms in the

CYP2D6 gene can affect the metablism f cdeine. one f the

plymrphisms may result in reduced efficacy f cdeine which

can be a ptential clinical prblem.

The case reprt f a breastfed nenate, wh died fllwing

maternal cdeine use pstpartum, highlights the risks f piid

txicity in patients with anther plymrphism – duplicatin f 

the CYP2D6 gene.11 This results in ultra-rapid metablism f 

cdeine and significantly increases the prductin f mrphine.

In adults this can lead t significant piid txicity despite

small dses f drug, and thus breastfed infants f such patients

are als at risk f serius txicity. The incidence f this gene

duplicatin varies in different ppulatins, frm apprximately

1% in Denmark and Finland t 10% in Greece and Prtugal and

up t 30% in Ethipia.

There are als ther genetic plymrphisms invlved in mrphine

metablism that theretically culd reduce its clearance.

Cautin needs t be exercised in terms f breastfeeding and

minimising the risk f piid txicity in bth mthers and babies.Shrt-term use is unlikely t pse a significant risk but lnger-

term r chrnic use can be ptentially dangerus, particularly

Use f NSAIDs after

30 weeks gestatin

is cntraindicated

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in thse peple wh are ultra-rapid metablisers due t the

CYP2D6 duplicatin. Mthers and babies shuld be carefully

bserved and mnitred fr signs f piid txicity. In mst

cases the ccurrence f central nervus system depressin

with piids is cnsistent between mther and baby (althugh

babies appear t be mre sensitive t the effects f piids) and

s if a mther appears t have adverse effects f piids there

shuld be a lw threshld fr examining the baby and excluding

txicity.12 If lnger-term pain relief is required, then ther drugs

such as NSAIDs shuld be cnsidered as first-line treatment.

Cnclusn and cmmndatns

At MtherSafe we reassure wmen regarding inadvertent

NSAID use, but recmmend paracetaml as first-line treatment

f fever and pain during pregnancy. Cdeine r anther piid

analgesic can be added t treat mre severe pain. NSAID use is

cntraindicated in the third trimester and alternative analgesics

shuld als be cnsidered in the first trimester.

Wmen and their dctrs shuld hwever be reassured that

there are safe ptins t treat pain, bth acute and chrnic,

during pregnancy and breastfeeding.

rncs

1. Henry A, Crwther C. Patterns f medicatin use during and

prir t pregnancy: the MAP study.

Aust N Z J obstet Gynaecl 2000;40:165-72.

2. Rebrdsa C, Kgevinas M, Hrvath-Puh E, Nrgard B,

Mrales M, Czeizel AE, et al. Acetaminphen use during

pregnancy: effects n risk fr cngenital abnrmalities.

Am J obstet Gynecl 2008;198:178. e1-7.

3. Erkan D, Patel S, Nuzz M, Gersa M, Merni PL, Tincani A,

et al. Management f the cntrversial aspects f the

antiphsphlipid syndrme pregnancies: a guide fr

clinicians and researchers. Rheumatlgy (oxfrd)

2008;47 Suppl 3:iii23-7.

4. Kzer E, Nikfar S, Cstei A, Bskvic R, Nulman I, Kren G.

Aspirin cnsumptin during the first trimester f pregnancy

and cngenital anmalies: a meta-analysis.

Am J obstet Gynecl 2002;187:1623-30.

5. Nielsen GL, Srensen HT, Larsen H, Pedersen L. Risk f 

adverse birth utcme and miscarriage in pregnant users

f nn-steridal anti-inflammatry drugs: ppulatin based

bservatinal study and case-cntrl study. BMJ

2001;322:266-70.

6. Li DK, Liu L, oduli R. Expsure t nn-steridal

anti-inflammatry drugs during pregnancy and risk f 

miscarriage: ppulatin based chrt study. BMJ

2003;327:368.

7. Glr JM, Muchant DG, Nrling LL. Prenatal maternal

indmethacin use resulting in prlnged nenatal renal

insufficiency. J Perinatl 1993;13:425-7.

8. van der Heijden BJ, Carlus C, Narcy F, Bavux F, Delezide AL,

Gubler MC. Persistent anuria, nenatal death, and renal

micrcystic lesins after prenatal expsure t indmethacin.

Am J obstet Gynecl 1994;171:617-23.

9. Nulman I, Rvet J, Stewart DE, Wlpin J, Pace-Asciak P,

Shuhaiber S, et al. Child develpment fllwing expsure

t tricyclic antidepressants r fluxetine thrughut fetal

life: a prspective, cntrlled study. Am J Psychiatry2002;159:1889-95.

10. Hale TW. Medicatins and mthers' milk. 14th ed.

Amarill (TX): Hale Publishing; 2010.

11. Kren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ.

Pharmacgenetics f mrphine pisning in a breastfed

nenate f a cdeine-prescribed mther. Lancet

2006;368:704.

12. Madadi P, Mretti M, Djkanvic N, Bzz P, Nulman I,

It S, et al. Guidelines fr maternal cdeine use during

breastfeeding. Can Fam Physician 2009;55:1077-8.

Conflict of interest: none declared 

Sl-tst qustns

The following statements are either true or false 

(answers on page 31) 

3. Paracetaml des nt crss the placenta.

4. NSAIDs shuld be avided during the third trimester.

Analgscs and pan l n pgnancy and bastdng

Dntal ntsPrepared by Michael McCullough , Chair, Therapeutics Committee, Australian Dental Association 

It is prbably prudent fr dentists nt t prescribe nn-steridal

anti-inflammatry drugs fr pain relief during pregnancy. If their

patients are experiencing prfund, persistent pain it wuld

be advisable t liaise with the patient's medical practitiner

fr apprpriate management. Imprtantly, accurate diagnsis

and timely dental treatment will dramatically and effectivelyreduce the pain fr these patients. This will diminish the

requirement fr systemic pain relief.

Dentists ften advise patients regarding pain management fr

dental pain and generally the recmmendatin fr pregnant

wmen t use paracetaml, as the first-line treatment f fever

and pain, is reasnable. Hwever, n ccasins the dental pain

experienced will warrant the shrt-term use f drugs which

include therapeutic dses f cdeine. The use f these drugs frshrt-term treatment (2–3 days) in wmen wh are pregnant r

breastfeeding shuld nt pse any adverse risk.