Medicines Q&As
UKMi Q&A 200.3
Can opioids be used for pain relief during pregnancy?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Updated: November 2012
Summary
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If possible, avoid all drugs during the first trimester. Non-pharmacological interventions should be
considered first line.
Paracetamol remains the analgesic of choice for mild to moderate pain relief.
Opioid analgesics can be used at any stage of pregnancy for the short-term treatment of moderate to
severe pain when other analgesics are not effective or not clinically indicated.
There is inadequate data on human pregnancy exposure to opioids to rule out teratogenic risks
completely, although the limited data available do not indicate substantial teratogenic effects.
Indiscriminate use should be avoided.
Opioids used near to term may cause neonatal respiratory depression and long-term use may lead to
withdrawal symptoms in the neonate. Withdrawal symptoms include tremors, irritability, sneezing, vomiting
and occasionally seizures.
Codeine may be considered the opioid analgesic of choice due to the largest amount of data of its use
during pregnancy. Overall, data are insufficient to exclude risks but do suggest that therapeutic doses of
codeine are unlikely to pose substantial harm to the foetus. The lowest effective dose should be used for
the shortest period of time.
Very limited data are available for the use of dihydrocodeine, tramadol and morphine during pregnancy.
The data that are available do not suggest that these agents put the foetus at increased risk.
Codeine, dihydrocodeine, tramadol and morphine have all been used during labour. Administration of
opioids during labour has been associated with neonatal respiratory depression. Abuse or prolonged use
has also been associated with withdrawal symptoms including tremors, irritability, diarrhoea, vomiting and
poor feeding.
Short term therapeutic use of opioids must be evaluated differently to that of opiate abuse or substitution
therapy for opiate abuse.
Codeine (and other opioids) may exacerbate constipation, which may already be a problem in the
pregnant woman.
Background
There are a number of opioid analgesics licensed for use in the UK for the treatment of moderate to severe pain
(1). This Q&A looks at the effects of four orally administered opioids when given during pregnancy: codeine,
dihydrocodeine, tramadol and morphine.
In general, the use of medicines should be avoided during pregnancy, especially during the first trimester. The
embryo is most vulnerable to teratogens during organogenesis, from the 4th to the 10th week of pregnancy.(2)
Drug exposure before organogenesis has an all-or-nothing effect: either the embryo does not survive or develops
without abnormalities. Drug effects later in pregnancy typically lead to multiple-organ involvement, developmental
syndromes or intrauterine growth retardation.(2) The use of all medicines in pregnancy should follow a risk versus
benefit assessment in order to minimise any negative effects on the developing foetus. Approximately 3% of
newborns have a significant congenital malformation, and of these, 2-3% have a clear environmental link.(2)
Many women experience pain during pregnancy, such as headaches or back pain or pelvic pain (3;4). Migraine
headaches affect a quarter of women of childbearing potential, though 50% to 80% of women with migraine and
30% of women with tension-type headaches report spontaneous improvements during pregnancy (3;5).
Gestational back pain affects 35% - 61% of pregnant women, developing in the 5th – 7th months of pregnancy and
is thought to be due to an altered posture as well as increased laxity of supporting muscles (6).
If the pain is inadequately treated, there may be adverse effects on both the mother and the foetus (3;5;7).
Chronic pain may lead to depression and anxiety and can also lead to poor oral intake resulting in poor nutrition
or dehydration, which may predispose pregnant women to sinus thrombosis and hyperemesis gravidum (5;8). In
some situations, use of medications may be prudent where the benefits of therapy outweigh the risks. Failing to
assist pregnant women in making analgesic choices may result in inappropriate use of over-the-counter
medicines or herbal remedies (3).
From the NHS Evidence Website www.evidence.nhs.uk
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Medicines Q&As
Minor aches and pains often do not require drug treatment, especially in the first trimester (6). Nonpharmacological treatments may be adequate in some conditions, for example adequate rest, hot and cold
compresses, massage, aromatherapy, acupuncture, physiotherapy, relaxation and exercise (3-6;9). These should
be considered first line before drug treatment (3-6;9). If analgesics are necessary, paracetamol is the drug of
choice (7;10). If the analgesic effect of paracetamol is inadequate, pregnant women may be treated as for nonpregnant women, using other agents along the analgesic ladder such as non-steroidal anti-inflammatory drugs
(NSAIDS) or opioids to provide effective pain relief (3;5;7;10). Safety of NSAIDs during pregnancy depends upon
the trimester and is not discussed in this Q&A.
Opioids may exacerbate constipation, nausea and vomiting which may already be a problem in the pregnant
woman. The risk and tolerability of adverse effects must be balanced against the pain that the pregnant woman is
experiencing.
Answer
Opioid analgesics can be used at any stage of pregnancy for the short-term treatment of moderate to severe pain,
but they may cause dependency and withdrawal symptoms in the neonate if they are used regularly (7;8). The
use of any opioid during pregnancy, particularly around the time of delivery, has a risk of causing neonatal
respiratory depression (7).
Studies evaluating the safety of opioid analgesics during pregnancy are limited and there are no prospective,
comparative studies (11). There may be confounders such as doses used, maternal diseases and other
medications (12). However, therapeutic doses of opioids have been used for many years by pregnant women
and have not been linked to an increased risk of major or minor malformations (11).
The majority of data on the use of codeine during pregnancy show inconsistence evidence of an increase in
malformations but its use can be justified if weaker analgesics are not effective (13); there are few reports of the
use of dihydrocodeine, tramadol or morphine but the data do not suggest an increase in teratogenicity. Use of
any opioid around the time of delivery may result in neonatal depression and prolonged use can cause neonatal
withdrawal symptoms. Effects of opioids on longer-term neurodevelopmental outcome following in utero
exposure is unknown (14). The use of opioids during pregnancy is not an indication for additional foetal
monitoring, unless there are other risk factors involved (13-16).
Codeine
There are inconsistent reports of malformations occurring after exposure to codeine during the first trimester (13).
While some studies found no association with congenital defects, others suggested an increased risk of a variety
of anomalies, including cardiovascular malformations, cleft lip and palate, respiratory tract malformations, inguinal
hernia and pyloric stenosis (12;13). However, these have not been substantiated in large epidemiological studies
in Europe and the USA (3). The absence of a consistent pattern and methodological limitations with possible bias
in these studies mean that it is not possible to state that codeine was definitely the causative agent (3;12;13).
There are a number of case control studies for the use of codeine during pregnancy which have conflicting
outcomes.
In two studies involving 141 infants with cardiac defects and 538 infants with neural tube defects , no association
was observed between exposure to codeine during the first trimester and an increased risk of anomalies (13). In
a survey of 390 infants exposed to several drugs including codeine, matched to 1254 normal infants, a higher rate
of congenital heart defects was found in the exposed infants (12). Two cohort studies, however, found no
increase in malformations in infants of 630 women who had used codeine during the first trimester and no specific
pattern of malformations, but the method of data collection do not allow for a causal relationship to be established
(13).
The use of codeine during pregnancy was assessed in two large surveillance studies. The first one (563 first
trimester exposures and 2552 exposures at any time during pregnancy), showed no evidence suggesting links to
major or minor malformations. It did show possible associations to respiratory tract or genitourinary defects,
umbilical or inguinal hernias, pyloric stenosis and hydrocephaly but this is yet to be independently confirmed (12),
In the second surveillance study (7640 newborns exposed to codeine during the first trimester), 375 major birth
defects were observed (325 were expected based on population data). Although the total number of defects was
greater than expected; the observed incidences of cardiovascular defects, oral clefts, spina bifida, polydactyly,
limb reduction defects and hypospadias were similar to those expected. Confounding factors such as maternal
disease, concurrent drug use and chance may have been involved (12).
In other case control studies, involving over 2000 infants who had first trimester exposure to an opioid (codeine
being the most common), a variety of anomalies were reported including cleft lip and palate, inguinal hernias and
musculoskeletal defects (12).
From the NHS Evidence Website www.evidence.nhs.uk
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Medicines Q&As
The UK Teratology Information Service (UKTIS) has data on 107 pregnancy outcomes where maternal use of
codeine was reported (13). Of the 50 pregnancies where codeine was used in therapeutic doses, 28 normal
infants were born. Nine were born with neonatal problems and two had congenital malformations (epigastric
hernia, spina bifida plus bilateral squint), all had been exposed to other medications during pregnancy, including
other analgesics, antidepressants, corticosteroids and anti-infectives. Fifty-two pregnancies were exposed to
codeine overdose. Forty normal infants, including one set of twins, were born, and two infants were born with
congenital malformations (mild positional talipes, right microphthalamus).
The neonatal abstinence syndrome is rare in mothers who are not addicts and there are few case reports. The
mother of one infant used a codeine-containing cough medicine 3 weeks prior to delivery and started using
codeine-containing analgesics 2 weeks before delivery (48mg codeine/day). A second mother consumed 90120mg codeine/day for the last 10 days of pregnancy. Both babies were born with Apgar scores 8-10 and in good
health. Typical symptoms of narcotic withdrawal were noted in all the infants (12). Two cases of perinatal
arterial stroke occurring in two infants whose mothers using codeine-containing cough medicine in the last two
weeks of pregnancy; this may have been due to other factors but the effects of neonatal opiate withdrawal could
not be ruled out.(13)
Overall, data are insufficient to exclude risks but do suggest that therapeutic doses are unlikely to pose
substantial harm to the foetus (12;13). The use of codeine during pregnancy as an analgesic can be justified
when paracetamol alone is not sufficient (10;13). Use of codeine near term, as with other opioids, may cause
neonatal withdrawal syndromes (tremor, jitteriness, poor feeding) and respiratory depression (13). Little
information is available on the outcome of neonates who have neonatal withdrawal symptoms (17).
Dihydrocodeine
No epidemiological studies of congenital anomalies in infants born to women exposed to dihydrocodeine during
pregnancy have been located (12;16). Most data published were confined to the use of dihydrocodeine during
labour and, as with other opioids, the use of dihydrocodeine near term or during labour has been associated with
respiratory depression in the neonate (12;16).
The UKTIS has prospective follow-up data on 93 cases of women exposed to dihydrocodeine during pregnancy
up to June 2011 (16). In 67 of these cases, dihydrocodeine was used therapeutically and 50 babies were born, of
which 42 were classed as normal infants. In the seven babies with neonatal problems at birth and the one who
was born with a congenital abnormality, the mothers had taken other medications during pregnancy, including
antidepressants, benzodiazepines, illicit drugs and alcohol. There were 10 elective terminations, six spontaneous
abortions and one intrauterine death. In 14 of the 93 pregnancies, dihydrocodeine was taken in overdose
(>240mg/day); eight healthy babies were born out of the 10 resulting live births. Of the two who were not healthy,
one developed deafness and the other had an immature right hip. The frequency of congenital malformations in
both groups (1/50 and 0/14) was not significantly higher than the background rate. Retrospective follow-up data
are available for 12 pregnancies following therapeutic exposure to dihydrocodeine (16). One baby was exposed
to a range of analgesics in the third trimester and born with hydrops fetalis, subsequently dying in the neonatal
period. All of the other eleven live births had been exposed to other medications during pregnancy, including
other analgesics, antidepressants, illicit drugs, warfarin and alcohol. Opioid withdrawal symptoms, irritation and
poor feeding occurred in those exposed in the third trimester.
The limited data that are available for the use of dihydrocodeine during pregnancy do not indicate an increased
risk of foetal toxicity (16). If an opioid is required during pregnancy, codeine would be the first choice as there are
more data available of its effects on the foetus. As with other opioids, neonatal respiratory depression may occur
on maternal exposure to dihydrocodeine near term (10;12).
Tramadol
No epidemiological studies on the effects of tramadol use in human pregnancy have been located (12;15). Some
animal studies showed embryotoxic and fetotoxic effects at maternally toxic doses, 3-15 times the maximum
human dose or higher, but no foetal toxicity was observed with lower doses that were not maternally toxic and no
teratogenic effects were seen with any of the doses (12). Other teratogenicity studies in mice and rats injected
with tramadol doses up to 120 mg/kg and 60 mg/kg, respectively did not show an increase in visceral or skeletal
abnormalities in the offspring or adverse effects on litter size or foetal weight (15).
There are a few case reports of tramadol withdrawal symptoms in the neonate, and some have been published
with scant information (18-20). Up to 450mg/day of tramadol was used during pregnancy to treat, most
commonly, backache; no further details on individual trimester exposure were given. Apgar scores, when
reported, were 9-10, apart from in one baby who had a score of 0 and required resuscitation after birth. The first
signs of tramadol withdrawal were seen 10 hours to 2 days after birth, and symptoms included crying fits,
agitation, tremor, poor feeding, vomiting, jerky movements and convulsions. None of the case studies gave any
details as to whether any congenital abnormalities occurred. There are three other case reports of healthy babies
born with no congenital anomalies following tramadol exposure throughout pregnancy (15).
From the NHS Evidence Website www.evidence.nhs.uk
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Medicines Q&As
The UKTIS has prospective data on pregnancy outcomes of 51 pregnancies exposed to tramadol at various
stages (15). Of the 39 prospective therapeutic exposures, the frequency of congenital malformations in live-born
infants (4/31) was not significantly higher than the background rate, although data were inadequate to exclude an
increase in rates of malformations overall, or specific malformations.
Based on experimental animal models and limited human data, the use of tramadol in pregnancy is not expected
to increase the risk of congenital anomalies. Neonatal withdrawal symptoms have been reported following
tramadol using during pregnancy and infants should be closely monitored for symptoms.
Morphine
No reports linking therapeutic morphine use to major congenital defects have been found and even though
morphine is a metabolite of codeine, data from the use of codeine during pregnancy have not been extrapolated
to morphine use (12). Limited data from the Boston Collaborative Perinatal Project did not suggest an association
between congenital anomalies and gestational exposure to morphine. The frequency of congenital abnormalities
was no greater than expected in the infants of 70 women who took morphine during the first trimester or of the
448 women who took morphine anytime during pregnancy (12). A possible association with inguinal hernia was
observed but causality has not been confirmed (12).
A review described six case reports of morphine exposure from weeks 18 to 30 of gestation, and one report of
morphine exposure throughout pregnancy. Five of the case reports were of women receiving intrathecal or
epidural morphine (4mg/day in three women, 35-60mg/kg/week in one woman, dose not stated in one woman).
The sixth woman received oral morphine 60mg twice a day from weeks 18 to 23, after which the dose was
increased to 360mg/day and paracetamol was added and then at week 32 amitriptyline 50mg and ketamine were
started. No major birth defects were reported from these cases. Two infants were full term and others were
delivered between 30 to 37 weeks. All were healthy, with the exception of the one born at 33 weeks to the mother
who received oral morphine plus other analgesia; the baby required ventilator support for 12 hours but did not
show signs of neonatal opioid withdrawal (21).
The UKTIS has prospective data on therapeutic exposures of 30 pregnancies to morphine (14). Of the 24 live
births, 19 were normal infants and of the five that had been exposed to other medications including other
analgesics, antibiotics, corticosteroids and anti-emetics, four infants had neonatal problems and one had a minor
congenital malformation. No major congenital malformations were reported. Three elective terminations and
three spontaneous abortions occurred in the first trimester.
The data available do not suggest that the use of morphine during pregnancy increases the risk of foetal toxicity
but is too limited to state that no increased risk exists (14). As with other opioids, neonatal respiratory depression
may occur on maternal exposure to morphine near term as it has been observed in neonates exposed to
morphine during labour (10;12) . Long term use has been associated with neonatal withdrawal syndrome;
symptoms seen included tremors, irritability, sneezing, diarrhoea, vomiting and occasionally seizures (10).
Limitations
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Data on exposure of human pregnancies to codeine were inconsistent. Limitations on methodologies
with possible bias did not allow causal relationship of anomalies to be established. Data available for all
opioids in this Q&A were inadequate to rule out risks completely.
Evidence of pregnancy outcomes of drug exposure is usually based on case control or cohort studies
due to ethical grounds. Limitations of these studies included other factors which need to be considered,
such as concurrent maternal diseases and other drug therapies that may have been taken. Prospective
data may also subject to reporting bias.
Opioids other than codeine, dihydrocodeine, tramadol and morphine have not been considered in this
Q&A.
This Q&A only provides guidance on the therapeutic use of opiates as analgesics and not as substitution
therapy for opioid abuse. Opioids in these two distinctive clinical indications with regard to their toxicity in
pregnancy should be evaluated differently.
This Q&A does not discuss the following:
o opioid-containing combination analgesics
o use in mothers with long-term serious conditions including renal impairment or liver disease
o long-term effects of opioids on infants exposed in utero.
From the NHS Evidence Website www.evidence.nhs.uk
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Medicines Q&As
References
(1)
British National Formulary, 64th edition. September 2012. Ed. Ryan RSM. British Medical Association
and Royal Pharmaceutical Society of Great Britain. Accessed via: www.bnf.org.
(2)
Rathmell JP, Viscomi CM, Ashburn MA. Management of non-obstetric pain during pregnancy and
lactation. Anesth Analg 1997; 85:1074-1087.
(3)
Marcus DA. Managing headache during pregnancy and lactation. Expert Rev Neurotherapeutics 2008;
8(3):385-395.
(4)
Pennick VE, Young G. Interventions for preventing and treating pelvic and back pain in pregnancy.
Cochrane Database of Sytematic Reviews 2007;(2):Art. No: CD001139.
(5)
Brandes JL. Headache related to pregnancy: management of migraine and migraine headache in
pregnancy. Current Treatment Options in Neurology 2008; 10:12-19.
(6)
National Collaborating Centre for Women's and Children's Health. Antenatal care: routine care for the
healthy pregnant woman. Clinical Guidelines March 2008. NICE
http://www.nice.org.uk/nicemedia/pdf/CG62FullGuidelineCorrectedJune2008.pdf Accessed on 06/06/08.
(7)
Pain relief during pregnancy. May 2012. UK Teratology Information Service Available at:
www.toxbase.org. Accessed on 30/10/12.
(8)
Kennedy D. Analgesics and pain relief in pregnancy and breastfeeding. Australian Prescriber 2011;
34(1):8-10.
(9)
Wang S-M. Backaches related to pregnancy: the risk factors, etiologies, treatments and controversial
issues. Curr Opin Anaesthesiol 2003; 16:269-273.
(10)
Schaefer C. Drugs during pregnancy and lactation. Second edition. Amsterdam: Elsevier Science B.V.,
2008.
(11)
Babb M, Koren G, Einarson A. Treating pain during pregnancy. Can Fam Physician 2010; 56:25-26.
(12)
Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9th edition. Philadelphia:
Lippincott, Williams & Wilkins, 2011.
(13)
Use of codeine in pregnancy. February 2009. UK Teratology Information Service Available at:
www.toxbase.org. Accessed on 29/10/12.
(14)
Use of morphine in pregnancy. February 2012. UK Teratology Information Service Available at:
www.toxbase.org. Accessed on 29/10/12.
(15)
Use of tramadol in pregnancy. November 2010. UK Teratology Information Service Available at:
www.toxbase.org. Accessed on 29/10/12.
(16)
Use of dihydrocodeine in pregnancy. June 2011. UK Teratology Information Service Available at:
www.toxbase.org. Accessed on 29/10/12.
(17)
Khan K, Chang J. Neonatal abstinence syndrome due to codeine. Arch Dis Child 1997; 76:F59-F60.
(18)
Borna H, Borna S. Tramadole withdrawal in a neonate: a case report (abstract only). Tehran University
Medical Journal 2012; 70(6):389-392.
(19)
Rodor F, De La Gastine B, Boyer M et al. Tramadol withdrawal in neonates (conference abstract).
Fundam Clin Pharmacol 2011; 25(Supp 1):92.
(20)
Willaschek C, Wolter E, Buchhorn R. Tramadol withdrawal in a neonate after long-term analgesic
treatment of the mother. Eur J Clin Pharmacol 2008; 65:429-430.
(21)
Wunsch MJ, Stanard V, Schnoll SH. Treatment of pain in pregnancy. Clin J Pain 2003; 19(3):148-155.
From the NHS Evidence Website www.evidence.nhs.uk
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Medicines Q&As
Prepared by
Alexandra Denby, Regional MI Manager, London MI Service (Northwick Park)
Contact
nwlh-tr.medinfo@nhs.net
Date Prepared
October 2012
Checked by
Sheena Vithlani, Principal pharmacist, London MI Service (Northwick Park)
Date of check
November 2012
Search strategy
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Embase [terms used: (PREGNANCY AND [MORPHINE OR CODEINE OR TRAMADOL OR
DIHYDROCODEINE] AND exp PAIN/dt) [Limit to: English Language and Humans and Publication Year
2010-Current]].
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Medline [terms used: ([MORPHINE OR CODEINE OR TRAMADOL OR dihydrocodeine.af] AND
PREGNANCY and exp PAIN/dt [Limit to: English Language and Humans and Publication Year 2010Current])
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In-house Database/resources
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Cochrane
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DARE
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NICE
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NTIS
From the NHS Evidence Website www.evidence.nhs.uk
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