Semi- synthetic prescription opi- oids include oxycodone, hydromorphone and buprenorphine. Synthetic prescription opioids include pethidine, fentanyl, metha-.
Aust N Z J Obstet Gynaecol 2018; 1–5 DOI: 10.1111/ajo.12823
REVIEW ARTICLE
Prescription opioid use in pregnancy Julie Blandthorn1 , Laura Leung2, Yuan Loke2, D. Martyn Lloyd-Jones3, Robin Thurman1,4, Ellen Bowman1,5 and Yvonne Bonomo1,3,6 1
Women’s Alcohol and Drug Service, Royal Women’s Hospital, Melbourne, Victoria, Australia
2
Pharmacy Department, Royal Women’s Hospital, Melbourne, Victoria, Australia
3
Prescription medications, including opioid analgesics, are increasingly prescribed in Australia and internationally. More women are presenting in pregnancy with prescription opioid use which can potentially cause harm to the mother and fetus. This article outlines the different types of prescription opioids, defines how pre-
Department of Addiction Medicine, St Vincent’s Hospital, Melbourne, Victoria, Australia
scription opioid use disorder presents clinically and suggests a rational clinical
4
their infants.
Maternal Fetal Medicine subspecialist affiliate, Royal Women’s Hospital, Melbourne, Victoria, Australia
5
Newborn Services, Royal Women’s Hospital, Melbourne, Victoria, Australia
approach to assess and manage patients in the context of pregnancy and
KEYWORDS
methadone, neonatal abstinence syndrome, pregnancy, prescription opioids
6
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia Correspondence: Julie Blandthorn, WADS, Royal Women’s Hospital, Locked Bag 300, (or Corner Grattan Sts and Flemington Rd), Parkville, Vic. 3052, Australia. Email: julie.blandthorn@thewomens. org.au Conflict of Interest: No authors have a conflict of interest of any sort. Received: 7 January 2018; Accepted: 2 April 2018
THE PRESCRIPTION OPIOID PROBLEM
pregnancy, there are additional considerations with exposure of the developing fetus to opioids.
Prescription medications including opioid analgesics are increas1
In this article, we outline the different types of prescription
ingly prescribed in Australia and internationally. Since the 1990s,
opioids, define how prescription opioid use disorder presents
opioid dispensing in Australia increased from 500 000 prescrip-
clinically and suggest a rational clinical approach to assess and
tions annually to 7.5 million in 2012 with corresponding increase
manage patients in the context of pregnancy.
in governmental cost from $8.5 million to $271 million.2 These increases in prescribing are at odds with consensus that opioids have limited benefit in the treatment of non-acute pain including
TYPES OF PRESCRIPTION OPIOIDS
chronic non-malignant pain.3,4 It is important all health professionals are aware of the po-
Opioids are substances that act on opioid receptors to produce
tential harms of opioid prescription, including overdose or depen-
analgesia, respiratory depression, sedation, constipation and
dence. Obstetricians and gynaecologists are likely to consult with
euphoric effects.5 Prescription opioids can be classified into nat-
women who misuse prescription opioids, that is, where medica-
ural, semi-synthetic and synthetic compounds. Morphine and co-
tions are used contrary to prescribed directions. In the context of
deine are both prescription opioids that are naturally occurring
wileyonlinelibrary.com/journal/anzjog
© 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
1
2
Prescription opioids in pregnancy
plant-derived compounds.6 Semi- synthetic prescription opi-
collaborative, multidisciplinary team approach that includes ob-
oids include oxycodone, hydromorphone and buprenorphine.
stetrician, psychiatrist, pain specialist, midwife and pharmacist is
Synthetic prescription opioids include pethidine, fentanyl, metha-
recommended to provide appropriate treatment and follow-up
done, alfentanil, remifentanil and tapentadol. Opioids are availa-
care in pregnancy.
ble in various routes of administration including oral, parenteral,
Antidepressants, anticonvulsants, local anaesthetics and clon-
transdermal or rectal; some oral opioids are available in slow or
idine may be used as analgesic adjuvants in the treatment of neu-
immediate release preparations. Tramadol and tapentadol have
ropathic pain in pregnancy. Amitriptyline15 and venlafaxine16 have
opioid-like activity as well as other modes of action: serotonin
not been associated with an increased risk of congenital malforma-
and noradrenaline re-uptake inhibition in the case of tramadol
tions;17,18 however, a neonatal withdrawal syndrome may develop
and noradrenaline reuptake inhibition in the case of tapentadol.
due to prenatal exposure, especially in late pregnancy.18,19 Due
Long- acting oxycodone is the most commonly used and pre-
to the possible risk of teratogenic effects and long-term neuro-
scribed opioid in Australia, whereas in Canada and Germany, the
psychological development, sodium valproate, should be avoided
most common are hydromorphone and fentanyl, respectively.7
in pregnancy.20,21 Other anticonvulsants such as gabapentin22–25 or pregabalin26 have shown no sign of teratogenic effect but the decision to treat should be made on an individual basis by consid-
THE ROLE OF PRESCRIPTION OPIOIDS
ering the risks and benefits to both mother and fetus.
Prescription opioid use during pregnancy is increasing.8,9 When prescription opioids are required for acute pain management during pregnancy, the selection and dosage of opioids should be
POTENTIAL PROBLEMS WITH OPIOIDS DURING PREGNANCY
tailored to the individual response. Treatment should be started with the lowest effective dose to achieve relief of pain and close
There is some evidence to suggest prescription opioid use in the
monitoring of the patients for response and potential side effects
early months of pregnancy may be associated with birth defects,
of treatment.7,9
in particular congenital heart defects, neural tube defects, talipes
Opioids should not be considered first-line therapy for patients with chronic noncancer pain.7
and orofacial clefts.27 However, most studies are retrospective with the potential for confounding and recall bias. Other studies
When prescription opioids are indicated, short-term mono-
have found no such associations.28,29 Therefore, a detailed ana-
therapy is preferred. Opioid requirements beyond 90 days should
tomical survey by ultrasound should be performed, with particu-
prompt clinical review of the management plan.10 Local regula-
lar note of opioid exposure in the pregnancy.
tions vary from state to state and must be followed when pre-
Individuals with a history of addiction or a mental illness are
scribing Schedule 8 medicines (substances and preparations for
at greater risk of misusing prescription opioids.30 Some indicators
therapeutic use which have high potential for abuse and addic-
of or flags for potential opioid misuse may include behaviours
tion) for a continuous period greater than eight weeks. State to
such as: requirement for escalating doses of the opioid without
state regulations are outlined in Appendix 2.
clear clinical reason, reports of lost or stolen prescriptions, other reasons for a repeat prescription before it is due, attending appointments and/or pharmacy while substance affected, pressur-
ALTERNATIVES TO PRESCRIPTION OPIOIDS DURING PREGNANCY
ing the practitioner to prescribe particular drugs, seeking drugs of dependence from other sources (emergency department/general practitioner) forging/altering prescriptions or presence of recent
Paracetamol is usually the first-line analgesia for management
intravenous ‘track’ marks.
of pain in pregnancy.11 It is a non-opioid analgesic, and although the full mechanism of action is not determined, its analgesic effect may include inhibition of central prostaglandin synthesis and modulation of inhibitory descending serotonergic pathways. At
APPROACH TO PRESCRIPTION OPIOIDS IN PREGNANCY
recommended dosages, paracetamol is safe to use in pregnancy.11 Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibu-
It is difficult to ascertain the prevalence of prescription opioid use
profen, diclofenac, celecoxib and meloxicam are usually the sec-
in pregnancy in Australia. However, all pregnant women taking
ond line of analgesia in non-pregnant patients. Due to the risks
prescribed opioids should be assessed for dependence (neuro-
or early pregnancy loss, oligohydramnios, fetal renal injury and
adaptation), risk of withdrawal and potential need for opioid
premature closure of the ductus arteriosus, use of NSAIDs should
treatment.31 Opioid dependence can be prevented through a lim-
12,13
be avoided in pregnancy.
ited timeframe in prescribing for acute pain needs.
Non-opioid analgesics may offer promising alternatives for
Weaning from opioids pre-pregnancy or early in pregnancy
pain management.14 Where chronic pain exists in pregnancy, a
may be possible if the woman is assessed as being unlikely to
3
J. Blandthorn et al.
be opioid dependent, the daily dose is not high (less than 60 mg oral morphine equivalent)4 and if doses are reduced slowly. If the
ADVERSE EFFECTS OF PRESCRIPTION OPIOIDS IN PREGNANCY
woman has considerable neuro-adaptation it will not be possible to reduce the dose of prescribed opioids due to significant with-
Some side-effects of prescription opioids are aggravated in preg-
drawal symptoms. Neuro-adaptation is more likely if the woman
nancy. Constipation may be exacerbated by the opioid action of
is on a high dose of opioids or if she has been on opioids for a
slowing gastrointestinal motility. This can result in haemorrhoids,
prolonged period (over two to three months). Withdrawal symp-
perineal varicosities, rectal pain and bowel obstruction.35
toms include myalgias, arthralgias, rhinorrhoea, agitation, ab-
Overdose resulting in respiratory depression is a real possi-
dominal cramping, muscular cramping, restlessness and during
bility, particularly when opioids are prescribed with other central
pregnancy, threatened preterm labour.
nervous system depressants (eg diazepam or other benzodiaze-
Regular psycho-social support and establishing a therapeutic relationship with a counsellor is needed in many cases to initiate and maintain reductions in taking opioids and include ongoing monitoring of treatment progress.
pines).36 This respiratory depression can have significant effects on fetal morbidity and mortality. In the non-pregnant population on methadone, obstructive sleep apnoea is found in up to 35% of patients and is more common in people with a higher body mass index, longer duration in methadone maintenance treatment and non-Caucasian race.37
OPIOID SUBSTITUTION TREATMENT IN PREGNANCY
These changes may be compounded in pregnancy due the normal
When neuro-adaptation has occurred, the opioid dose to main-
drugs. However, neither agent has been linked with teratogenicity
tain this state usually increases over the course of the pregnancy.
or fetal malformations. The provision of methadone along with
Reasons for opioid dose increase in pregnancy include the rise in
comprehensive care has been shown to provide far greater ben-
volume of distribution due to increased blood volume, increased
efits than risks.39
physiological changes to sleep reported in the peripartum period.38 Buprenorphine and methadone are listed as Category C
metabolism and faster clearance.
32
When pregnant women are
taking methadone, methadone plasma levels are significantly lower during the third trimester compared to earlier trimesters,
OPIOIDS IN THE POSTNATAL PERIOD
hence the need to increase pharmacotherapy doses. Split-dosing may be advantageous for women on high-dose methadone in
Practitioners need to carefully consider discharging women with
the third trimester of pregnancy when metabolism and clearance
opioids following birth due to the risk of dependence and the ef-
31
fect these drugs can have on parenting safety. One study40 in
Maternal treatment of opioid dependence in pregnancy im-
2017 in the US of 164 720 Medicaid funded women who delivered
rates increase and steady-state long-acting opioid levels decline.
proves maternal and neonatal outcomes. For pregnant opioid-
vaginally, showed that one in ten filled an outpatient prescription
dependent women taking high doses of prescription opioid and/
for opioids within five days of discharge.
or demonstrating aberrant behaviours, opioid substitution treatment (OST) should be prescribed. Advantages, disadvantages, medication options and costs must be discussed with the patient prior to commencement of OST. Safe, well- studied options of
ADVERSE EFFECTS OF OPIOID EXPOS URE ON THE NEONATE
OST in pregnancy are either buprenorphine (Subutex® tablets) or methadone (liquid 5 mg/mL). Buprenorphine is a partial opi-
The incidence and severity of neonatal abstinence syndrome
oid agonist; methadone is a full opioid agonist. While methadone
(NAS) is variable and correlates poorly with maternal opiate sub-
maintenance treatment has been the gold standard for more
stitution therapy dosage.41 NAS is influenced by other exposures
than 40 years, buprenorphine poses less risk of respiratory de-
(including maternal prescribed medications, polypharmacy, to-
pression and overdose, particularly if the woman continues to
bacco and alcohol exposure, socioeconomic status), opioid type
use simultaneously other opioids.33 Methadone may be recom-
and breast feeding.41,42 Allelic gene variations (maternal and fetal)
mended over buprenorphine if high doses are required (>100 mg
and epigenetic mechanisms which impact on maternal drug me-
oral morphine equivalent) as higher therapeutic levels are achiev-
tabolism, placental transfer and fetal/infant handling can impact
able.
34
The highest dose of buprenorphine is 32 mg daily at which
point opioid receptor saturation is likely to have been reached.34
NAS development and may, in future, enable more specifically designed mother/infant management.41,42
Buprenorphine formulations can be buprenorphine alone or
Infants who are exposed to regular opiates predominantly in
combined with naloxone. The combination formula was intro-
the last three months of pregnancy whether prescribed or illicit,
duced to diminish the likelihood of buprenorphine being injected.
are at risk of developing drug withdrawal (NAS). NAS manifests
In pregnancy and breastfeeding, the use of buprenorphine only,
following abrupt discontinuation of opioids at birth and indicates
without naloxone (ie Subutex®) is usually advocated.31
the fetus has become neuroadapted in utero.43
4
Prescription opioids in pregnancy
Opioid-exposed infants are assessed from birth for five days for characteristics of NAS using the modified Finnegan scoring tool44 which assesses dysfunction in three domains: central nervous system, autonomic (metabolic/vasomotor/respiratory) and gastrointestinal. Diagnosis of NAS is made on the clinical pre-
A C K NO W L ED G EM ENT S The authors would like to acknowledge the work of the National Naloxone Reference Group and in particular to Ingrid van Beek who provided helpful comments.
sentation of the infant on a background of maternal opioid use. Alternate diagnoses which may cause similar signs must always be considered and investigated appropriately, such as infection, hypoglycaemia and hypocalcaemia.45 Supportive treatment involves non-pharmacological therapy such as a quiet environment, a pacifier, wrapping and cuddling. Pharmacologic treatment commences when the severity of symptoms on the modified Finnegan scoring system reaches a recognised level to commence medication. The scoring system is used to initiate, adjust and wean pharmacological therapy.43 Opioid treatment for opioid withdrawal is the preferred treatment based on the current literature,45,46 usually in the form of oral morphine. In severe cases, concurrent sedation may be indicated where phenobarbital or clonidine is recommended.43,47 While most infants exposed to opioids in pregnancy display some signs of NAS, the incidence of those requiring pharmacological treatment ranges from 2.6 to 16.2/1000 births.48 Involvement of child protection services should be assessed on an individual basis depending on whether the aberrant use of prescription opioids raises concern about the welfare, potential neglect or lack of safety of the infant. Maternal medication with methadone or buprenorphine is not a contraindication to breast feeding. Breastfeeding advice should reflect consideration of all maternal medications and substance use as well as the benefits of breast feeding for mother and infant.
CONCLUSION Obstetricians and other health professionals need to be aware of the potential harms of prescription opioids. A holistic approach including interdisciplinary cooperation is imperative to addressing the abuse of these medications. Women planning pregnancy need to be educated about the appropriate use and potential harms of prescription opioids. Ongoing unwanted side effects of long- term opioids should be monitored for and addressed promptly as they arise. Opioids should not be first-line analgesics but when indicated can be very effective for short-term management of pain. Opioids in pregnancy bring specific issues for consideration including increasing dose requirements and potential for NAS in the newborn. Health professionals need to be aware of the escalating harm of prescription opioids in the community, and be able to respond appropriately to curb this preventable cause of death and disability.
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SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section at the end of the article. Appendix S1. Case study. Appendix S2. Australian state permit information and contact details.
