science of Medicine

Opioid Use Disorder and Pregnancy

by Frederick T. O’Donnell, MD & Daniel L. Jackson, MD

Advances in health Abstract drug overdoses than have died in motor

information technology Over-prescription of opioid vehicle crashes, with young adults aged
have given providers pain medications and increases 18-25 being affected the most.7 The
increased leverage in in heroin use have contributed to estimated annual cost of substance use
the sharp rise in opioid-related disorders in the U.S., including direct
confronting the burden health care costs, lost productivity, and
hospitalizations and overdose
of substance use deaths among young adults in costs related to violence and crime, is
disorders. the United States, including $442 billion.8 Abuse of prescription
pregnant women. This has imposed drugs has become so prevalent that
substantial direct and indirect Federal, State, and local agencies,
costs to our nation’s health care including the Surgeon General, have
system. Effective treatment with called on all physicians and public health
methadone and buprenorphine is agencies to improve prevention efforts,
available, but significant barriers to diagnosis and management strategies,
care may restrict access for many. and to modify prescribing practices in
Improved screening tools and order to combat the growing problem of
expanded access to treatments for OUD in the United States.9
substance use disorders are keys to
addressing the epidemic of opioid History
use disorder. In the 1990s, there was renewed
attention on the under-treatment of
Introduction chronic pain as a public health problem
Opioid Use Disorder (OUD), a in the United States. The Institute
problematic pattern of opioid use that of Medicine report, Relieving Pain in
causes clinically significant impairment America,10 called for more frequent and
or distress,1 has become epidemic comprehensive assessment of pain
in the United States, due largely to (the “5th vital sign”) by physicians in
the over-prescription of opioid pain all specialties, including primary care.
relievers during the past two decades. Many physicians, inadequately trained in
Since 1999, the number of opioid treating chronic pain, found themselves
prescriptions has quadrupled, as have caught between overprescribing opioids
the number of drug overdose deaths and undertreating pain. Over the next
in the U.S., 60% of which involve decade, liberal prescribing practices
opioids including heroin.2,3 In 2014, and the aggressive marketing of long
opioids accounted for a record 28,647 acting, extended release formulations
overdose deaths in the U.S.4 In that of opioids (e.g., OxyContinTM) had
Frederick T. O’Donnell, MD, (left), Assistant same year, heroin was involved in 338 of some unintended consequences. The
Professor of clinical Anesthesiology, Missouri’s 1,067 drug overdose deaths.2 increase in opioid prescribing coincided
department of Anesthesiology and In 2012, U.S. physicians wrote 259 with increased rates of opioid addiction,
Perioperative Medicine; Daniel L. Jackson,
MD, (right), Assistant Professor of Clinical million opioid prescriptions, many for overdose deaths and hospitalizations,
obstetrics and Gynecology, department patients, including pregnant women, and entry into drug treatment
of Obstetrics, Gynecology and Women’s with chronic, non-cancer related pain.5,6 programs.11 Practitioners, and the
Health, University of Missouri Women’s and
Children’s Hospital, Columbia, Missouri. Each year since 2013 more Americans, medical community in general, largely
Contact: [email protected] including Missourians, have died of overestimated the efficacy of opioids in

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treating chronic pain and underestimated their associated risks nearly $3,000 (U.S.) to less than $500.23 One of the authors
of addiction, overdose, and death. Although very effective (FTO) has been told by a patient at the University of Missouri
for the short term treatment of acute pain with a low risk of with OUD that a gram of pure heroin can be purchased for
addiction, 12 prolonged use of opioid analgesics (i.e., greater as little as $200 in Columbia, Missouri. The gram is then
than six weeks) for chronic, non-cancer related pain is not typically divided into 10 “hits” that are sold individually.
efficacious for reducing pain scores or improving functionality
or quality of life.13 Further, the risk of addiction for patients on Management of Opioid Use Disorder
long term opioid therapy for chronic pain is estimated to be The diagnostic criteria for opioid use disorder include
26-35%.14, 15 the development of tolerance, and a strong desire or urge to
In response to the epidemic of OUD, State and Federal use opioids (craving) despite negative social, occupational, and
agencies have tightened regulatory controls on the dispensing financial consequences.1 Patients who abruptly discontinue
and sale of prescription pain medications. In October 2016, opioids, voluntarily or otherwise, after long term regular
the DEA announced new regulations that will reduce the use are at risk for the physical and psychologic symptoms
manufacture of some prescription opioids by 25-34% in of acute opioid withdrawal, which include pain, autonomic
2017.16 To assist efforts at the state level, the Centers for hyperactivity, sweating, nausea, vomiting, diarrhea, anxiety, and
Disease Control and Prevention (CDC) has developed the insomnia. Withdrawal symptoms occur when opioids rapidly
“Prevention for States” program, which provides funding to dissociate from their receptors in the brain and spinal cord.
states with innovative solutions to address prescription drug Avoidance of withdrawal symptoms is one reason that patients
overdose and abuse. Twenty-nine states (Missouri is not with opioid use disorder continue to use and misuse opioids,
included) have received a share of these funds to institute even though they may wish to stop.
safer prescribing practices. Prescription Drug Monitoring The standard of care for treating opioid use disorder
Programs (PDMPs), electronic databases that track the is medication-assisted treatment (MAT) that combines
statewide prescription and dispensing of controlled substances, daily medically-supervised administration of FDA-approved
have been instrumental in limiting opioid prescribing in medications with behavioral therapy and counseling.24 MAT
some states. Laws requiring prescribers in New York and is effective in facilitating recovery from OUD, preventing
Tennessee to query their state’s PDMP prior to prescribing relapses, improving social and occupational functioning, and
opioid analgesics have been effective in reducing the number in reducing criminal behavior and the spread of infectious
of patients filling multiple prescriptions for the same drugs diseases.25 The most effective treatment for withdrawal
(“doctor shopping”).17 Similar laws in Florida have stopped remains opioid replacement therapy with long acting opioids
high volume pain clinics (“pill mills”) from prescribing and such as methadone and buprenorphine. These medications
dispensing large quantities of opioid analgesics to patients with prevent withdrawal symptoms and opioid cravings by
no justifiable need for them. Since 2010, overdose deaths in continuous occupation of endogenous opioid receptors.
Florida due to oxycodone have decreased by 50%.18 Despite Methadone, a full agonist at the endogenous mu opioid
being in the second highest quartile of opioid prescriptions per receptor, has long been the mainstay of treatment for opioid
100 people, Missouri is the only state without a PDMP.19 addiction. Methadone has a long half-life and is ideally suited
for once daily oral dosing, but it carries the risks of respiratory
Heroin depression and is among the most commonly implicated
Although regulatory efforts to curtail opioid prescribing prescription opioids in overdose deaths.26 Despite its risks,
have reduced the supply of prescription opioids, demand by methadone has been shown to reduce mortality in patients
non-medical users remains high because of the experiences with opioid use disorder by half.27 Methadone is available only
or feelings they cause. Increasingly since 2005, heroin has from federally-regulated specialty clinics approved to prescribe
filled this void as an inexpensive, readily available, and easy- and dispense the drug to patients who meet strict inclusion
to-use alternative to prescription opioids. According to the criteria. Most states provide Medicaid coverage for methadone
2015 U.S. National Survey on Drug Use and Health, over maintenance therapy, but most of the 17 states that do not are
300,000 American adults reported using heroin in the past located in areas of the U.S. with high rates of OUD and heroin
year.20 The number of overdose deaths from heroin increased use (e.g., the South, Midwest, and Ohio River Valley).28
from 1,878 in 2004 to 10,574 in 2014, and have tripled since Unlike methadone, buprenorphine is only a partial
2010 when a tamper resistant formulation of OxyContinTM agonist at the mu receptor. This partial activity prevents
was introduced.21 It is estimated that 80% of new heroin users withdrawal, but also blocks the action of full opioid agonists
abused prescription opioids prior to using heroin.22 Over taken concomitantly.29 Buprenorphine is thus limited in its
the past 30 years, the cost of a gram of heroin has gone from potential to cause sedation and respiratory depression, a

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 science of Medicine

figure 1. opioid pain medications.34

The 4Ps Plus© Pregnant women with opioid
Parents use disorder are at increased
risk for adverse pregnancy
 Did either of your parents ever have a problem with alcohol or drugs? outcomes including preterm
Partner
labor, fetal death, growth
 Does your partner have a problem with alcohol or drugs? restriction, and neonatal
Past abstinence syndrome, which
increased by 300% from
 Have you ever drunk beer, wine, or liquor?
Pregnancy 2000 to 2009.35,36
Universal screening
 In the month before you knew you were pregnant, how many cigarettes did you smoke? for substance use disorders,
 In the month before you knew you were pregnant, how many beers/how much wine/how
including opioid use
much liquor did you drink?
 In the month before you knew you were pregnant, how much marijuana did you smoke? disorder, is recommended in
Reprinted with permission, NTI Upstream pregnancy, and should occur
at the initial prenatal visit
safety advantage over methadone.30 Buprenorphine is available and be performed again once
as a rapidly dissolving sublingual tablet or buccal film, some per trimester for those who screen positive for past use. This
formulations of which contain small amounts of the opioid should be done using a validated screening tool such as the 4Ps
antagonist naloxone (Narcan ) to deter intravenous injection
TM Plus questionnaire (see Figure 1),37 an instrument to quickly
of the drug. Compared to methadone, buprenorphine is not identify obstetric patients at risk for misusing alcohol, tobacco,
restricted to specialty clinics and is available by prescription and illicit drugs, or the three question set of “In the past
from office-based physicians who are specially trained in year how many times have you had more than four alcoholic
treating opioid use disorder and have DEA approval to drinks per day, used tobacco, or taken illegal drugs or used
prescribe it. Although outpatient buprenorphine therapy is prescription drugs for non-medical purposes?”.38 Screening
covered by Medicaid in all 50 states, it may be inaccessible by means of a questionnaire is recommended over the use of
universal urine drug screens, which have poor sensitivity and
in many areas due to a shortage of physicians licensed by the
specificity for chronic use, and it is essential that the topic
DEA to prescribe it.
of substance use disorder be broached in a non-judgmental
Although both are effective, the choice between
fashion. Care for women with opioid use disorder should be
methadone and buprenorphine depends on individual
approached in a manner similar to that for women with other
patient factors such as proximity to treatment programs.
chronic conditions such as diabetes, chronic hypertension,
Whenever long term opioid therapy is elected for, patients are
obesity, or any of the myriad of maternal comorbidities that
encouraged to participate in educational programs as well as
complicate pregnancy.
cognitive and behavioral therapy such as individual or group The goal of treating maternal OUD is to use the lowest
counseling and participation in self-help groups like Narcotics possible dose of methadone or buprenorphine in order to
Anonymous. Although maintenance therapy with methadone eliminate cravings and withdrawal. While it has traditionally
or buprenorphine can be tapered down over time and in some been taught that maternal withdrawal during opioid
cases discontinued altogether, most individuals require lifelong detoxification is harmful to the fetus, a recent publication by
treatment as relapse rates are high.31 Bell, et al. challenges this notion.39 Patients will frequently
In addition to its proven efficacy, medication-assisted state a desire to wean off of MAT during pregnancy in order
treatment of OUD is cost saving. Every dollar spent on to minimize the risk of neonatal abstinence syndrome (NAS).
treatment of substance use disorders saves $4 in health care We generally recommend against this approach due to the
costs and $7 in criminal justice costs.32 unacceptably high risk of relapse, which ranges from 35 to
75% depending on the intensity of outpatient therapy.
Pregnancy In regards to the fetus, maternal opioid use disorder
Since 2002, the incidence of first time heroin use has carries significant risks. Maternal overdose and the associated
doubled among women and among young adults aged 18-25 risk of coma, aspiration, hypothermia, and cardiovascular
years, a demographic that includes many pregnant women.33 collapse can be life threatening for the developing fetus.
According to the American College of Obstetrics and Neonates exposed to opioids in utero have a risk of neonatal
Gynecology, 1% of pregnant women report nonmedical use of abstinence syndrome (NAS) that is as high as 90%.34

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NAS is characterized by neonatal irritability, temperature activity of buprenorphine. Furthermore, an individual on long
dysregulation, poor feeding, failure to thrive, and in some term buprenorphine therapy with refractory pain is unlikely
cases seizures. This condition may last for up to 10 weeks after to achieve adequate analgesia with typical mu receptor agonists
delivery and may necessitate a prolonged NICU admission.40 (oxycodone, hydrocodone, morphine, etc) because large doses
Some data suggests a lower rate of NAS with buprenorphine of these medications will be necessary to overcome the higher
therapy as opposed to methadone, but this data is far from binding affinity of the buprenorphine.
conclusive.41 Although buprenorphine alone (SubutexTM) has As part of the treatment plan, it is essential to assure
been traditionally preferred over buprenorphine-naloxone patients that the care team will do everything possible to
(SuboxoneTM) for pregnant women due to concerns about the manage the pain associated with labor and delivery and
fetal effects of naloxone, oral naloxone is biologically inert and that the treatment of surgical pain will not increase the risk
a growing body of data supports the safety of buprenorphine- of relapse. If a patient enters prenatal care on MAT, it is
naloxone use in pregnancy. recommended that the same provider continue to manage
The peripartum period is a particularly challenging time her MAT during pregnancy. In cases where MAT is initiated
to provide care for women with OUD. Due to chronic opioid by an obstetric provider, arrangements should be made for
use and the development of tolerance, these individuals may continued treatment with MAT post-partum, which may entail
require larger doses of pain medications than providers are cooperation with a methadone clinic, primary care provider,
typically accustomed to giving. This can lead to the patient or addiction psychiatrist as appropriate. It is also important
being accused of ‘drug seeking behavior’ and her pain going to arrange for consultation between the patient and the
untreated. pediatricians or neonatologists who will be caring for the baby
Our approach to caring for women on MAT at the time after delivery. The care of the child affected by maternal opioid
of delivery is to maximize the use of multimodal analgesia use does not end at delivery and the patient should have an
and to use regional anesthesia whenever possible. Neuraxial opportunity to ask questions regarding the post-partum care
anesthesia (i.e., spinal or epidural) is the preferred method plan.
for both vaginal and cesarean delivery. Of note, there is no Although MAT with either methadone or buprenorphine
contraindication to intrathecal morphine in the setting of is recognized as the standard of care for treating OUD during
MAT use. In women with OUD undergoing vaginal delivery, pregnancy, significant barriers to care exist and prevent more
we also treat pain with acetaminophen and NSAIDS and if than half of pregnant women with OUD from receiving the
necessary increase the dose of methadone or buprenorphine. recommended treatments.43 Many women with OUD live in
In women who continue to have refractory pain, we will use states where methadone is not covered under Medicaid, or
adjunctive opioid therapy in the form of oral medication or live in areas where there are no physicians who are licensed
patient controlled analgesia (PCA) as appropriate (intravenous to prescribe buprenorphine. Women in the criminal justice
or transdermal fentanyl in the setting of buprenorphine system are even less likely to receive standardized care for
use) with early outpatient follow up with the patient’s MAT OUD. In addition to issues relating to accessibility and
provider. funding, women are significantly less likely to receive MAT
Pregnant women on MAT with buprenorphine and (or even to seek prenatal care at all) in states that permit child
methadone require careful attention in regards to medication abuse charges for illicit drug use during pregnancy. Although
interactions. The use of opioid agonist/antagonists such as Tennessee is currently the only state in which a woman can
butorphanol (Stadol™) or nalbuphine (Nubain™) is absolutely face criminal charges for substance abuse during pregnancy,
contraindicated in patients on methadone or buprenorphine 18 states permit civil child abuse charges that may result in
due to the risk of precipitated withdrawal. Additionally, our termination of parental rights. Missouri has no such laws
practice is to avoid the concurrent use of full opioid agonists and does not require drug testing or physician reporting of
with buprenorphine. Because of buprenorphine’s higher suspected substance use disorders during pregnancy.28 Missouri
binding affinity for the mu receptor compared with full is also one of only 12 states that offers pregnant women
agonists (except fentanyl),42 individuals undergoing induction priority access to treatment programs for substance use
of buprenorphine therapy must be free of opioids and in disorders and does not impose limits on the dose or duration
withdrawal before starting buprenorphine. In an individual of buprenorphine therapy.
with opioid dependence who has a full opioid agonist in her
system and is therefore not in withdrawal, giving a dose of Future Directions
buprenorphine will result in the partial agonist buprenorphine The opioid epidemic continues to shape Federal, State,
displacing the full agonist from the mu receptors, which would and local health care policies on substance use disorders. The
in turn precipitate withdrawal due to the lower mu agonist Comprehensive Addiction and Recovery Act, signed into law in

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July 2016, provides new funding for measures to prevent and health care policies that make MAT more widely available and
treat opioid use disorder, and such strategies must continue to integrate it into existing general health care settings, thereby
evolve. improving access to care and reducing the stigma of substance
use disorders. The Office of National Drug Control Policy has
Prevention advocated for therapeutic, rather than punitive, approaches
Primary prevention of substance use disorders depends to addressing opioid use disorder and treating it as a chronic
on effective prevention education. School and community- medical condition rather than a moral failing or lack of
based prevention programs (e.g., Communities that Care) that willpower.
teach skills to resist negative social influences have proven to The 2010 Affordable Care Act (ACA) requires health care
reduce rates of initiation and escalation of alcohol, tobacco, plans to provide coverage for mental health and substance
and drug use among adolescents and young adults.21 Many use disorder services, one of the 10 designated categories
such programs, though effective, are underutilized and poorly of “essential health benefits”.21 However, a relative shortage
implemented. It is estimated that only 8-10% of U.S. high of physicians who are certified to treat patients with OUD
schools utilize evidence-based programs to prevent substance is a significant barrier to delivering care. The 2000 Drug
misuse.44 An emerging field within public health is improving Addiction Treatment Act increased the number of physicians
the implementation and dissemination of evidence-based permitted to prescribe buprenorphine for treating OUD by
prevention programs at the community level, where they are waiving the requirement to obtain a separate DEA registration
most effective. for that purpose. In 2016, the Federal Substance Abuse and
Despite some successful efforts to curtail the prescription Mental Health Services Administration (SAMHSA) increased
and consumption of opioids, opioid pain relievers are still the buprenorphine-naloxone prescriber limit from 100
the most prescribed class of drugs in the United States.45 patients to 275 patients. However, fewer than 4% of office-
Prescription drug monitoring programs have shown promise, based physicians in the U.S. are authorized to prescribe
but in many states they are underutilized because their use buprenorphine as part of MAT, and even fewer obstetricians
is voluntary.46 A national PDMP, or interconnecting those can provide such care. According to SAMHSA, 215 physicians
of individual states could potentially prevent patients from in Missouri are licensed to prescribe buprenorphine, including
crossing state lines to obtain and fill multiple prescriptions, one of the authors (DLJ). Increasing prescribing capacity
but would require further investments in health information will be necessary to meet the increasing demand for OUD
technologies and infrastructure. More widespread adoption treatment. Information on obtaining a DEA physician waiver
of programs such as the CDC Guideline for Prescribing Opioids for for prescribing buprenorphine is available at http://www.
Chronic Pain can help promote responsible and safe prescribing samhsa.gov/medication-assisted-treatment.
practices. Another provision of the ACA allows states to expand
Another key aspect of preventing OUD is stemming Medicaid coverage to include individuals who qualify based
the flow of heroin and illegally produced fentanyl, as well on income, many of whom are affected by, or at risk for
as counterfeit prescription opioids, into the United States. developing, substance use disorders including OUD. This
Most of the heroin sold in the U.S. comes from Mexico expanded coverage includes mental health services and
and South America, where it enters the Southwestern U.S. substance use disorder treatments in addition to general
via established drug trafficking routes.47 Heroin seizures at medical care. Missouri is one of 19 states not currently
the border have tripled over the past five years. In response participating in the voluntary expansion of Medicaid. An
to this, the Office of National Drug Control Policy’s 2015 estimated 3 million people who would qualify for expanded
National Drug Control Strategy includes a Southwest Border Medicaid coverage live in states that don’t participate in
Counternarcotics Strategy to combat drug trafficking and Medicaid expansion.48
organized criminal activity. Similar law enforcement strategies Advances in health information technology have given
are in place at the U.S.-Canada and U.S.-Caribbean borders. providers increased leverage in confronting the burden of
substance use disorders. Telehealth, computerized Prescription
Treatment Drug Monitoring Programs, and electronic medical records
Given the increasing burden of opioid use disorder in allow greater efficiency in treating patients with OUD and
the U.S., we face the formidable public health challenge of have much potential to expand OUD treatment services into
expanding access to proven treatment modalities for people areas where they are currently unavailable. Another barrier to
who need them most. It is estimated that only 1 in 10 persons providing treatment for OUD is a lack of reimbursement for
with a substance use disorder receives medication-assisted screening and counseling services. To this end, the Office of
treatment (MAT). It is therefore imperative to develop National Drug Control Policy is pursuing initiatives to update

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science of Medicine

coding and increase reimbursement for Screening, Brief 23. Compton WM, Jones CM, Baldwin GT. Relationship between nonmedical
prescription-opioid use and heroin use. N Engl J Med 2016;374:154-163.
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Disclosure
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