Agatha S. Critchfield, MD

Clinical colleagues in psychiatry have given us a new definition, framework and context for assessment of OUD with the publication of the Diagnostics and Statistical Manual 5 (DSM-5) in 2013.

 The longstanding model and language of substance abuse and dependence have been largely replaced by a single disorder along a continuum of mild to severe. The current language used to describe a substance problem was updated to reflect changing patterns of abuse. Criteria were changed to better account for cultural and socioeconomic effects on populations. 

Treatment for OUD in pregnancy must include a multifaceted, comprehensive approach as behavioral interventions, psychosocial support and medication administration have been shown to improve maternal and neonatal outcomes.

 Pharmacotherapy for treatment of OUD (referred to as medication-assisted therapy [MAT]) has been utilized in pregnancy since the 1970s.

 Initially this was achieved with methadone and later with buprenorphine-based products. The benefits of MAT use in pregnancy stem from avoidance of symptomatic withdrawal. When cyclic use and withdrawal from illicitly obtained opioids is controlled, patients have the opportunity to establish and maintain medical and prenatal care and to address comorbid conditions. This reduction in medical and social risks associated with substance use in pregnancy leads to improved social, obstetric, and neonatal outcomes.

The opioid crisis: Prenatal and postnatal care

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013.

Winklbaur B, Kopf N, Ebner N, Jung E, Thau K, Fischer G. Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates. Addiction 2008;103:1429-40

Kosten TR, George TP. The Neurobiology of Opioid Dependence: Implications for Treatment. Science & Practice Perspectives. 2002;1(1):13-20.

NIH National Institute on Drug Abuse. Medications to treat opioid addiction. 

https://www.drugabuse.gov/publications/research-reports/medications-to-treat-opioid-addiction/overview

Jones HE, Martin PR, Heil SH et al. Treatment of opioid-dependent pregnant women: clinical and research issues. 

Articles

If a patient exhibits at least two of these 11 behaviors, it may signal a problematic pattern of opioid use leading to clinically significant impairment or distress.

OUD diagnostic criteria

 is a full agonist of the µ-opioid receptor and has been utilized since the 1970s as the standard treatment for OUD in pregnancy.

 It is dispensed on a daily basis by registered comprehensive addiction treatment programs. Currently, it is not legal for physicians outside of such licensed treatment facilities to prescribe methadone to treat OUD (although the drug can be prescribed on an inpatient basis for continuation or initiation of MAT). All providers should be aware that potential significant medication interactions exist with methadone – including, but not limited to, some nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors, antiretroviral medications, protease inhibitors, tricyclic antidepressants or rifampin. In addition, there is a risk of maternal respiratory depression and QTc prolongation.

 is a partial agonist of the µ-opioid receptor, thereby giving it an improved safety profile. It decreases the activity of full opioid agonists (e.g., methadone, heroin, morphine, oxycodone). Accumulated recent evidence supports use of buprenorphine in pregnancy

 and it is available as either a mono-product (buprenorphine alone, Subutex) or as a combined product with naloxone (buprenorphine/naloxone, [e.g., Suboxone). The naloxone component is not active if taken in the proper fashion (sublingually); however, a patient will experience significant withdrawal symptoms if she injects the medication (naloxone is an opioid antagonist that will displace opioids from receptors). For that reason, the combined product is used to prevent improper intravenous use of the buprenorphine. Historically, providers have had concerns about providing the combined product in pregnancy; however, accumulating data support use of buprenorphine/naloxone in pregnancy.

For more information on OUD in pregnancy -

1. American College of Obstetricians and Gynecologists. Opioid use and opioid use disorder in pregnancy. Committee Opinion No. 711. Obstet Gynecol. 2017;130:e81–94.

2. Jones HE, Kaltenbach K, Heil SH e tal. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320-2331.

3. Debelak K, Morrone WR, O’Grady KE, Jones HE. Buprenorphine + naloxone in the treatment of opioid dependence during pregnancy-initial patient care and outcome data. Am J Addict. 2013;22(3):252-254.

4. Lund IO, Fischer G, Welle-Strand GK et al. A Comparison of Buprenorphine + Naloxone to Buprenorphine and Methadone in the Treatment of Opioid Dependence during Pregnancy: Maternal and Neonatal Outcomes. Subst Abuse. 2013;7:61-74.

Both treatmetn methods require careful considerations when determining how to care for pregnant patients with OUD.

Methadone vs buprenorphine in pregnancy

The nation is in the midst of an opioid crisis and the statistics are staggering. The Centers for Disease Control and Prevention (CDC) reports that 2 million Americans are addicted to opioids.

 Opioid use in pregnancy has mirrored the general population, increasing each year.

 The escalation of use in pregnancy has brought a concurrent rise in the rates of infants born with Neonatal Abstinence Syndrome (NAS) and a tragic increase in overdose deaths. Opioid Use Disorder (OUD) is a medical condition characterized by a problematic pattern of opioid use that causes clinically significant impairment or distress (Table 1). It is sometimes referred to as opioid use or dependence or addiction.

 Ob/gyns are on the front lines of this epidemic and have a responsibility to recognize, treat, refer and advocate for the pregnant women with OUD. Understanding the biology, epidemiology, evaluation, and current data regarding effective treatment options during pregnancy is necessary in order to have a framework for treating this complex disease.          

Opioids have a powerful effect on the brain - both positive and negative. Opioids are natural or synthetic chemicals that interact with mu receptors on nerve cells in the gastrointestinal tract, spinal cord and the brain, thereby reducing feelings of pain.

 This class of drugs includes the illegal drug heroin, synthetic opioids such as fentanyl, and pain medications available legally by prescription, such as oxycodone, hydrocodone, codeine, morphine, and many others. Although these drugs are generally considered safe when taken for a short time and as prescribed by a physician, the individual response to them varies markedly. Although not completely understood, there is great heterogeneity in mu receptor structure, functional activation and localization within the cells and regions of the brain.

 This diversity may, in part, account for the varied responses seen clinically. In addition, opioids are also known to disrupt the neuronal machinery of the brain-reward center. When in balance, the cells in the ventral tegmental area (VTA) produce dopamine and release it into the nucleus accumbens (NAc), giving rise to feelings of pleasure. Feedback from the prefrontal cortex back to the VTA helps us overcome drives to obtain pleasure through actions that may be unsafe or unwise. However, this feedback has been noted to be dysregulated in individuals who later develop substance use disorders.

Addiction is a complex brain disorder characterized by compulsive drug seeking despite extremely negative consequences. Repeated exposure to escalating dosages of opioids alters the brain, causing 2 different but interrelated clinical problems: tolerance and dependence.

 Tolerance is characterized by the need to take escalating dosages of a drug to achieve the same effect. Dependence is the susceptibility to withdrawal symptoms in the absence of the drug. 

With addiction, this powerful biological effect of opioids is translated into a set of behaviors that are challenging for the individual, family, community and society as the reward center of the brain and drug seeking becomes the dominant and all-consuming focus for the individual.

The National Institute of Drug Abuse (NIDA) reports that 20% to 30% of patients prescribed opioids for chronic pain misuse them. About 10% of those prescribed opioids for chronic pain will develop OUD. An estimated 5% who misuse prescription opioids will transition to heroin. Of those currently using heroin, 80% started their addiction by misusing prescription opioids.

OUD and consequent overdose deaths have reached an all-time high.

 In February 2018, the National Institutes of Health reported that 115 deaths occurred daily because of opioid overdose.

 The CDC estimates that 64,070 people living in the United States died from overdoses (all kinds) in 2016, an increase from 52,404 overdose deaths in 2015.

 Fentanyl was the number one cause fueling this dramatic increase and responsible for almost 17,000 deaths.

 Drug overdose is now the leading cause of accidental death (categorized as poisonings at the CDC) in the United States, surpassing motor vehicle crashes in 2011. Although death is a tragic outcome and an important metric, the societal cost is far broader, affecting families, children, the workforce, penal system, healthcare and communities. NIDA estimates that the financial cost is over $600 billion each year.

NEXT: Diagnosing and treating OUD in pregnancy

 The longstanding model and language of substance abuse and dependence have been largely replaced by a single disorder along a continuum of mild to severe. The current language used to describe a substance problem was updated to reflect changing patterns of abuse. Criteria were changed to better account for cultural and socioeconomic effects on populations (Table 1).

While a review of behavioral interventions is beyond the scope of this article, we will review currently available pharmacotherapies for pregnant women with OUD, and briefly discuss accumulated evidence regarding Medication-Assisted Withdrawal (MAW).  

Methadone is a full agonist of the µ-opioid receptor and has been utilized since the 1970s as the standard treatment for OUD in pregnancy.

 It is dispensed on a daily basis by registered comprehensive addiction treatment programs. Currently, it is not legal for physicians outside of such licensed treatment facilities to prescribe methadone to treat OUD (although the drug can be prescribed on an inpatient basis for continuation or initiation of MAT). All providers should be aware that potential significant medication interactions exist with methadone – including, but not limited to, some nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors, antiretroviral medications, protease inhibitors, tricyclic antidepressants or rifampin. In addition, there is a risk of maternal respiratory depression and QTc prolongation. 

Some data suggest that physiologic changes in pregnancy may require dose adjustments.

 This is not universal, however, and should be based on evidence of withdrawal rather than provided reflexively. Other studies have supported the use of split dosing with methadone to reduce maternal symptoms of withdrawal.

Buprenorphine is a partial agonist of the µ-opioid receptor, thereby giving it an improved safety profile. It decreases the activity of full opioid agonists (e.g., methadone, heroin, morphine, oxycodone). Accumulated recent evidence supports use of buprenorphine in pregnancy

 In our own OUD in pregnancy program, we utilize the combined product. 

Buprenorphine can be prescribed by specially licensed physicians in private office settings. Currently available evidence suggests that, while the absolute risk of developing NAS remains the same (approximately 50% of infants), those infants exposed prenatally to buprenorphine (rather than methadone) will experience NAS that is shorter and easier to treat.

 No long-term neurodevelopmental outcome data are yet available. Providers should be aware that buprenorphine is rarely associated with hepatotoxicity and that concurrent use of benzodiazepines (or other sedatives such as alcohol) significantly increases risk of overdose.

 It should be noted that polysubstance abuse is extremely common. As such, providers should be aware of the potential need for concurrent evaluation and treatment for other substance use disorders. 

Providers interested in learning more about buprenorphine licensing are encouraged to visit 

https://www.samhsa.gov/medication-assisted-treatment/buprenorphine-waiver-management

For a comparison of methadone vs buprenorphine, see Table 2. 

Next: Medication assisted withdrawal (MAW)

This approach involves stabilizing a patient with OUD with opioids (often methadone or buprenorphine) and subsequent slow, tapered withdrawal of that medication. Historically, MAW was discouraged in pregnancy due to concerns about fetal stress.

 However, recent data indicate that slow, controlled MAW is unlikely to be associated with poor obstetric outcomes. Regardless, the concern for maternal relapse rates remains high and long-term maternal complication and relapse rates have not been evaluated.

for pregnant women with OUD, MAT remains the recommended therapy of choice.

Women on MAT should have their medication doses continued through their labor and postpartum courses. Epidural and spinal anesthesia are appropriate unless contraindicated. Patients maintained on methadone for MAT should NOT receive partial opioid agonist-antagonists such as butorphanol, nalbuphine, or pentazocine because that may precipitate withdrawal. Postoperative pain can be successfully treated with acetaminophen, nonsteroidal anti-inflammatory drugs and full agonist opioids such as oxycodone) as needed. Many patients with a history of OUD experience hypersensitivity to pain and poor pain tolerance although that most often occurs in the first 24 hours post-cesarean-when it can be expected that patients may require extra pain medication (up to 50% more). There is no evidence to support increased incidence of relapse in patients on MAT who receive properly prescribed opioid medications for pain control.

As long as no contraindications exist, breastfeeding should be encouraged. The benefits to both mother and infant are numerous, including improvement in NAS. 

Upon discharge and in follow-up, careful communication with the prescribing provider and psychosocial support services are essential. 

Neonatal abstinence syndrome (NAS) is the postnatal withdrawal syndrome experienced by infants who are exposed to opioids, either illicit or prescribed. While NAS is generally considered to be less severe in infants exposed to prescribed MAT, published rates vary (30%–80%). Symptoms usually evolve over 12 to 72 hours (up to 120 hours).

Development and severity of NAS likely depends on the interaction of several factors including substance exposure/timing, gestational age, genetic/epigenetic factors, smoking, polysubstance use and/or other medications.

 Development of NAS does not appear to be related to the dose of MAT that patients are prescribed.

Many hospitals have protocols for observation and treatment of NAS. While usually treated pharmacologically, NAS is also treated with adjunctive, non-pharmacologic methods such as massage.

 Rooming-in has been shown to both decrease NAS rates and improve maternal-neonatal bonding.

 Breastfeeding is associated with improved bonding, decreased rates of NAS, less need for medication and shorter hospital stays.

In July 2017 in response to the opioid crisis, Dr. Nora Volkow (NIDA Director) and Dr. Francis Collins (NIH Director) jointly published a special report in 

 outlining major strategic initiatives intended to focus research on new therapies for treatment of overdose along with new therapies that target the neurobiology of chronic pain and addiction.

 In summary, what one may take from this call to action is that all hands must be “on deck” as we move forward into the future. Public and private funding sources must partner and all clinicians, including ob/gyns, must embrace the consideration of new treatment options for OUD, even in pregnant and parenting women, as research becomes available. This includes the possibility of new formulations of existing medications, novel modulation of the brain-reward circuitry or vaccines for substances of abuse. As ob/gyns in 2018, our response to this crisis must be to understand the powerful effect of opiates, become good stewards of our prescribing privilege and understand the resources available in our communities for evaluation and treatment.

Disclosures: The authors report no potential conflicts of interest with regard to this article.

1. Centers for Disease Control and Prevention. Prevent Opioid Use Disorder. 

https://www.cdc.gov/drugoverdose/prevention/opioid-use-disorder.html

2. NIH National Institute on Drug Abuse. Dramatic Increases in Maternal Opioid Use and Neonatal Abstinence Syndrome. 

https://www.drugabuse.gov/related-topics/trends-statistics/infographics/dramatic-increases-in-maternal-opioid-use-neonatal-abstinence-syndrome

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https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis

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https://www.cdc.gov/drugoverdose/epidemic/index.html

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https://www.drugabuse.gov/related-topics/trends-statistics

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11. Winklbaur B, Kopf N, Ebner N, Jung E, Thau K, Fischer G. Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates. Addiction 2008;103:1429-40

12. NIH National Institute on Drug Abuse. Medications to treat opioid addiction. 

13. Jones HE, Martin PR, Heil SH et al. Treatment of opioid-dependent pregnant women: clinical and research issues. 

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17. Debelak K, Morrone WR, O’Grady KE, Jones HE. Buprenorphine + naloxone in the treatment of opioid dependence during pregnancy-initial patient care and outcome data. 

18. Lund IO, Fischer G, Welle-Strand GK et al. A Comparison of Buprenorphine + Naloxone to Buprenorphine and Methadone in the Treatment of Opioid Dependence during Pregnancy: Maternal and Neonatal Outcomes. 

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 https://www.samhsa.gov/medication-assisted-treatment/treatment/buprenorphine

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25. Volkow ND, Collins FS. Role of science in addressing the Opioid crisis. 

Ob/gyns are on the front line of the opioid epidemic and have a responsibility to recognize, treat, refer, and advocate for pregnant women with opioid use disorder.