FDA Boxed Warning on Immediate-Release Opioid Medications and All Prescription Opioids

  • Practice Advisory PA
  • March 2016

(Reaffirmed March 2020)


On March 22nd, 2016, the U. S. Food and Drug Administration (FDA) announced required, class-wide safety labeling changes for immediate-release opioid pain medications. As part of these changes, the FDA is now requiring a new boxed warning (“black box” warning) about the serious risks of misuse, abuse, addiction, overdose, and death on all prescription opioids. The boxed warning will also include a precaution that chronic maternal opioid use during pregnancy can result in neonatal abstinence syndrome (NAS, referred to in the FDA warning as “neonatal opioid withdrawal syndrome or “NOWS”), described as a condition that “may be life-threatening if not recognized and treated using protocols developed by neonatology experts.” The FDA has included messaging that treatment should not be abruptly stopped in a physically dependent patient, although this is not specifically stated in regards to a pregnant patient, nor is this messaging in the boxed warning.

ACOG has been, and remains, extremely active in addressing clinical, advocacy, and legal issues related to opioid use and misuse, particularly as it relates to pregnancy-related and neonatal effects. As part of these efforts, ACOG has communicated with both the Centers for Disease Control and Prevention (CDC) and FDA regarding these issues; an ACOG statement, released March 16, 2016, includes information regarding communications with the CDC.

Neonatal Abstinence Syndrome

Neonatal abstinence syndrome is the most established risk to newborns from chronic use of opioids in pregnancy, but it is expected and treatable, and does not appear to pose permanent risks to the neonate. The FDA warning emphasizes the potential greater risk if NAS is “unexpected” or “unrecognized” but there are no data that support the distinction between recognized and unrecognized opioid use and subsequent neonatal death. In fact death is incredibly rare and, although it has occurred in context of opioid withdrawal, NAS was not the cause of neonatal death 1. Furthermore, concerns related to “unexpected” or “unrecognized” NAS are related to the process of identifying women using chronic opioids and are not a direct result of the medication or drug itself. While opioid use clearly contributes to the clinical spectrum of NAS, the identification of women who use opioids chronically is a separate issue. Opposite to the intended effect of FDA’s new labeling rules, this identification may become more challenging with the universal implementation of a boxed warning on opioids.

Impact on Care of Pregnant Women

The concern with the new boxed warning is the interpretation of the warning and potential impact on care of the pregnant woman. Health care providers and patients who may not be fully aware of these nuances surrounding opioid prescribing for pregnant women may assign an inordinate amount of attention to the boxed warning. As a result, patients may be denied access to medically indicated opioid prescriptions (either for pain management or opioid-assisted therapy), potentially resulting in an abrupt discontinuation of opioids. Evidence clearly shows that withdrawal from opioid use during pregnancy may be associated with relapse and potentially severe adverse outcomes 2. In balancing risks and benefits of continuing opioids, the balance is often in favor of continuing medically prescribed opioids, preferably with opioid-assisted therapy, to minimize the risks to the woman and fetus/neonate.

It is also concerning that this boxed warning was specifically assigned to immediate-release formulations. Immediate-release formulations can certainly be used or abused chronically, but there are clearly appropriate indications for the use of opioids for pain management in pregnancy and the postpartum period, such as trauma, surgery, renal lithiasis, and other conditions. ACOG agrees with the CDC and FDA that opioids should only be used for treatment of pain when alternatives are not appropriate nor effective. However, a boxed warning may negatively impact the appropriate use of opioids in acute pain management for pregnant women, further limiting appropriate pain management options.

For Obstetrician-Gynecologists and Other Obstetric Providers

  • Obstetrician-gynecologists and other obstetric providers should not hesitate to offer opioids for appropriate indications in pregnant women based on a concern for NAS.
  • Obstetrician-gynecologists and other obstetric providers and the patient should together carefully weigh risks and benefits when making decisions about whether to initiate opioid therapy for chronic pain 3.
  • For women, including pregnant women, with an opioid use disorder, the standard of care is opioid-assisted therapy 2. For pregnant women with opioid use disorder, opioid-assisted therapy has been associated with improved maternal outcomes and should be offered 2 3.
  • The possibility of an infant developing NAS should be discussed with patients on both chronic opioid therapy for pain and use disorder.
  • Obstetrician-gynecologists and other obstetric providers caring for pregnant women receiving opioids for pain or receiving buprenorphine or methadone for opioid use disorder should arrange for delivery at a facility prepared to monitor, evaluate for, and treat neonatal abstinence syndrome. In instances when travel to such a facility would present an undue burden on the pregnant woman, it is appropriate to deliver locally, monitor and evaluate the newborn for neonatal abstinence syndrome, and transfer the newborn for additional treatment if needed 3.

ACOG appreciates the efforts of organizations, including the FDA, to address the opioid epidemic. However, we have significant concerns regarding the unintended consequences and potential negative impact of the boxed warning on the care of pregnant women. NAS is certainly an important clinical entity which can be managed without long-term consequences. However, the boxed warning overemphasizes the risks of NAS without appropriately acknowledging that there are even greater risks associated with abrupt cessation of opioids in the population most effected: pregnant women who chronically use these medications. It is imperative that all stakeholders work together to provide critically important messaging regarding this issue for both health care providers and patients.

Clinical information and resources relevant to chronic opioid use in pregnancy, as well as NAS, are available at These resources include Committee Opinion 524: Opioid Abuse, Dependence, and Addiction in Pregnancy and Committee Opinion 633: Alcohol Abuse and Other Substance Use Disorders: Ethical Issues in Obstetric and Gynecologic Practice. We strongly recommend obstetrician-gynecologists and other obstetric providers refer to these clinical resources while caring for pregnant women who use opioids.


  1. Kelly LE, Rieder MJ, Bridgman-Acker K, Lauwers A, Madadi P, Koren G. Are infants exposed to methadone in utero at an increased risk for mortality? J Popul Ther Clin Pharmacol 2012;19:e160-5. PMID: 22580362.
    Article Locations:
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  2. Opioid abuse, dependence, and addiction in pregnancy. Committee Opinion No. 524. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;119:1070-6. PMID: 22525931.
    Article Locations:
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  3. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain - United States, 2016. Centers for Disease Control and Prevention. MMWR Recomm Rep 2016;65:1-49. PMID: 26987082.
    Article Locations:
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A Practice Advisory is issued when information on an emergent clinical issue (e.g. clinical study, scientific report, draft regulation) is released that requires an immediate or rapid response, particularly if it is anticipated that it will generate a multitude of inquiries. A Practice Advisory is a brief, focused statement issued within 24-48 hours of the release of this evolving information and constitutes ACOG clinical guidance. A Practice Advisory is issued only on-line for Fellows but may also be used by patients and the media. Practice Advisories are reviewed periodically for reaffirmation, revision, withdrawal or incorporation into other ACOG guidelines. 

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