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Practice Advisory on Codeine and Tramadol for Breastfeeding Women

  

April 27, 2017

This is an area of evolving care and practice. Fellows should check periodically for revisions and updates. ACOG, SMFM, and ABM will communicate important changes and updates to these guidelines.

On April 20, 2017, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication and announced revisions to the labels of all prescription medicines containing codeine and tramadol. Among the label changes is a strengthened warning that breastfeeding is not recommended while using medicines containing codeine or tramadol, because of the potential for serious adverse effects in the infant due to opioid overdose (1). While this report underscores the need for anticipatory guidance regarding opiate effects in all patients, obstetrician-gynecologists and other obstetric providers should ensure that application of this guidance does not interfere with pain control in non-pregnant breastfeeding women or disrupt breastfeeding.

Safe management of pain in non-pregnant women who are breastfeeding begins with maximizing the use of multi-modal non-opioid analgesics such as regional anesthetic techniques, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen, where appropriate and feasible.

The American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), and the Academy of Breastfeeding Medicine (ABM) recommend that obstetrician-gynecologists and other obstetric providers adopt the following strategies to enable adequate pain control and continued breastfeeding if opiate analgesia is required:

1) Consider prescribing an opioid analgesic other than codeine or tramadol. According to the American Academy of Pediatrics Committee on Drugs, butorphanol, morphine, or hydromorphone are preferred agents for breastfeeding mothers requiring narcotics for pain control (2). Morphine and hydromorphone can be dosed via oral or IV route.

2) If a codeine-containing medication is considered the preferred choice, the risks and benefits of this drug and the reasoning behind the FDA warning should be discussed with each family.

Regardless of the medication selected, it is prudent to counsel mothers prescribed opiate analgesics about the risk of central nervous system depression of both mother and breastfed infant, and to limit the duration of opiate prescriptions to the shortest reasonable course expected for an acute pain problem.

The new FDA guidance reflects established concerns about individual differences in opiate metabolism. Codeine and tramadol need to be metabolized to their active, analgesic, form by CYP2D6, and there is considerable variation in the amount and efficiency of this enzyme between individuals. Among so-called CYP2D6ultra-rapid metabolizers,” typical dosing of these agents can result in high serum levels, and the active metabolites can pass into breast milk. There are several published case reports of breastfed infants with excessive sleepiness or depressed breathing in the setting of maternal codeine use, as well as one report of an infant death (3). Tramadol is also metabolized by CYP2D6; the FDA did not find any published reports of toxicity in breastfed infants, but because the drug and its metabolites are present in breast milk, its use is not recommended.

The frequency of CYP2D6 ultra-rapid metabolizers ranges from 0.5% in China to as high as 29% in Ethiopia, making this a clinically significant polymorphism (Figure 1) (4). In the United States, the prevalence is 4-5%. In addition, about 6% of individuals in the United States are poor metabolizers, and therefore receive insufficient pain control with codeine. Given variation in rates of metabolism, empiric dosing of codeine can put patients at risk of increased side effects or of insufficient pain relief.

Although not addressed in the FDA guidance, oxycodone and hydrocodone are also partially metabolized to more potent forms, oxymorphone and hydromorphone, respectively, by CYP2D6. Following oxycodone administration, ultra-rapid metabolizers experience more pronounced pain relief and pupil constriction (5). Hydrocodone metabolism to hydromorphone also varies by genotype (6).

Given interindividual variation in metabolism of opiates, as well as the risk of maternal side effects in rapid metabolizers, it is prudent to advise women prescribed opiates to monitor for excessive sedation and other side effects. Motherisk guidelines for monitoring mothers and babies for central nervous system depression while using medications containing codeine during breastfeeding have been published (Box 1) (7). In a study of 238 breastfeeding mothers using these guidelines, neonatal sedation was reported in 2.1% of infants, and was not associated with differences in genotype (7). These results suggest that such safety guidelines reduce the risk of neonatal sedation with maternal opioid use.

Hydromorphone is not metabolized by CYP2D6, and side effects in breastfeeding mother-infant dyads are therefore not dependent on maternal or infant genotype. A small study of intranasal hydromorphone found that if mothers received 4 mg of hydromorphone every 6 hours, infants would be expected to receive less than 1% of a therapeutic dose, on a mg-per-kg basis: infants would ingest 0.002 mg/kg/day (8), which is well below the oral dose recommended for infants and children (0.03-0.06 mg/kg/dose every 4 hours prn) (9). Obstetrician-gynecologists and other obstetric providers should be aware that IV hydromorphone is four to five times more potent than oral hydromorphone.  For opiate-naive patients, a starting dose of 0.3 to 1 mg IV every 2 to 3 hours is recommended (Table 1) (10).

Morphine is also more potent in IV form compared with oral form. Two to five mg IV is equivalent to 10 to 30 mg by mouth. Morphine is present in varying small quantities in the breast milk of women who have received epidural, IV, or oral morphine, although its somewhat poor oral bioavailability may make it less risky for breastfeeding infants than other opioid choices (11).

Obstetrician-gynecologists and other obstetric providers caring for breastfeeding women must ensure adequate pain control and simultaneously avoid doses of opioid medications that may be toxic to mothers and/or to their breastfed infants. It may be prudent to use starting doses of opioids on the low end of suggested ranges, with careful titration to clinical effect and close monitoring for side effects. Additional strategies to encourage use of regional anesthetic techniques, nonsteroidal anti-inflammatory medications, and acetaminophen can help minimize risk while providing adequate pain control for breastfeeding mothers (12).

Figure 1: Frequency (%) of CYP2D6 poor metabolizers (bold) and ultra-rapid metabolizers (italic) in different populations.

(Click on the figure above for a larger image.)

Reprinted from Cascorbi I. Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication. Eur J Clin Invest 2003;33(suppl 2):17-22. Available at: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2362.33.s2.3.x/full. Retrieved April 24, 2017. 

 

Box 1: Motherisk Guidelines for Safe Use of Medications That Contain Codeine During Breastfeeding

In most cases, the occurrence of CNS depression is consistent between the mother and the baby. If the mother suffers from symptoms of CNS depression (eg, somnolence, grogginess), a physician should examine the baby for signs of CNS depression as well.

  • If the baby is not fed well, does not wake up to be fed, does not gain weight, or shows limpness, he or she should be examined by a physician.

  • Central nervous system depression in the baby appears to worsen after 4 days probably, owing to the accumulation of morphine with more breastfeeding. If possible, codeine should not be used for longer than 4 days. If pain still necessitates codeine, an attempt should be made to decrease the dose or to switch to non-codeine painkillers (eg, NSAIDs).

  • Women who convert more codeine to morphine have a duplication of the gene encoding for cytochrome P450 2D6. This genetic predisposition can be detected by genetic test. This test, although not available in most hospitals, is available on the market.

  • Although codeine is widely used in North America, 9 randomized studies comparing the use of codeine with various NSAIDs in laparotomy cases (ie, abdominal surgery) failed to show codeine to be superior in pain relief.

Reprinted from Madadi P, Moretti M, Djokanovic N, Bozzo P, Nulman I, Ito S, et al. Guidelines for maternal codeine use during breastfeeding. Can Fam Physician 2009;55:1077-8. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776794. Retrieved April 24, 2017. 

 

Table 1

Suggested Initial Opioid Doses for Opiate-Naive Adult Patients

Agent

IV

PO

Codeine

N/A

30 - 60 mg orally every 4 - 6 hours

Hydrocodone

N/A

5 - 10 mg orally every 6 hours

Hydromorphone

0.3 - 1 mg IV every 2 - 4 hours

2 - 4 mg orally every 3 - 4 hours

Morphine

2 - 5 mg IV every
2 - 4 hours

10 - 30 mg orally every 4 hours

Oxycodone

N/A

5 - 15 mg orally every 4 - 6 hours

Adapted from: Mariano ER. Management of acute perioperative pain. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on April 25, 2017.)

 

References

  1. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Silver Spring (MD): FDA; 2017. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm. Retrieved April 24, 2017.

  2. Sachs HC. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Committee On Drugs. Pediatrics 2013;132:e796-809. Available at: http://pediatrics.aappublications.org/content/132/3/e796.long. Retrieved April 24, 2017. 

  3. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.
    Lancet2006;368:704. Available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69255-6/abstract. Retrieved April 24, 2017

  4. Cascorbi I. Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication. Eur J Clin Invest 2003;33(suppl 2):17-22. Available at: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2362.33.s2.3.x/full. Retrieved April 24, 2017. 

  5. Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol 2010;160:919-30. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935998. Retrieved April 24, 2017. 

  6. Linares OA, Fudin J, Daly AL, Boston RC. Individualized hydrocodone therapy based on phenotype, pharmacogenetics, and pharmacokinetic dosing. Clin J Pain 2015;31:1026-35. Available at: http://journals.lww.com/clinicalpain/pages/articleviewer.aspx?year=2015&issue=12000&article=00002&type=abstract. Retrieved April 24, 2017.

  7. Kelly LE, Chaudhry SA, Rieder MJ, 't Jong G, Moretti ME, Lausman A, et al. A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk. PLoS One 2013;8:e70073. Available at: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070073. Retrieved April 24, 2017. 

  8. Edwards JE, Rudy AC, Wermeling DP, Desai N, McNamara PJ. Hydromorphone transfer into breast milk after intranasal administration. Pharmacotherapy 2003;23:153-8. Available at: http://onlinelibrary.wiley.com/doi/10.1592/phco.23.2.153.32081/abstract. Retrieved April 24, 2017. 

  9. Hale TW, Rowe HE. Hydromorphone. In: Medications and mothers' milk. 17th ed. New York (NY): Springer; 2017. p. 466.

  10. Mariano EW. Management of acute perioperative pain [after login]. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Available at: https://www.uptodate.com/contents/management-of-acute-perioperative-pain. Retrieved April 25, 2017.

  11. National Library of Medicine. Morphine. In: Drugs and Lactation Database (LactMed). Available at:
    http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r? dbs+lactmed:@term+@DOCNO+370. Retrieved April 25, 2017.

  12. Sutton CD, Carvalho B. Optimal pain management after cesarean delivery. Anesthesiol Clin 2017;35:107-24. Available at: http://www.anesthesiology.theclinics.com/article/S1932-2275(16)30080-5/abstract.  Retrieved April 24, 2017. 


     

This Practice Advisory was developed by the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the Academy of Breastfeeding Medicine in collaboration with Alison Stuebe, MD, MSc, and Sarah Reece-Stremtan, MD.



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. 

This document reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed.

Publications of the American College of Obstetrician and Gynecologists are protected by copyright and all rights are reserved. The College's publications may not be reproduced in any form or by any means without written permission from the copyright owner. 


The American College of Obstetricians and Gynecologists (The College), a 501(c)(3) organization, is the nation’s leading group of physicians providing health care for women. As a private, voluntary, nonprofit membership organization of approximately 58,000 members, The College strongly advocates for quality health care for women, maintains the highest standards of clinical practice and continuing education of its members, promotes patient education, and increases awareness among its members and the public of the changing issues facing women’s health care. The American Congress of Obstetricians and Gynecologists (ACOG), a 501(c)(6) organization, is its companion organization. www.acog.org

 

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