Pain Medicine 2015; 16: 628–632 Wiley Periodicals, Inc.

Ethics Forum Opioid Use and Lactation: Protecting the Child in the Context of Maternal Pain Care Opioid use in the breastfeeding mother is a topic that carries a degree of controversy, with some experts reporting that short-term maternal use is usually safe [1] and others citing clear risks in ultrarapid metabolizers, in particular [2]. The decision to prescribe opioids in new mothers is fraught with unique considerations and caution against risks, given that the medications may directly impact the neonate or infant. Researchers who conducted a study of oxycodone administration following Caesarean section (N 5 50) found a significant correlation between maternal plasma and milk levels (R(2) 5 0.81) 24 hours after opioid administration, though they found detectable levels in the plasma of only one neonate [3]. The authors concluded that while oxycodone does accumulate in breast milk, the benefits of maternal comfort and successful initiation of breastfeeding appear to outweigh the minimal risks to neonates, though they called for careful monitoring for signs of opioid exposure, such as sedation, poor attachment, gastrointestinal symptoms, and respiratory depression [3]. In earlier publications, authors recommended against oxycodone use in breast feeding due to lack of studies on safety considerations such as excretion and repeated dosing [4,5]. Opioid therapy for chronic pain falls squarely under this umbrella as repeated dosing is a certainty. In this Ethics Forum, we welcome two esteemed experts, Dr. Ian Carroll and Dr. Priti Dalal to discuss and debate the difficult topic of opioid use in the breastfeeding mother. Here, Dr. Ian Carroll leads off the discussion with a review of the risks and a call for limits to infant opioid exposure. Dr. Dalal counters with a careful consideration of the imperative to appropriately treat maternal pain while calling for caution and an individualized approach. Where is the balance in regards to reducing maternal pain while protecting neonates and infants from harm? Can the infant risks be contained or abolished? We are pleased to present a rich discussion that sheds light on a topic that is often globally underappreciated. References 1 Hendrickson RG, McKeown NJ. Is maternal opioid use hazardous to breast-fed infants? Clin Toxicol (Phila) 2012;50(1):1–14. 2 Madadi P, Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder JS, et al. Safety of codeine during breastfeeding: Fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Phys 2007;53(1):33–5. 3 Seaton S, Reeves M, McLean S. Oxycodone as a component of multimodal analgesia for lactating 628

mothers after Caesarean section: Relationships between maternal plasma, breast milk and neonatal plasma levels. Aust N Z J Obstet Gynaecol 2007; 47(3):181–5. 4 Spigset O, Hagg S. Analgesics and breast-feeding: Safety considerations. Paediatr Drugs 2000;2(3):223– 38. 5 Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000;343(2):118–26. BETH D. DARNALL, PhD* AND MICHAEL E. SCHATMAN, PhD, CPE† *Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, California; † Foundation for Ethics in Pain Care, Bellevue, Washington, USA Opioids and Lactation: Insufficient Evidence of Safety The scope of considering whether opioids in breast milk are “safe” should be extended beyond existing simple narrow assessments of the low likelihood of causing immediate infant respiratory depression. Even 1 month of regular opioid use creates structural and functional changes in reward and emotional centers in the already developed adult human brain [1]. What adverse effects do opioids in maternal breast milk have on the developing mind of a neonate or infant? In breast feeding babies of opioid-consuming mothers, sufficient opioids accumulate in the baby to exert pharmacologic effects: analgesia and side effects such as sedation [2,3]. In addition, rare cases of opioid overdose have resulted from exposure to maternal opioids through breast milk. One retrospective cohort study of 533 breast-feeding mother-infant pairs identified that 20% of infants from mothers consuming oxycodone and 17% of infants of mothers consuming codeine had symptoms of CNS depression compared to such symptoms in only 0.5% of infants of mothers consuming acetaminophen (P < 0.001) [3]. Opioids can accumulate in babies despite only small quantities of maternal opioids excreted in breast milk because neonates and babies less than 6 months have as much as a fourfold reduced ability to clear the small quantities of opioids consumed compared to babies older than 6 months [4–7]. In short, breast feeding in these babies is creating unintended and undesirable infant opioid exposure. Animal studies support the existence of biologic mechanisms through which early-life exposure to opioids creates lifelong changes in responses to opioid exposure, stress, hormonal function, and aggressiveness [8–16]. In humans, the decades long delay between early life-exposure to opioids and the

Ethics Forum manifestation of alterations in cognition, motivation, emotional processing, and addiction risk have prevented large prospective controlled trials that could reassure prescribers that breast feeding in maternal opioid consumers is safe. However, opioid addicts have been compared to their own nonaddicted siblings to examine exposure to intrapartum analgesics documented decades earlier in their birth records. Infants who became opioid addicts had nearly five times the exposure to maternal analgesics than their nonaddicted siblings, and there was a dose– response with increasing addiction risk seen with increased obstetric drug exposure [17]. Similar work has suggested that human adult amphetamine addiction is similarly influenced by early-life, peripartum maternal analgesic exposure [18]. While these studies examined intrapartum rather than lactation-induced opioid exposure to the baby, they nonetheless provide evidence of lifelong risk conferred by brief, early-life, opioid exposure. Thus, the real concern is not whether breast fed infants of opioid consuming mothers will be at risk of respiratory depression, but to what extent they may be at risk of lifelong, subtle, alterations in cognitive, emotional, and motivational function. We should be honest with our patients that in these domains these drugs are not known to be safe, and we have substantial reason to believe they are not safe. Every effort should be made to limit infant exposure to opioids through breast milk. Chronic opioid use, in particular, among breast feeding mothers should be assumed to be unsafe for the developing mind of the infant until further data suggests otherwise. Moderate to severe maternal pain can still be treated with opioids when appropriate, but mothers requiring opioid therapy should consider forgoing breast feeding. Alternatively, mothers and pain management specialists can discuss the appropriateness of alternative modes of opioid delivery such as intrathecal use of hydrophilic opioids that generally reduce systemic levels by a factor of 10- to 100fold—although even this level is not known to be safe.

References 1 Younger JW, Chu LF, D’Arcy NT, Trott KE, Jastrzab LE, Mackey SC. Prescription opioid analgesics rapidly change the human brain. Pain 2011;152:1803– 10. 2 Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast milk and resultant exposure of a nursing infant. J Toxicol Clin Toxicol 1990;28:365–70.

mechanistic modeling study. Clin Pharmacol Ther 2009;86:634–43. 5 Knibbe CA, Krekels EH, van den Anker JN, DeJongh J, Santen GW, van Dijk M, et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet 2009;48:371–85. 6 de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999;36:439–52. 7 McRorie TI, Lynn AM, Nespeca MK, Opheim KE, Slattery JT. The maturation of morphine clearance and metabolism. Am J Dis Child 1992;146:972–6. 8 Arjune D, Bodnar RJ. Post-natal morphine differentially affects opiate and stress analgesia in adult rats. Psychopharmacology (Berl) 1989;98:512–7. 9 Zimmerman E, Sonderegger T, Bromley B. Development and adult pituitary-adrenal function in female rats injected with morphine during different postnatal periods. Life Sci 1977;20:639–46. 10 Martin JT, Nehlsen-Cannarella SL, Gugelchuk GM, Fagoaga O. Prenatal morphine exposure interacts with adult stress to affect type and number of blood leucocytes. Adv Exp Med Biol 1996;402:89–94. 11 Hol T, Niesink M, van Ree JM, Spruijt BM. Prenatal exposure to morphine affects juvenile play behavior and adult social behavior in rats. Pharmacol Biochem Behav 1996;55:615–8. 12 Gagin R, Cohen E, Shavit Y. Prenatal exposure to morphine alters analgesic responses and preference for sweet solutions in adult rats. Pharmacol Biochem Behav 1996;55:629–34. 13 Gagin R, Cohen E, Shavit Y. Prenatal exposure to morphine feminizes male sexual behavior in the adult rat. Pharmacol Biochem Behav 1997;58:345–8. 14 Gagin R, Kook N, Cohen E, Shavit Y. Prenatal morphine enhances morphine-conditioned place preference in adult rats. Pharmacol Biochem Behav 1997; 58:525–8.

3 Lam J, Kelly L, Ciszkowski C, Landsmeer ML, Nauta M, Carleton BC, et al. Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia. J Pediatr 2012;160:33–7e2.

15 Shavit Y, Cohen E, Gagin R, Avitsur R, Pollak Y, Chaikin G, et al. Effects of prenatal morphine exposure on NK cytotoxicity and responsiveness to LPS in rats. Pharmacol Biochem Behav 1998;59:835–41.

4 Willmann S, Edginton AN, Coboeken K, Ahr G, Lippert J. Risk to the breast-fed neonate from codeine treatment to the mother: A quantitative

16 Schwarz JM, Hutchinson MR, Bilbo SD. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific 629

Ethics Forum epigenetic programming of anti-inflammatory IL-10 expression. J Neurosci 2011;31:17835–47. 17 Jacobson B, Nyberg K, Gronbladh L, Eklund G, Bygdeman M, Rydberg U. Opiate addiction in adult offspring through possible imprinting after obstetric treatment. BMJ 1990;301:1067–70. 18 Jacobson B, Nyberg K, Eklund G, Bygdeman M, Rydberg U. Obstetric pain medication and eventual adult amphetamine addiction in offspring. Acta Obstet Gynecol Scand 1988;67:677–82. IAN R. CARROLL MD, MS Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, California, USA The Need to Treat Maternal Pain in the Breastfeeding Mother: Are Opioids Safe? Do we have an ethical imperative to treat pain in women who are breastfeeding? In essence, there are two patient entities to be considered: the mother and the breastfed infant. The drugs used in the treatment of maternal pain may have potentially deleterious effects on the breastfed infant. Safety of the infant is paramount, but inadequate treatment of maternal pain seems unethical. In fact, under treatment of pain in a breastfeeding woman may make it difficult for the woman to breast feed the baby, and may contribute to maternal depression [1]. The American Academy of Pediatrics recommends that infants be exclusively breastfed up to 6 months, followed by continuation of breastfeeding (along with complementary foods) up to the first year of life or even longer depending on the mother and the child [2]. However, one of the factors affecting the decision to breast feed may be maternal opioid therapy. While nonopioid analgesics may be used in the treatment of mild pain to moderate pain, in case of severe pain and for the treatment of chronic pain, opioid analgesics may be preferred, albeit debatable [3]. Although, several different kinds of opioid analgesics are currently available, caution must be used when treating and managing pain in cases of women who are breastfeeding their babies. The clinically used opioids have different pharmacological properties and may be administered by various routes. Thus, while considering treatment of maternal pain with opioids, consideration must be given to: 1) infant factors (age less than 2 months, prematurity, whether exclusively breast fed, pre-existing diseases, and syndromes); 2) maternal factors (type and severity of pain, duration of analgesic requirements, dosage requirements, pharmacogenetic variations); and finally, 3) drug factors (e.g., meperidine has active metabolites with a long half-life, increased risk of respiratory depres630

sion in cases of breastfed infants with combined genetic polymorphisms of the CYP2D6 and the UGT2B7 genes), to guide critical decisions with regard to breastfeeding [4,5]. The strategies that may be used to control maternal pain may include nonpharmacological techniques, nonopioid analgesics and opioid analgesics. Where possible, the intrathecal or epidural route of administration of opioids is preferred [6]. The preferred injectable forms are fentanyl and morphine, due to their low oral bioavailability in the infant [6,7]. There are no standardized guidelines in this scenario, but the breastfed infant must be monitored for signs of sedation and respiratory depression. In the chronic pain setting, there are not enough data to comment on the safety of use of opioids in the pregnant woman. Use of morphine and other analgesics (e.g., cannabinoids) by a breastfeeding mother, for control of chronic pain, may lead to higher levels of the drug and its metabolites in the infant [8]. However, two case reports describing the use of transdermal fentanyl patches and intrathecal morphine via a pump have been reported [9,10], and in both cases, the levels of the fentanyl or morphine were undetectable in the infant. A study reported that, of 100 case reports of possible adverse effects of any drug on the nursing infant, 78% occurred in infants in the first 2 months of life [11] with serious side-effects reported with maternal use of opioids (codeine, methadone, and meperidine) in case of neonates and expremature infants [11]. Administration of single doses of morphine may not cause detrimental effects for the breastfed infant [12]. However, when repeated doses are administered, the concentrations of morphine in the breast milk may be variable [13]. Hence, caution is advised for nursing mothers who need repeated doses of opioids for the treatment of acute or chronic pain, especially in case of infants under two months of age [11]. Perhaps, cautious maternal administration of oral morphine may be acceptable in case of infants greater than 6 months of age. As a last resort, under special circumstances, judicious use of maternal opioid therapy should not be completely deferred when other treatment options have failed or proved inadequate. The option of pumping and discarding the breast milk or discontinuing breastfeeding should be considered in situations where chronic high dose maternal opioid therapy is indicated, as it would be inappropriate to let the mother suffer in pain. Each case should be judged by its own merits. A team approach, involving the physicians (pain physician, surgeon, anesthesiologist, and pediatrician), lactation specialist, and the breastfeeding patient is very important in the counselling and management of this challenging situation. References 1 Schaefer KM. Breastfeeding in chronic illness: The voices of women with fibromyalgia. MCN Am J Matern Child Nurs 2004;29(4):248–53. 2 Rautava S, Walker WA. Academy of Breastfeeding Medicine founder’s lecture 2008: Breastfeeding—An

Ethics Forum extrauterine link between mother and child. Breastfeed Med 2009;4(1):3–10. 3 Atkinson TJ, Schatman ME, Fudin J. The damage done by the war on opioids: The pendulum has swung too far. J Pain Res 2014;7:265–8. 4 Berlin CM, Jr., Paul IM, Vesell ES. Safety issues of maternal drug therapy during breastfeeding. Clin Pharmacol Ther 2009:85(1):20–2. 5 Madadi P, Ross CJ, Hayden MR, Carleton BC, Gaedigk A, Leeder JS, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: A casecontrol study. Clin Pharmacol Ther 2009;85(1): 31–5. 6 Montgomery A, Hale TW. ABM clinical protocol #15: Analgesia and anesthesia for the breastfeeding mother. Breastfeed Med 2006;1(4):271–7. 7 Dalal PG, Bosak J, Berlin C. Safety of the breastfeeding infant after maternal anesthesia. Paediatr Anaesth 2014;24(4):359–71. 8 Djulus J, Moretti M, Koren G. Marijuana use and breastfeeding. Can Fam Phys 2005;51:349–50. 9 Cohen RS. Fentanyl transdermal analgesia during pregnancy and lactation. J Hum Lact 2009;25(3): 359–61. 10 Oberlander TF, Robeson P, Ward V, Huckin RS, Kamani A, Harpur A, McDonald W. Prenatal and breast milk morphine exposure following maternal intrathecal morphine treatment. J Hum Lact 2000; 16(2):137–42. 11 Anderson PO, Pochop SL, Manoguerra AS. Adverse drug reactions in breastfed infants: Less than imagined. Clin Pediatr (Phila) 2003;42(4):325–40. 12 Feilberg VL, Rosenborg D, Broen Christensen C, Mogensen JV. Excretion of morphine in human breast milk. Acta Anaesthesiol Scand 1989;33(5): 426–8. 13 Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast milk and resultant exposure of a nursing infant. J Toxicol Clin Toxicol 1990;28(3):365–70. PRITI G. DALAL, MD, FRCA Department of Anesthesiology, Penn State Hershey Medical Center, Penn State Children’s Hospital, Hershey, Peninsula, USA

Protecting the Infant from Unknown Risks Dr. Dalal cites literature and guidelines for minimizing the effects of short-term postpartum opioid use, with several studies reporting that single-dose administration may have no detrimental effects on the neonate. In the case of opioid prescription for chronic pain, repeated doses and long-term use are likely. Dr. Dalal notes that caution should be advised in nursing mothers who require repeated opioid dosing. The question is how one interprets “caution.” While the literature often cites careful monitoring for infant drowsiness or other indices of central nervous system depression, these recommendations are predicated on the assumptions that any risks are transitory and minimal as long as they are identified and addressed. A more conservative approach best ensures that neonatal and infant risks are contained or abolished, and therefore such assumptions must be disregarded. Dr. Dalal calls for avoidance of opioids for mild and moderate pain, and individualized selection in breastfeeding mothers with severe chronic pain. Indeed, ethical and ideal treatment of severe maternal pain may include opioids as one component of a treatment approach that is both multimodal and multidisciplinary in nature, though most patients will not have access to such ideal treatment. Nevertheless, the challenge is to minimize the risks to the infants of mothers with severe chronic pain who are receiving repeated opioid doses or chronic opioid therapy. In these cases, while mothers are on chronic opioid therapy, breastfeeding should be discouraged as infant safety supersedes basic rationales for breastfeeding, including improved nutrition, immunity, and maternal bonding. Drs. Dalal and Carroll both point to a lack of data regarding the infant risks associated with repeated opioid administration in breastfeeding mothers. Furthermore, Dr. Carroll extends the argument and cites a lack of safety data regarding the long-term effects of opioids on the developing child. He also cogently cites the adult literature which suggests changes in the central nervous system following 4 weeks of daily oral opioids. In this Ethics Forum, the issue at hand is not whether administration of chronic opioid therapy in new mothers is appropriate; rather, it is whether breastfeeding should be discouraged in new mothers who are receiving opioids for chronic pain. We conclude that containment or abolition of infant risks for potential opioid harms can best be achieved if mothers with severe pain on chronic opioid therapy defer breastfeeding. Ideally, infant care includes alternative strategies to ensure nutrition and bonding are optimized in the absence of breastfeeding. What does an opioid prescribing physician do in the case where a new mother patient insists on breastfeeding her neonate or young infant, despite having received appropriate education about the potential

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Ethics Forum risks to her child? While the mother is the patient, by default and extension the neonate is the patient, as well. Here the ethical dilemma becomes one of respecting the mother’s autonomy vs protecting the well-being of the infant. A physician may consider ceasing to prescribe, though the patient may simply seek medication elsewhere. Beneficent stewardship may require additional actions, such as coordinated discussion/care with other treating physicians (e.g., the infant’s pediatrician, the mother’s primary care physi-

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cian, and/or OB/GYN) to determine how to best protect the health of the child. BETH D. DARNALL, PhD* AND MICHAEL E. SCHATMAN, PhD, CPE† *Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, California; † Foundation for Ethics in Pain Care, Bellevue, Washington, USA

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