Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications

Abstract

Safety of maternal drug therapy during breastfeeding may be assessed from estimated levels of drug exposure of the infant through milk. Pharmacokinetic (PK) principles predict that the lower the clearance is, the higher the infant dose via milk will be. Drugs with low clearance (<1 mL/[kg·min]) are likely to cause an infant exposure level greater than 10% of the weight‐adjusted maternal dose even if the milk‐to‐plasma concentration ratio is 1. Most drugs cause relatively low‐level exposure below 10% of the weight‐adjusted maternal dose, but opioids require caution because of their potential for severe adverse effects. Furthermore, substantial individual variations of drug clearance exist in both mother and infant, potentially causing drug accumulation over time in some infants even if an estimated dose of the drug through milk is small. Such PK differences among individuals are known not only for codeine and tramadol through pharmacogenetic variants of CYP2D6 but also for non‐CYP2D6 substrate opioids including oxycodone, indicating difficulties of eliminating PK uncertainty by simply replacing an opioid with another. Overall, opioid use for pain management during labor and delivery and subsequent short‐term use for 2‐3 days are compatible with breastfeeding. In contrast, newly initiated and prolonged maternal opioid therapy must follow a close monitoring program of the opioid‐naive infants. Until more safety data become available, treatment duration of newly initiated opioids in the postpartum period should be limited to 2‐3 days in unsupervised outpatient settings. Opioid addiction treatment with methadone and buprenorphine during pregnancy may continue into breastfeeding, but infant conditions must be monitored.

Pharmacologic Management of Common Ailments in Women Who Are Breastfeeding

“…In a case report, the continuous use of codeine in a woman who was an ultrarapid metabolizer was the suspected cause of death in her infant . However, limiting maternal codeine use to 2 to 3 days, rather than the nearly 2 weeks as described in the case, may have prevented accumulation in the infant and thus averted this unfortunate outcome . Nevertheless, codeine use is discouraged because of its relatively high rates of sedation in infants and unpredictable metabolism .…”

“…It is a milder opiate with a comparatively large body of data documenting its use during breastfeeding, with few cases of infant sedation and no cases of infant death associated with its use to date . Although morphine has a low RID, it has active metabolites with unknown effects in the infant and warrants continuous monitoring for sedation, as with all opiates . Hydromorphone (Dilaudid) is also considered acceptable because of its low RID and lack of active metabolites; however, it is a stronger opiate with fewer data about its use during breastfeeding …”

“…Opiates not recommended include oxycodone (Oxycontin), hydrocodone (Hycodan), and codeine (Codeine) . All of these agents are metabolized to varying degrees by the CYP2D6 enzyme to more potent bioactive metabolites . CYP2D6 activity varies widely between individuals resulting in higher or lower than anticipated serum concentrations of active metabolites .…”

“…All of these agents are metabolized to varying degrees by the CYP2D6 enzyme to more potent bioactive metabolites . CYP2D6 activity varies widely between individuals resulting in higher or lower than anticipated serum concentrations of active metabolites . For example, duplications of the CYP2D6 gene cause increased metabolism of codeine to its active metabolite morphine, resulting in greater analgesic and potentially sedative effects than would otherwise be expected in both the woman and her infant .…”

Developmental Pharmacotherapy: The Interface Between Ontogeny and Drug Effect

“…Unfortunately, and mostly due to a lack of factual knowledge, many clinicians will simply, often in a cavalier fashion, recommend temporary or even permanent discontinuation of breastfeeding with maternal drug therapy so as to simply avoid any possible complications. Ito effectively and thoroughly reviews the importance of breastfeeding, the PK principles of drug distribution into breast milk, infant exposure through feeding, infant PK, and possible PD effects. Ito uses real‐world case studies of underlying maternal illness requiring drug treatment while breastfeeding to highlight many important nuances to consider in making a clinical decision to continue or stop breastfeeding—the risk‐benefit analysis.…”