Codeine Toxicity Via Breast MilkCan This Occur and Implications for Opiate Therapy in ChildrenMichael Rieder MD Ph.D FRCPC FCAHS FBPhS FRCP(Edinburgh)Address: Dr. Michael RiederDivision of Paediatric Clinical Pharmacology‘ Department of PaediatricsChildren’s Hospital of Western Ontario800 Commissioner’s Road EastLondon, OntarioN6A 5W9519-685-8177 Ext 75121mrieder@uwo.caWord Count: 1895Keywords: Codeine, Opiates, Neonates, Morphine, ToxicityDr. Rieder has no Conflicts of Interest related to the content of this manuscriptAbstractCodeine is commonly used in combination analgesic products. Their use during breast feeding can be associated rarely with serious adverse effects related to genetic polymorphisms effecting codeine’s metabolism and disposition. Clinicians treating infants of breast-feeding mothers should be aware of this rare but potentially serious complication.In 2006 a case of codeine toxicity via breast milk with fatal consequences was published in Lancet [1]. This manuscript described a 13 day old infant whose mother was prescribed a codeine-acetaminophen analgesic after a traumatic delivery who died of morphine and codeine toxicity. This raised the issue of codeine and morphine transmission via breast milk as part of the broader consideration of the role – or lack thereof- of codeine in pediatric and perinatal care. While this was the first fatal case published with reference to codeine, it does draw on literature describing cases of lethargy and poor feeding of breast-feeding infants from 1985 on whose mothers were using codeine containing products for analgesia [2]. Further, a recent study using the EudraVigilance data base identified 15 infants whose deaths were related to opiate exposure via breast-feeding [3].This and other cases highlighted the potential risk to breast fed infants of opiate transmission via breast milk and the potential impact of genetic variations on risk of untoward outcomes. In the years since this manuscript was published, further research has helped to uncover issues that relate to the metabolic disposition of codeine, the impact on potential risk to the infant and the safety of codeine in children in general [4-6]. This has included a manuscript detailing thoughtful pharmacokinetic modeling of maternal codeine therapy that found that toxicity in infants was likely occur but also was likely to be to rare [6]. These findings have impacted regulatory guidance on the use of codeine-containing products in a number of countries. This has not been without debate. In 2020 a mini-review questioned the plausibility of codeine toxicity via breast milk [7]. While the review raises important questions, there are issues in the data supporting this assertion.To address this is accurate it is important to first consider the pharmacology of codeine. Codeine is a pro-drug, 3-methyl morphine, with a methyl group on the 3-carbon hydroxyl position [8]. The bulk of codeine’s analgesic activity appears to be via conversion to morphine and codeine 6-glucuronide, as morphine has a 200-fold greater affinity to the opioid mµ receptor compared to codeine and the 6-glucuronide appears to be more potent than morphine [8-10]. Codeine is also metabolized to norcodeine. Demethylation of codeine to morphine is mediated by CYP2D6, an enzyme known to have polymorphic expression as depending on genotype one can be a poor metabolizer, an extensive metabolizer or an ultra-rapid metabolizer [11]. The phenotype is not uniformly distributed, as ultra-rapid metabolizers are rare in northern European populations [1% or less] but common in the Mediterranean littoral, the Middle East, the Horn of Africa and South India [11].There is an important further consideration. In the case of breast-feeding mothers, drug toxicity in the infant is a sum of pharmacological activity across the mother-baby dyad. Simply put, drug toxicity is typically the consequence of the amount of drug generated being less than the amount excreted. Thus is important to remember that breast-feeding represents a mother-infant dyad – in the context of maternal therapy, drug metabolism occurs not only in the mother but in the infant. How does this apply in the case of codeine?The modeling work of Willmann et al. concluded that codeine toxicity via breast-feeding would be rare but possible notably in the case of mothers with the CYP2D6 ultra-rapid metabolizer phenotype [6]. They also concluded that warnings should be extended to normal/extensive metabolizers given overlap in serum concentrations between the two phenotypes [6]. The mini-review by Zipursky and Juurlink noted that codeine metabolism was complex – which is unquestionably true – but that a central issue was the infant’s metabolism of codeine to morphine was a central part of toxicity while the contribution of the maternal dyad in terms of codeine by the with passage via breastmilk, and that reduced CYP2D6 activity is early after birth renders toxicity implausible [6]. The work of Stevens et al. suggesting CYP2D6 activity in infants is submaximal using in vitro using human microsomes is cited as support for this position [12]. However, there are important limits to in vitro data and the use of human microsomes as a tool for studying in vitro to model issues of drug metabolism in vivo has been shown to be much less than optimal [13]. In this context, there is elegantin vivo work by Allegaert’s group in Belgium which quite clearly demonstrates the early development of robust phenotypic-specific CYP2D6 activity in infants, supporting the hypothesis that codeine – which has demonstrated breast milk transfer – can be metabolized by the infant, contributing to the generation of metabolites in a setting where excretion is suboptimal [14]. This is an important consideration not cited in the mini-review by Zipursky and Juurlink in that the modeling work of Willmann et al. assumed CYP2D6 activity infants being in the range of 10% of adult values, while in vivo work using metabolic probes in infants demonstrates in fact that there is a rapid concordance between CYP2D6 genotype and phenotype [15].Further to this issue, if we return to concept of the mother-infant dyad, while it appears that maternal CPY2D6 phenotype is a key element in codeine toxicity via breastmilk, there is an additional consideration with respect to the circumstances of pregnancy that bears consideration. Over the course of pregnancy CYP2D6 activity has been found to increase, with a nearly 50% increase over baseline by the last weeks of gestation [16]. Thus it is likely that maternal production of morphine with transmission via breast milk is considerably greater than might be otherwise predicted.The final issue with respect to metabolism relates to the potential for route switching. As noted, one of metabolic products of codeine is codeine 6-glucuronide, the formation of which is mediated by UDP-Glucuronosyltransferase-2B7 (UGT2B7). Zipursky and Juurlink again cite in vitro data suggesting that the infant in the Lancet case should have had robust capacity to glucuronate codeine [7]. However, the studies cited were in vitro studies using a small number of samples spanning the first year of life to 25 years of age [17, 18]. Data derived in vivo from infants in contrast demonstrated that there was limited capacity for opiate glucuronidation in the first two weeks of life, suggesting that limitation of metabolic capacity via glucuronidation could lead to route switching to demethylation and hence higher than anticipated morphine concentrations [19, 20].While these issues have addressed drug metabolism notably in terms of the potential to demethylate codeine to morphine, the other part of the equation in terms of toxicity relates to clearance. As noted above, toxicity can often be simply considered as a situation where the amount of toxin generated exceeds the capacity for toxin elimination.The assumption made in the mini-review that renal excretion would be expected to be robust based on the observation of five wet diapers on the day before death is that urine flow is a surrogate for renal function [7]. However, renal drug elimination is a complex process which even assessments such as glomerular filtration rate fail to completely capture [21, 22]. While glomerular filtration rate at birth at term is typically 30% of adult surface-area corrected values, there are other key elements in renal drug administration whose ontogeny is much less understood [21, 22]. As well, morphine is a substrate of OCT1 transporter, and while the ontogeny remains unclear it appears that expression may be low at birth as well as subject to genetic variation, which would have the effect of reducing elimination, notably in rare cases where there is increased accumulation [23-26].The review also notes the lack of fatal cases in the literature. However, as noted above there are cases and case series of adverse effects in breast-fed infants of mothers being treated with codeine dating back to 1985 and in the case of other opiates from 1885 [2]. As well, as modeled by Willmann et al. adverse events are likely to be rare and serious ones even more [6]. There is data suggesting that short [3 day or less] courses of codeine therapy for breast-feeding mothers has no negative impacts on outcomes such as hospital admission versus mothers who were not prescribed codeine-containing products [27]. This is germane as the infant reported in the Lancet case died after 12 day of life, during which his mother was taking a codeine-acetaminophen analgesic while the infant was breast-feeding robustly every three hours [1]. To return to our simple paradigm, this suggests that toxin accumulation was exceeding the capacity to excrete.It could also be noted that while the tragic fact of opiate deaths is infants is real, the circumstances in this case are not consistent with what is typically seen in these unfortunate cases [28].Willmann et al. conclude that serious adverse events due to maternal codeine therapy in the context of breast-feeding are likely to be uncommon and due to unique combinations of risk factors [6]. One must concur. This is not uncommon for serious adverse drug events – as an example, 2,000 children can take sulfonamides and while 1,999 tolerate the drug well one will develop life-threatening Stevens-Johnson Syndrome [29]. However the view that it is implausible as stated in the mini-review by Zipursky and Juurlink is not tenable notably given the considerable in vivo evidence which supports the conclusions of Willmann et al. [6, 7]. There are very few absolutes in medicine and, respectfully, believing the codeine toxicity via breast-feeding is impossible is not one of them.In addition to the cases noted above in association with codeine use during breast-feeding there have been a number of serious adverse effects and deaths associated with codeine therapy in children [30-35]. The observation has been made that severe respiratory depression and death in the context of codeine monotherapy is primarily seen in children [36]. The mechanism[s] responsible may relate to age-related difference in codeine disposition in children versus adults, suggesting that perhaps were there are therapeutic alternatives they may be preferable [36].So what is the clinician to take from this going forward? First, that serious and life-threatening events in the context of maternal therapy with codeine while breast feeding are uncommon but can occur and that clinicians need to mindful of this. Uncommon is not unknown.It also noted that while short courses of codeine therapy [less than 3 days] are likely to be safe, consideration should be made for longer term therapy for the use of alternate therapy such as NSAIDs. Given that there are alternate analgesics available, the choice of analgesics for women who will breast feed after delivery should consider all possible therapeutic choices. As well, consideration should be given to the prudent recommendation of Willmann et al. that extensive metabolizers are at risk of high morphine concentrations and that should be included in labeled warnings [6].One can also conclude that genotypic-driven drug therapy is likely to be way forward, and as Precision Medicine moves more and more into routine clinical care clinicians should be alert to the use of genomic data to drive safe prescribing. This is becoming increasingly true and as Artificial Intelligence and Electronic Medical Records come more and more into use and are more and more integrated this presents a significant opportunity to provide real time guidance to further the common goal of safe prescribing for mothers and children as well as for the maternal-child research community to derive the data that can drive these opportunities [37].
