Codeine Sulfate

Compound of cough and pain medication. The cytochrome P450-CYP2D6 enzyme catalyzes morphine.

It is excreted in breast milk in small amounts, much lower than the dose used for newborns and infants.

The plasma levels of infants whose mothers take them are very low, less than usual therapeutic levels and assuming an insignificant relative dose, less than 1.5% ^{(Meny 1993, Naumburg 1988, Findlay 1981)}, so it was considered safe for use during breastfeeding. ^{(Bar-Oz 2003, WHO 2002, AAP 2001, Moretti 2000, Spigset 2000, Mitchell 1999, Meny 1993)}

However, excessive sedation in the mother or infant may occur if they are rapid metabolizers of codeine to morphine due to an excess of the gene linked to the P450-2D6 enzyme: this occurs in <1% of Chinese, Japanese and Hispanic people; 3% African Americans; 1-10% of Caucasians and 16-29% of North Africans, Ethiopians and Saudis ^{(Halder 2015, Sachs 2013)}. The genetic diagnosis of this characteristic is not available in usual clinical practice. ^{(Madadi, 2011)}

Codeine through breast milk has been linked to the appearance of neonatal apnea ^{(Naumburg, 1988)}, drowsiness ^(Ito 1993), neurological depression ^{(Madadi, 2008)} and, above all, a fatal outcome: a newborn whose mother had this genetic abnormality died at 13 days; the mother was taking 60 mg of codeine twice daily, morphine levels were normal in breast milk, but very high in the child's plasma ^{(Madadi 2007, Koren 2006)}. Subsequently, the causality of codeine in this case has been denied or called into question. ^{(Zipursky 2020, Bateman 2008, Ferner RE 2008, Young 2007)}

A link has been found between the use of codeine during pregnancy and breastfeeding and the risk of developing neuroblastoma in the infant. ^{(Cook, 2004)}

Because of all this, and with newborns having a limited capacity for opioid elimination ^{(Willmann 2009)} and the existence of more effective alternatives, many authors and institutions advocate completely discouraging its use in infants and breastfeeding mothers. ^{(Lamvu 2018, FDA 2017, Al-Adhami 2016, Lazaryan 2015, AEMPS 2015, Sachs 2013, EMA 2013)}

Other authors advocate cautious use (some even in the case of rapid metabolizers), using the lowest possible effective dose and for no more than 3-4 days and monitoring for signs of sedation in mother and infant. ^{(Ito 2018, Royal Berkshire-NHS 2016, Halder 2015, Reece-Stremtan-ABM Protocol#21 2015, Chow 2015, Kelly 2013, UKMi NHS 2013, Rowe 2013, Montgomery-ABM protocol#15 2012, Amir 2011, Madadi 2009, Madadi 2007, FDA 2007)}

The use of non-steroidal anti-inflammatory drugs (NSAIDs) better controls pain and with fewer side effects than codeine alone or in combination with paracetamol ^{(Palanisamy 2014, Hendrickson 2012, van den Anker 2012, Madadi 2009, Nauta 2009, Willmann 2009)}, and codeine is not included either in international consensus on the treatment of migraines. ^{(Bordini 2016, Worthington 2013)}

Follow WHO standards for childbirth attendance, reduce cesarean sections and episiotomies, and therefore the need for analgesics in the first few days.