Distribution of R‐ and S‐methadone into human milk during multiple, medium to high oral dosing

Abstract

Aims To measure the interdose milk to plasma ratio (M/P) of R-and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (>40 mg daily), and to assess likely infant exposure. Methods Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of i40 mg day . Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0±4, 4±8, 8±12, 12±16, 16±20, and 20±24 h after dose. R-and S-methadone were quanti®ed by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/P AUC was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg x1 . Results For immature milk (n=8) the M/P AUC for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n=2) the M/P AUCs for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R-and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R-plus S-methadone together was 2.8% (1.7, 3.9%). Conclusions Breastfeeding during medium to high dose methadone appears to be`safe' according to conventional criteria because the dosage is <10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the riskbene®t ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be suf®cient to prevent the neonatal abstinence syndrome.

Can methadone concentrations predict the severity of withdrawal in infants at risk of neonatal abstinence syndrome?

“…The median dose of the three women who exclusively breast fed and whose babies developed NAS severe enough to warrant treatment was significantly lower than the six exclusively breast fed infants in the untreated group (20 v 80 mg/day, p = 0.019), but whether this affects the initial cord concentration, the quantity of methadone in the milk, or both cannot be determined, as methadone concentrations in maternal milk were not evaluated. The excretion of methadone in human milk is variable and related to maternal plasma concentrations, but is not thought to be significant enough to prevent NAS, 19 despite reports describing withdrawal in infants with sudden cessation of breast feeding. 20 We were unable to determine the quantity of milk, and therefore the potential dose of methadone, the babies received.…”

Maternal and neonatal factors impacting response to methadone therapy in infants treated for neonatal abstinence syndrome

“…[4][5][6] The onset, duration and severity of NAS may be impacted by the types and degree of fetal drug exposure and by neonatal treatment strategies, [7][8][9][10][11][12][13] use of tobacco during pregnancy, 14 gestational age 15,16 and use of maternal breast milk (MBM) as the primary source of nutrition. [17][18][19][20] The interactions of these factors and the composite impact on response to pharmacologic therapy for NAS have not been adequately elucidated in a large cohort of infants.…”

Estimated Infant Exposure to Enantiomer-Specific Methadone Levels in Breastmilk

“…The large variation in methadone concentrations in maternal plasma and breastmilk may be explained in part by difference in cytochrome activity. For example, it is plausible that the outlier sample came from a woman who is a slow metabolizer of methadone, emphasizing the point made by Begg et al 10 for individualizing management as much as possible.…”

“…However, the methadone levels we report are consistent with previously reported study findings, including our finding of higher concentrations of R-than Smethadone in breastmilk. 10 Finally, for the RID calculation, maternal third trimester weight was used, which likely overestimates maternal weight after birth. To determine the potential impact of lower maternal weight on RID, the RID calculations were rerun assuming a 5 kg weight loss, an estimate of the average weight loss at delivery.…”

“…Enantiomer-specific methadone concentrations in breastmilk were reported in a single study of eight cases. 10 Begg et al 10 found that R-methadone concentrations were nearly twice that of S-methadone in breastmilk. Characterization of infant exposure to methadone via breastmilk ideally includes assay of the more potent R-enantiomer.…”