Breastfeeding, a public health priority, improves outcomes for infants. Methadone is dispensed as a racemic mixture; R-methadone is the active enantiomer. Pharmacologic data for R-methadone in breastmilk could improve risk–benefit decision-making for treatment of lactating women. This study estimated infant exposure to R- and S-methadone via breastmilk by theoretic infant dose (TID) and relative infant dose (RID) and reported the milk-to-maternal plasma (M/P) ratio.
Methods:
Women treated with methadone doses of 40–200 mg/day (mean, 102 mg/day) provided concomitantly collected plasma and breastmilk samples 1–6 days after delivery. Most (16 of 20) samples were taken at the time of peak maternal plasma levels; thus infant exposure estimates are for maximum possible exposure. Concentrations of R- and S-methadone were measured in maternal plasma and breastmilk; M/P ratio, TID, and RID were calculated for each enantiomer and total methadone.
Results:
The 20 participants were 18–38 years old and publicly insured; a quarter did not complete high school, and only one was not white. R-Methadone concentration was 1.3–3.0 times that of S-methadone in all breastmilk samples. The mean (SD) R-, S-, and total methadone M/P ratios were 0.52 (0.28), 0.28 (0.15), and 0.40 (0.21), respectively. Mean (range) R-, S-, and total methadone TID were 0.02 mg/kg/day (0.004–0.099), 0.013 mg/kg/day (0.002–0.071), and 0.033 mg/kg/day (0.006–0.170), respectively. Mean (range) RID of R-, S-, and total methadone were 2.7% (0.7–10.1%), 1.6% (0.3–7.2%), and 2.1% (0.52–8.8%), respectively.
Conclusions:
R-Methadone is found in higher concentrations than S-methadone in breastmilk. Even at high methadone doses, breastmilk methadone concentrations were relatively low and support American Academy of Pediatrics recommendations that dose should not be a factor in determining whether women on methadone breastfeed.
Get full access to this article
View all access options for this article.
References
1.
Office on Women's Health, U.S. Department of Health and Human Services. Health and Human Services Blueprint for Action on Breastfeeding. Washington, DC, 2000.
2.
GartnerLM, MortonJ, LawrenceRAet al.Breastfeeding and the use of human milk. Pediatrics, 2005; 115:496–506.
3.
American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics, 2001; 108:776–789.
4.
American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics, 1994; 93:137–150.
5.
GeraghtyB, GrahamEA, LoganBet al.Methadone levels in breast milk. J Hum Lact, 1997; 13:227–230.
6.
Wojnar-HortonRE, KristensenJH, YappPet al.Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme. Br J Clin Pharmacol, 1997; 44:543–547.
7.
BlinickG, InturrisiCE, JerezEet al.Methadone assays in pregnant women and progeny. Am J Obstet Gynecol, 1975; 121:617–621.
8.
KreekMJ. Methadone disposition during the perinatal period in humans. Pharmacol Biochem Behav, 1979; 11,Suppl:7–13.
BeggEJ, MalpasTJ, HackettLPet al.Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing. Br J Clin Pharmacol, 2001; 52:681–685.
11.
JanssonLM, ChooRE, HarrowCet al.Concentrations of methadone in breast milk and plasma in the immediate perinatal period. J Hum Lact, 2007; 23:184–190.
12.
McCarthyJJ, PoseyBL. Methadone levels in human milk. J Hum Lact, 2000; 16:115–120.
13.
Abdel-LatifME, PinnerJ, ClewsSet al.Effects of breast milk on the severity and outcome of neonatal abstinence syndrome among infants of drug-dependent mothers. Pediatrics, 2006; 117:e1163–e1169.
14.
ArlettazR, KashiwagiM, Das-KunduSet al.Methadone maintenance program in pregnancy in a Swiss perinatal center (II): Neonatal outcome and social resources. Acta Obstet Gynecol Scand, 2005; 84:145–150.
15.
BallardJL. Treatment of neonatal abstinence syndrome with breast milk containing methadone. J Perinat Neonatal Nurs, 2002; 15:76–85.
16.
Academy of Breastfeeding Medicine Protocol Committee. ABM clinical protocol #21: Guidelines for breastfeeding and the drug-dependent woman. Breastfeed Med, 2009; 4:225–228.
17.
GendronMP, MartinB, OraichiDet al.Health care providers' requests to Teratogen Information Services on medication use during pregnancy and lactation. Eur J Clin Pharmacol, 2009; 65:523–531.
18.
ItoS, KorenG, EinarsonTR. Maternal noncompliance with antibiotics during breastfeeding. Ann Pharmacother, 1993; 27:40–42.
19.
ItoS, LieuM, ChanWet al.Continuing drug therapy while breastfeeding. Part 1. Common misconceptions of patients. Can Fam Physician, 1999; 45:897–899.
20.
ItoS, MorettiM, LiauMet al.Initiation and duration of breast-feeding in women receiving antiepileptics. Am J Obstet Gynecol, 1995; 172:881–886.
21.
EapCB, BertschyG, BaumannPet al.High interindividual variability of methadone enantiomer blood levels to dose ratios. Arch Gen Psychiatry, 1998; 55:89–90.
22.
FosterDJ, SomogyiAA, BochnerF. Methadone N-demethylation in human liver microsomes: Lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol, 1999; 47:403–412.
23.
GerberJG, RhodesRJ, GalJ. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality, 2004; 16:36–44.
24.
TotahRA, SheffelsP, RobertsTet al.Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology, 2008; 108:363–374.
25.
KharaschED, HofferC, WhittingtonDet al.Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport. Anesthesiology, 2009; 110:660–672.
26.
CrettolS, DéglonJ-J, BessonJet al.Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther, 2005; 78:593–604.
27.
KristensenK, ChristensenCB, ChristrupLL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci, 1995; 56:PL45–PL50.
28.
Institute of Medicine Committee on Federal Regulation of Methadone Treatment; Division of Biobehavioral Sciences and Mental Disorders. Federal Regulation of Methadone Treatment. National Academy Press: Washington, DC, 1995.
29.
LeavittSB, ShindermanM, MaxwellSet al.When “enough” is not enough: New perspectives on optimal methadone maintenance dose. Mt Sinai J Med, 2000; 67:404–411.
30.
EapCB, BourquinM, MartinJet al.Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend, 2000; 61:47–54.
31.
LehotayDC, GeorgeS, EtterMLet al.Free and bound enantiomers of methadone and its metabolite, EDDP in methadone maintenance treatment: Relationship to dosage?Clin Biochem, 2005; 38:1088–1094.
32.
JanssonLM, ChooR, VelezMLet al.Methadone maintenance and breastfeeding in the neonatal period. Pediatrics, 2008; 121:106–114.
33.
FosterDJ, SomogyiAA, WhiteJMet al.Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients. Br J Clin Pharmacol, 2004; 57:742–755.
34.
KristensenJH, IlettKF, DusciLJet al.Distribution and excretion of sertraline and N-desmethylsertraline in human milk. Br J Clin Pharmacol, 1998; 45:453–457.
35.
Moses-KolkoEL, MeltzerCC, HelselJCet al.No interruption of lactation is needed after 11C-WAY 100635 or 11C-raclopride PET. J Nucl Med, 2005; 46:1765.
36.
BennettP. Use of the monographs on drugs. BennettP. Drugs and Human Lactation. Elsevier: Amsterdam, 1996; 67–74.
37.
HaleTW. Medications and Mother's Milk, 13th. Hale Publishing: Amarillo, TX, 2008.
38.
TukeyJW. Exploratory Data Analysis. Addison-Wesley: Reading, MA, 1977.
39.
EapCB, CuendetC, BaumannP. Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: Role of the variants of alpha 1-acid glycoprotein. Clin Pharmacol Ther, 1990; 47:338–346.
40.
EapCB, CrettolS, RougierJSet al.Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther, 2007; 81:719–728.
41.
LinC, SombergT, MolnarJet al.The effects of chiral isolates of methadone on the cardiac potassium channel IKr. Cardiology, 2009; 113:59–65.
42.
AdamopoulosDA, KapollaN. Prolactin concentration in milk and plasma of puerperal women and patients with galactorrhea. J Endocrinol Invest, 1984; 7:273–276.
43.
NissenE, Uvnas-MobergK, SvenssonKet al.Different patterns of oxytocin, prolactin but not cortisol release during breastfeeding in women delivered by caesarean section or by the vaginal route. Early Hum Dev, 1996; 45:103–118.
44.
IbeOE, AustinT, SullivanKet al.A comparison of kangaroo mother care and conventional incubator care for thermal regulation of infants < 2000 g in Nigeria using continuous ambulatory temperature monitoring. Ann Trop Paediatr, 2004; 24:245–251.
45.
CattaneoA, DavanzoR, WorkuBet al.Kangaroo mother care for low birthweight infants: A randomized controlled trial in different settings. Acta Paediatr, 1998; 87:976–985.
46.
MoreliusE, TheodorssonE, NelsonN. Salivary cortisol and mood and pain profiles during skin-to-skin care for an unselected group of mothers and infants in neonatal intensive care. Pediatrics, 2005; 116:1105–1113.
47.
ChantryCJ, HowardCR, AuingerP. Full breastfeeding duration and associated decrease in respiratory tract infection in US children. Pediatrics, 2006; 117:425–432.
48.
WoodwardA, DouglasRM, GrahamNMet al.Acute respiratory illness in Adelaide children: Breast feeding modifies the effect of passive smoking. J Epidemiol Community Health, 1990; 44:224–230.
49.
MalpasTJ, DarlowBA. Neonatal abstinence syndrome following abrupt cessation of breastfeeding. N Z Med J, 1999; 112:12–13.
50.
McCarthyJJ, LeamonMH, ParrMSet al.High-dose methadone maintenance in pregnancy: Maternal and neonatal outcomes. Am J Obstet Gynecol, 2005; 193:606–610.
51.
WachmanE, ByunJ, PhilippB. Breastfeeding rates among mothers of infants with neonatal abstinence syndrome. Breastfeed Med, 2010; 5:159–164.
52.
CrowellDT. Weight change in the postpartum period. A review of the literature. J Nurse Midwifery, 1995; 40:418–423.
