Abstract
Rationale: Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum. Objectives: Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D. Methods: Methadone dose changes and timed plasma samples were obtained for women on methadone (n = 25) followed prospectively from third trimester of pregnancy to 3 months postpartum. Results: Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase = 23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase = 19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7-24.9 h; S-methadone, 8.02-18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1-2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum. Conclusions: Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery.
Original language | English (US) |
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Pages (from-to) | 441-451 |
Number of pages | 11 |
Journal | Psychopharmacology |
Volume | 225 |
Issue number | 2 |
DOIs | |
State | Published - Jan 2013 |
Funding
Acknowledgments This study was funded by The Children’s Hospital of Pittsburgh Research Advisory Committee and The Gerber Foundation. Study visits were conducted in the Magee-Womens Hospital Clinical and Translational Research Center which is supported by the National Institutes of Health through Grant Numbers UL1 RR024153 and UL1TR000005. Medela, Inc. supported this study by providing the breast pump supplies to collect breastmilk samples and educational materials. Dr. Bogen’s contribution to this work was supported by K12 HD043441 (BIRCWH Award). Support for the time of Dr. Wisner, Mr. Helsel, and Dr. Perel was funded by R01 MH 075921 (K. Wisner, PI). This project was also supported in part by the award 5MO1 RR00056 and P30CA047904 for the genotyping analyses by Drs. Romkes and Nukui. We would like to thank the staff of NATP, in particular Millie Hopkins, for their support of this project.
Keywords
- CYP2B6
- CYP2C19
- CYP3A4
- Half-life
- Pharmacokinetics
- Postpartum
- Pregnancy
- R-Methadone
- Rac-methadone
- S-Methadone
ASJC Scopus subject areas
- Pharmacology