Pharmacologic evidence to support clinical decision making for peripartum methadone treatment

• Published in: Psychopharmacology Vol. 225; no. 2; pp. 441 - 451
• Main Authors: Bogen, D. L., Perel, J. M., Helsel, J. C., Hanusa, B. H., Romkes, M., Nukui, T., Friedman, C. R., Wisner, K. L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.01.2013; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aryl Hydrocarbon Hydroxylases - genetics; Biomedical and Life Sciences; Biomedicine; Clinical trials; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A - genetics; Decision Making; Decision making models; Dosage and administration; Dose-Response Relationship, Drug; Drug therapy; Female; Genotype; Half-Life; Health aspects; Humans; Longitudinal Studies; Methadone; Methadone - administration & dosage; Methadone hydrochloride; Methods; Neurosciences; Opiate Substitution Treatment - methods; Opioid-Related Disorders - rehabilitation; Original Investigation; Oxidoreductases, N-Demethylating - genetics; Patient outcomes; Peripartum Period; Pharmacology; Pharmacology/Toxicology; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy Complications - drug therapy; Pregnancy Trimester, Third; Pregnant women; Prospective Studies; Psychiatry; Stereoisomerism; Young Adult; Pregnancy; Rac-methadone; CYP2B6; S-Methadone; R-Methadone; Half-life; Pharmacokinetics; CYP3A4; Postpartum
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-012-2833-7

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.