title: Pharmacologic evidence to support clinical decision making for peripartum methadone treatment.
abstract: BACKGROUND
  Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, Division of General Academic Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3414 Fifth Ave, CHOB 3rd floor, Pittsburgh, PA 15213, USA. bogendl@upmc.edu
authors.forename: D L
authors.initials: DL
authors.lastname: Bogen
authors.forename: J M
authors.initials: JM
authors.lastname: Perel
authors.forename: J C
authors.initials: JC
authors.lastname: Helsel
authors.forename: B H
authors.initials: BH
authors.lastname: Hanusa
authors.forename: M
authors.initials: M
authors.lastname: Romkes
authors.forename: T
authors.initials: T
authors.lastname: Nukui
authors.forename: C R
authors.initials: CR
authors.lastname: Friedman
authors.forename: K L
authors.initials: KL
authors.lastname: Wisner
mesh_terms: D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003657:Decision Making; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008137:Longitudinal Studies; D008691:Methadone / Q000008:administration & dosage*; D058850:Opiate Substitution Treatment / Q000379:methods; D009293:Opioid-Related Disorders / Q000534:rehabilitation*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D058725:Peripartum Period; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D011263:Pregnancy Trimester, Third; D011446:Prospective Studies; D013237:Stereoisomerism; D055815:Young Adult
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D008691:Methadone