Pharmacologic evidence to support clinical decision making for peripartum methadone treatment

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 three 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 hours; S-methadone 8.02-18.9 hours) were about half of those reported in non-pregnant populations. In 3 women with weekly 24-hour 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.

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

“…For example, none of the studies that investigated antibiotics [47,52,53] or anesthetic and analgesic drugs [102] provided data on clinical outcomes. On the other hand, studies of addiction management drugs and antidepressant drugs reported clinical data, showing a positive correlation between decreased drug exposure and diminished clinical effects in pregnancy [70,202]. A study investigating cardiovascular drugs that reported clinical outcomes did not demonstrate significant positive clinical correlations [127].…”

Pharmacokinetics of drugs in pregnancy

“…27 Similarly, methadone metabolism varied with the specific genotype of CYP2B6. 28 Enzyme activity varies with ethnicity, gender, age, and certain disease states that are unrelated to pregnancy. Commonly, enzymes have numerous substrates, and different drugs may undergo metabolism by several enzymes.…”

The Effect of Methadone Dose Regimen on Neonatal Abstinence Syndrome

“…Swift et al (1989) in a single case study calculated a methadone half-life of 8.1 hours, which they felt documented the need for an altered dosing regimen in pregnancy. Finally, a recent study of methadone pharmacokinetics across childbearing documented shorter half-life (as low as 11 hours) and larger clearances during pregnancy, prompting the authors to conclude that "serious consideration should be given to offering women split methadone dosing" (Bogen et al, 2013). Despite the forgoing evidence, single dose regimens remain the common practice, including being used as the comparator condition in the National Institute of Drug Abuse study comparing the use of methadone and buprenorphine in pregnancy (Jones et al, 2010).…”