Altered methadone pharmacokinetics in methadone-maintained pregnant women

We studied the influence of human pregnancy on the maternal disposition and effects of methadone. Nine healthy pregnant women who had been on p.o. methadone maintenance for at least 2 months were studied between 20 and 34 weeks of gestation (phase I), 35 and 40 weeks (phase II), 1 to 4 weeks post partum (phase III) and 8 to 9 weeks post partum (phase IV). Two subjects who breast-fed their infants had plasma and breast milk samples collected simultaneously. With or without normalization for dose and body weight, trough plasma concentrations of methadone were significantly lower and total or unbound methadone clearances greater during pregnancy than after delivery. Plasma protein binding of methadone was lower during pregnancy but the difference was only statistically significant between phases I and IV. The greater ratios of urinary excretion of the major metabolites to total and unbound methadone areas under the curve during pregnancy suggests that methadone metabolism was enhanced. The ratios of concentrations of methadone in milk to plasma were constant in two subjects, 0.32 +/- 0.06 and 0.61 +/- 0.07, respectively. Some of the women reported symptoms of methadone withdrawal during pregnancy, even when the daily methadone dose did not change. Because of the lower plasma methadone concentrations, increased methadone doses may be required during pregnancy to achieve methadone maintenance.