Alterations in Methadone Metabolism During Late Pregnancy

Abstract

Traditionally, methadone maintenance therapy has been a once-daily dosing schedule. The current study evaluates the effectiveness of this regimen during pregnancy. A total of 23 pregnant and 16 non-pregnant opioid-dependent patients were studied in two phases to evaluate pregnancy-dependent changes in methadone pharmacokinetics. In the first phase, pregnant patients had a statistically significant higher elimination rate constant (k) and lower half-life compared to non-pregnant controls. In the second phase, the apparent clearance (Cl/F) was significantly greater during pregnancy, with preliminary data suggesting that this observation results from a decrease in the fraction of dose absorbed (F). The implications of these findings on dosing regimens during pregnancy is discussed.

Respiratory effects of chronic in utero methadone or morphine exposure in the neonatal guinea pig

“…Guinea pigs [12] and humans [25,38] hyperventilate during pregnancy, which is suppressed by opioids, and both species have a hemomonochorial placenta with similar permeability characteristics [6,31]. Importantly, the elimination half-life of methadone is 15 hrs in the pregnant guinea pig [37] which is comparable to that in humans [16,36,41]. In contrast, the elimination half-life of morphine in the pregnant guinea pig is 1.3 hr [40].…”

“…We hypothesize that in utero methadone exposure will result in similar locomotor and respiratory disturbances. However, due to its long elimination half-life in pregnant guinea pigs [37], we expect methadone-induced changes to be of slower onset and longer duration than morphine whose elimination half-life is about one tenth as long, while both values are comparable to pregnant human subjects [16,36,40,41].…”

Neonatal Abstinence Syndrome

“…28 Nevertheless, methadone treatment also has been related to the increased incidence of NAS. 12,29 Research on the pharmacokinetics of methadone during pregnancy has led to the administration of higher methadone doses than were used 20 years ago 30,31 ; however, it is unclear if these increases in maternal methadone dose have further increased the incidence of NAS. [32][33][34][35][36][37] Buprenorphine, a semisynthetic partial m-opioid receptor agonist and a complete k-opioid receptor antagonist, has been found to be equally safe and efficacious and has become an effective alternative to methadone for opioid dependency during pregnancy.…”

Dosing and Monitoring of Methadone in Pregnancy: Literature Review

“…The literature search yielded 1 case report 16 and 10 studies [9][10][11][17][18][19][20][21][22][23] discussing the use of methadone in pregnant women. Methadone pharmacokinetics in pregnancy was studied in 3 pharmacokinetic trials, [9][10][11] and split dosing of methadone in pregnant women was described in the case report 16 and in 3 dosing trials.…”

“…3,6 Several studies have suggested that the dosage of methadone should be increased for pregnant women to ensure maintenance concentrations similar to those in nonpregnant patients. [9][10][11] This need for escalating dosages may be explained by the numerous physiologic changes that a woman experiences during pregnancy, which may result in alterations in the pharmacokinetics of methadone, specifically its absorption, distribution, metabolism, and elimination.…”