Changes to methadone clearance during pregnancy

Measurement of plasma methadone concentration to investigate the rate of clearance of methadone prescribed for heroin dependence in the first, second and third trimesters of pregnancy. A secondary objective was to evaluate the outcome of pregnancy.

Longitudinal within subject study of nine pregnant opioid dependent subjects prescribed methadone at the Leeds Addiction Unit, an outpatient community based treatment centre. Plasma concentration versus time data for methadone was collected during each trimester and post-partum for our subjects. Data was available for the first and second trimesters for 4/9 cases. All but one of the subjects provided data during the third trimester and data post-partum was collected from three respondents. Measurements of methadone levels in plasma were carried out using high performance liquid chromatography (HPLC).

Trough mean plasma methadone concentrations reduced as the pregnancies progressed from 0.12 mg/L (first trimester) to 0.07 mg/L (third trimester). The weight-adjusted clearance rates gradually increased from a mean of 0.17 to 0.21 L/hr/kg during pregnancy, although patterns differed substantially between the nine women. An assessment of relative clearance of methadone using two patients for whom we have had all three CL values (trimester 1-3) demonstrated notable change of CL (P = 0.056) over time. Eight of our subjects delivered (3 males), within two weeks of their due date the ninth (male) was premature (21 days). The mean length of gestation was 39.7 weeks (SD = 10 days) and none of the neonates met criterion for 'low birth weight' mean = 3094, SD = 368 g). Five neonates spent time (0.5-28 days) in a special care baby unit (SCUBU) and 4 of these displayed signs of methadone withdrawal.

General Practitioners and hospital doctors should recognise the significant benefits of prescribing methadone for heroin-dependent women during pregnancy. We recommend that if a pregnant opioid user complains of methadone withdrawal symptoms (i.e. that the methadone dose does not "hold" them) the prescribing clinician takes this observation seriously and considers a more detailed assessment. Further work on key factors undergoing changes during pregnancy accounting for differences in methadone metabolism in the mother, fetus and neonate are required.