High Accumulation of Methadone Compared with Buprenorphine in Fetal Rat Brain after Maternal Exposure

Experimental animal studies are valuable in revealing a causal relationship between prenatal exposure to opioid maintenance treatment (OMT) and subsequent effects; however, previous animal studies of OMT during pregnancy have been criticized for their lack of clinical relevance because of their use of high drug doses and the absence of pharmacokinetic data. Hence, the aim of this study was to determine blood and brain concentrations in rat dams, fetuses, and offspring after continuous maternal exposure to methadone or buprenorphine during gestation and to examine the offspring for neonatal outcomes and withdrawal symptoms. Female rats were implanted with a 28-day osmotic minipump delivering methadone (10 mg/kg per day), buprenorphine (1 mg/kg per day) or vehicle 5 days before mating. Continuous exposure to methadone or buprenorphine induced stable blood concentrations in the dams of 0.25 ± 0.02 µM and 5.65 ± 0.16 nM, respectively. The fetal brain concentration of methadone (1.89 ± 0.35 nmol/g) was twice as high as that in the maternal brain, whereas the fetal brain concentration of buprenorphine (20.02 ± 4.97 pmol/g) was one-third the maternal brain concentration. The opioids remained in the offspring brain several days after the exposure ceased. Offspring prenatally exposed to methadone, but not buprenorphine, displayed reduced body weight and length and increased corticosterone levels. No significant changes in ultrasonic vocalizations were revealed. Our data in rat fetuses and neonates indicate that OMT with buprenorphine may be a better choice than methadone during pregnancy. SIGNIFICANCE STATEMENT: Concern has been raised about the use of opioid maintenance treatment during pregnancy because of the important role of the endogenous opioid system in brain development. Here, we show that the methadone concentration in the fetal rat brain was twice as high as that in the maternal brain, whereas the buprenorphine concentration was one-third the maternal concentration. Furthermore, buprenorphine allowed more favorable birth outcomes, suggesting that buprenorphine may be a better choice during pregnancy.