Buprenorphine and norbuprenorphine concentrations associated with clinical withdrawal during pregnancy.

Abstract

Dosing of buprenorphine during pregnancy is based on dosing recommendations for non-pregnant people. This approach is not appropriate as buprenorphine concentrations, for a given dose, are lower in pregnant than non-pregnant people. Furthermore, it is unclear if buprenorphine concentrations preventing withdrawal are similar in pregnant and non-pregnant people. We sought to determine the plasma buprenorphine and norbuprenorphine concentrations at the time of withdrawal symptoms in 20 pregnant persons on a stable dose of sublingual buprenorphine. Previous evening and study day morning doses were withheld and at arrival to our research center, blood was obtained while pupillary diameter, COWS and craving scores were recorded frequently until withdrawal symptoms occurred and then the usual morning dose of buprenorphine was administered, and all measurements repeated 6 times over the ensuing 2h. At withdrawal, the plasma concentration (mean ± SD) of buprenorphine was 0.79 ± 0.44ng/ml, range 0.3-1.7ng/ml and norbuprenorphine 1.54 ± 1.01ng/ml, range 0.3-4.7ng/ml. After dosing, these concentrations peaked after 30-45min while pupillary diameter, COWS and craving scores synchronously returned toward baseline but with maximal effects lagging the peak in plasma drug concentration by 45-60min. The minimal concentration of buprenorphine required to suppress withdrawal symptoms is similar to that in non-pregnant people. The lag in the pharmacodynamic responses supports a central mu receptor effect of buprenorphine. The wide range of buprenorphine concentration at withdrawal suggests considerable variation in mu receptor responsiveness to buprenorphine and supports individualized dosing in pregnant people.