Ohio Valley Node-Network (OVNN) of the NIDA Clinical Trial (HIV supplement MOMS)

Maintenance with sublingual (SL) buprenorphine (BUP) is efficacious for opioid use disorder (OUD) but can be associated with misuse/diversion and poor medication adherence. Hence, NIDA has been working with pharmaceutical companies to develop extended-release (XR) BUP formulations. Two BUP-XR products (CAM2038 from Braeburn Pharmaceuticals and RBP-6000 from Indivior), both of which are subcutaneously injected and form a gel deposit under the skin that releases BUP at a steady rate for up to one month, are expected to be FDA-approved in early 2018. While these formulations will likely benefit many individuals with OUD, they may be particularly beneficial in pregnant women. The growing opioid-use epidemic in the U.S. has been associated with a significant increase in the prevalence of pregnant opioid-dependent women and neonatal abstinence syndrome (NAS). NAS is associated with adverse health effects for the infant and with costly hospitalizations. In 2012, the average length of stay (LOS) for NAS was 16.9 days and the average cost was $66,700. In 2013, about 4% of total neonatal intensive care unit days were attributed to infants with NAS, compared to just 0.6% in 2004. Pregnant women with OUD face a number of challenges, including psychosocial stressors and psychiatric co-morbidity that may serve to reduce medication adherence. In addition, research has found that the most common concerns of BUP-maintained pregnant women are the health of their unborn infant and the potential for NAS; expecting 100% adherence to daily self-administration of a medication that a woman worries may harm her unborn child may be unrealistic and could be remedied with an XR formulation given by medical staff. Another limitation of BUP-SL is the daily peak-trough cycles of BUP, with weaker treatment effects at trough; the BUP-XR products obviate this daily cycle with steady concentrations of BUP over the dosing period. The avoidance of the daily peak-trough cycle may have an additional benefit in pregnant women in that this cycle is associated with adverse effects for the fetus, including decreased fetal heart rate and heart rate variability; these effects should be minimized through the use of BUPXR. While the reasons are not entirely clear, treatment retention rates in BUP-maintained pregnant women are problematic, with a randomized double-blind study (MOTHER) reporting 33% drop-out in participants randomized to BUP compared to 18% in the methadone group. A recent study evaluating fetal effects of BUP dosing reported a sizeable attrition rate, with measures obtained for only 42% of eligible participants. Postpartum treatment retention may be even more problematic with data from our methadone clinic revealing that 36% discontinue treatment by 3 months postpartum, and 62% discontinue by 6 months postpartum. 21 Moreover, data from our perinatal clinic reveal that 53% of women maintained on BUP-SL discontinue treatment by 3 months postpartum, and 75% discontinue treatment by 6 months postpartum (unpublished). For mothers of a newborn, with all the demands that motherhood entails, once-monthly dosing has the potential to dramatically improve treatment retention rates and overall medication effectiveness. During both pregnancy and postpartum, we predict that the benefits of BUP-XR in improved medication adherence and avoidance of the daily peak-trough cycle will translate into improved pregnancy and neonatal outcomes as well as improved treatment retention, and hence, less chance of relapse, compared to daily BUP-SL treatment. It is important to note, though, that improved medication adherence during pregnancy also translates into potentially more exposure to BUP and the degree to which this will impact incidence and severity of NAS is unclear. The specific aims of this project are to compare the effects of BUP-XR and BUP-SL on: 1) Neonatal outcomes, with neonatal LOS as the primary outcome; 2) participant treatment retention and illicit opioid use during pregnancy; and 3) treatment retention and illicit opioid use during 6-months postpartum.