Toward the use of buprenorphine in infants for neonatal opioid withdrawal syndrome: summary of an NIH workshop (original) (raw)
Related papers
Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome
Clinical and Translational Science, 2021
Results from BBORN, a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of BPHORE, a new trial with buprenorphine in a similar population were to 1) optimize initial dose, up-titration to achieve symptom control and weaning steps of pharmacologic treatment and 2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when uptitration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose-dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 ug/kg/day, 33% titration and 15% wean rate. Five subjects required adjuvant therapy. EC50 values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model-based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.
Buprenorphine treatment of pregnant opioid-dependent women: maternal and neonatal outcomes
Drug and Alcohol Dependence, 2001
This open-label prospective study examined maternal and neonatal safety and efficacy outcome measures during and following prenatal buprenorphine exposure. Three opioid-dependent pregnant women received 8 or 12 mg sublingual buprenorphine tablets daily for 15-16 weeks prior to delivery. Results showed that buprenorphine in combination with comprehensive prenatal care was safe and effective in these women. Prenatal exposure to buprenorphine resulted in normal birth outcomes, a mean of 4.33 days (minimum possible=4) hospitalization, and a 'relatively mild' neonatal abstinence syndrome comprised primarily of tremors (disturbed), hyperactive moro and shortened sleep after feeding. The infants required no pharmacological treatment. Onset of neonatal abstinence signs occurred within the first 12 h after birth, peaked by 72 h and returned to below pre-12 h levels by 120 h. It is concluded that buprenorphine has potential utility for the treatment of pregnant opioid-dependent women.
Use of buprenorphine in pregnancy: patient management and effects on the neonate
Drug and Alcohol Dependence, 2003
It is estimated that 55 Á/94% of infants born to opioid-dependent mothers in US will show signs of opioid withdrawal. Buprenorphine has been reported to produce little or no autonomic signs or symptoms of opioid withdrawal following abrupt termination in adults. To date, there have been 21 published reports representing approximately 15 evaluable cohorts of infants exposed to buprenorphine in utero. Of approximately 309 infants exposed, a neonatal abstinence syndrome (NAS) has been reported in 62% infants with 48% requiring treatment; apparently greater than 40% of these cases are confounded by illicit drug use. The NAS associated with buprenorphine generally appears within 12 Á/48 h, peaks at approximately 72 Á/96 h, and lasts for 120 Á/168 h. These results appear similar to or less than that observed following in utero exposure to methadone. From a review of the literature, buprenorphine appears to be safe and effective in both mother and infant with an NAS that may differ from methadone both qualitatively and quantitatively. #
Substance Abuse: Research and Treatment, 2013
Given that buprenorphine + naloxone is prescribed for opioid-dependent pregnant women, it is important to examine the extent to which it differs from buprenorphine alone, methadone, or methadone-assisted withdrawal on neonatal and maternal outcomes. Summary statistics on maternal and neonatal outcomes were collected from 7 previously published studies examining treatment for opioid-dependent pregnant women that represented a range of research methodologies. Outcomes from these studies were compared to the same outcomes for 10 women treated with the combined buprenorphine + naloxone product. There were no significant differences in maternal outcomes for buprenorphine + naloxone compared to buprenorphine, methadone, or methadone-assisted withdrawal. Preliminary findings suggest no significant adverse maternal or neonatal outcomes related to the use of buprenorphine + naloxone for the treatment of opioid dependence during pregnancy. However, further research should examine possible differences between buprenorphine + naloxone and buprenorphine alone or methadone in fetal physical development.
Drug and Alcohol Dependence, 2005
This study was designed to compare the neonatal abstinence syndrome (NAS) in neonates of methadone and buprenorphine maintained pregnant opioid-dependent women and to provide preliminary safety and efficacy data for a larger multi-center trial. This randomized, double-blind, double-dummy, flexible dosing, parallel-group controlled trial was conducted in a comprehensive drug-treatment facility that included residential and ambulatory care. Participants were opioid-dependent pregnant women and their neonates. Treatment involved daily administration of either sublingual buprenorphine or oral methadone using flexible dosing of 4-24 mg or 20-100 mg, respectively. Primary a priori outcome measures were: (1) number of neonates treated for NAS; (2) amount of opioid agonist medication used to treat NAS;
Neonatal outcomes and their relationship to maternal buprenorphine dose during pregnancy
Drug and Alcohol Dependence, 2014
Background-Buprenorphine pharmacotherapy for opioid-dependent pregnant women is associated with maternal and neonatal outcomes superior to untreated opioid dependence. However, the literature is inconsistent regarding the possible existence of a dose-response relationship between maternal buprenorphine dose and neonatal clinical outcomes. Methods-The present secondary analysis study (1) examined the relationship between maternal buprenorphine dose at delivery and neonatal abstinence syndrome (NAS) peak score, estimated gestational age at delivery, Apgar scores at 1 and 5 minutes, neonatal head circumference, length, and weight at birth, amount of morphine needed to treat NAS, duration of NAS treatment, and duration of neonatal hospital stay; and (2) compared neonates who required pharmacotherapy for NAS to neonates who did not require such pharmacotherapy on these same outcomes, in 58 opioid-dependent pregnant women receiving buprenorphine as participants in a randomized clinical trial. Results-(1) Analyses failed to provide evidence of a relationship between maternal buprenorphine dose at delivery and any of the 10 outcomes (all p-values>.48); and (2) significant
Addiction (Abingdon, England), 2016
To assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder. We searched PubMed, Embase and the Cochrane Library from inception through February 2015 for randomized controlled trials (RCT) and observational cohort studies (OBS) that compared buprenorphine with methadone for treating opioid-dependent pregnant women. Two reviewers independently assessed titles and abstracts of all search results and full texts of potentially eligible studies reporting original data for maternal/fetal/infant death, preterm birth, fetal growth outcomes, fetal/congenital anomalies, fetal/child neurodevelopment, and/or maternal adverse events. We ascertained each study's risk of bias using validated instruments and assessed the strength of evidence for each outcome using established methods. We computed effect sizes using random-effects models for each outcome with 2 or more studies. Three RCTs (N = 223) and 15 cohort OBS (N = 1923) met inclusion crit...
Journal of Pharmacology and Experimental Therapeutics, 2019
Buprenorphine is the preferred treatment for opioid use disorder during pregnancy but can cause fetal opioid dependence and neonatal opioid withdrawal syndrome (NOWS). Notably, withdrawal severity is independent of maternal buprenorphine dose, suggesting that interindividual variance in pharmacokinetics may influence risk and severity of NOWS. Using a rat model of NOWS, we tested the hypothesis that clinically relevant doses of the active metabolite norbuprenorphine (NorBUP) can induce in utero opioid dependence, manifested as naltrexoneprecipitated withdrawal signs in the neonate. Pregnant Long-Evans rats were implanted with 14day osmotic minipumps containing vehicle, morphine (positive control), or NorBUP (0.3-10 mg/kg/day) on gestation day (GD) 9. By 12 hours post-delivery, an intraperitoneal injection of the opioid antagonist naltrexone (1 or 10 mg/kg) or saline was administered to pups. Precipitated withdrawal signs were graded by raters blinded to treatment conditions. In a separate group, NorBUP concentrations in maternal and fetal blood and brain on gestation day 20 were determined by liquid chromatography-tandem mass spectrometry. Steady-state maternal blood concentrations of NorBUP in dams infused with 1 or 3 mg/kg/day were comparable to values reported in pregnant humans treated with buprenorphine (1.0 and 9.6 ng/mL, respectively), suggesting a clinically relevant dosing regimen. At these doses, NorBUP increased withdrawal severity in the neonate as evaluated by ten withdrawal indicators. These findings support the possibility that NorBUP contributes to fetal opioid dependence and NOWS following maternal buprenorphine treatment during pregnancy.
Buprenorphine-naloxone use in pregnancy for treatment of opioid dependence
Canadian Family Physician, 2016
Objective To examine the maternal course and neonatal outcomes for women using buprenorphine-naloxone for opioid dependence in pregnancy. Design Retrospective cohort study comparing outcomes for the group of pregnant patients exposed to buprenorphine-naloxone with outcomes for those exposed to other narcotics and those not exposed to narcotics. Setting Northwestern Ontario obstetric program. Participants A total of 640 births in an 18-month period from July 1, 2013, to January 1, 2015. Main outcome measures Maternal outcomes included route and time of delivery, medical and surgical complications, out-of hospital deliveries, change in illicit drug use, and length of stay. Neonatal outcomes included stillbirths, incidence and severity of neonatal abstinence syndrome, birth weight, gestational age, Apgar scores, and incidence of congenital abnormalities. Results Thirty pregnant women used buprenorphine-naloxone for a mean (SD) of 18.8 (11.2) weeks; an additional 134 patients were expos...