Buprenorphine in Neonatal Abstinence Syndrome.
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ABSTRACT:
SUBMITTER: Kraft WK
PROVIDER: S-EPMC5739935 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
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Buprenorphine in Neonatal Abstinence Syndrome.
Clinical pharmacology and therapeutics 20171128 1
Infants exposed in utero to opioids will demonstrate a withdrawal syndrome known as neonatal abstinence syndrome (NAS). Buprenorphine is a long-acting opioid with therapeutic use in medication-assisted treatment of opioid dependency in adults and adolescents. Emerging data from clinical trials and treatment cohorts demonstrate the efficacy and safety of sublingual buprenorphine for those infants with NAS who require pharmacologic treatment. Pharmacometric modeling will assist in defining the exp ...[more]
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Project description:Objective: To summarize the available data for using buprenorphine in neonatal abstinence syndrome and discuss these data in context of the current standard of care therapies, oral morphine and oral methadone. Data Sources: A literature search was conducted using PubMed (1949-May 2018) and EMBASE (1980-May 2018). Combinations of the search terms "buprenorphine," "neonatal," and "neonatal abstinence syndrome" were used. Study Selection and Data Extraction: All full-length, English-language studies were included in this review. Data Synthesis: A total of 4 studies were included in this review including 1 retrospective cohort study, 2 prospective single-center open-label randomized trials, and 1 prospective single-center, double-blind study. Oral morphine was the comparator in 3 studies, and oral methadone was the comparator in one. Buprenorphine was associated with a significant reduction in duration of treatment in 3 of the 4 studies and was associated with a significant reduction in duration of hospital stay in 3 of the 4 studies. In the randomized, double-blinded trial, buprenorphine had a significantly reduced duration of treatment (15 vs 28 days, P < .001) and duration of hospital stay (21 vs 33 days, P < .001). The requirement of adjunct treatment was similar between groups in all 4 studies, and buprenorphine did not have any significant adverse reactions in comparison with morphine and methadone. Conclusions: Buprenorphine appears to be a safe option for treating neonatal abstinence syndrome that is potentially superior to the current standard of care therapies with respect to duration of treatment and hospital length of stay.
| S-EPMC6231284 | biostudies-literature
Project description:BackgroundMethadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy.MethodsWe conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites. Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference.ResultsTreatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091), and had a significantly shorter duration of treatment for the neonatal abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance with prespecified thresholds for significance). There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events.ConclusionsThese results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00271219.).
| S-EPMC3073631 | biostudies-literature
Project description:BackgroundCurrent pharmacologic treatment of the neonatal abstinence syndrome with morphine is associated with a lengthy duration of therapy and hospitalization. Buprenorphine may be more effective than morphine for this indication.MethodsIn this single-site, double-blind, double-dummy clinical trial, we randomly assigned 63 term infants (≥37 weeks of gestation) who had been exposed to opioids in utero and who had signs of the neonatal abstinence syndrome to receive either sublingual buprenorphine or oral morphine. Infants with symptoms that were not controlled with the maximum dose of opioid were treated with adjunctive phenobarbital. The primary end point was the duration of treatment for symptoms of neonatal opioid withdrawal. Secondary clinical end points were the length of hospital stay, the percentage of infants who required supplemental treatment with phenobarbital, and safety.ResultsThe median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days vs. 28 days), as was the median length of hospital stay (21 days vs. 33 days) (P<0.001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group (P=0.36). Rates of adverse events were similar in the two groups.ConclusionsAmong infants with the neonatal abstinence syndrome, treatment with sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than treatment with oral morphine, with similar rates of adverse events. (Funded by the National Institute on Drug Abuse; BBORN ClinicalTrials.gov number, NCT01452789 .).
| S-EPMC5662132 | biostudies-literature
Project description:Neonatal abstinence syndrome (NAS)--a clinical entity of infants from in utero exposure to psychoactive xenobiotic and buprenorphine--has been successfully used to treat NAS. However, nothing is known about the pharmacokinetics (PK) of buprenorphine in neonates with NAS. To our knowledge, this is the first study to investigate the population pharmacokinetic of sublingual buprenorphine in neonates with NAS.A retrospective population PK analysis of: (1) neonates with NAS treated with sublingual buprenorphine in randomized, double blinded clinical study and (2) data from healthy adults from a previously published pharmacokinetic study.Neonatal intensive care unit and general clinical research unit.Twenty-four neonates with NAS and five healthy adults.All participants received sublingual buprenorphine per study protocol.A total of 303 PK data from 29 neonates and adults were used for model development. A population pharmacokinetic analysis was conducted using a first order conditional estimation with interaction in the NONMEM software program. A two-compartment linear PK model with first-order absorption process best described the pharmacokinetics of sublingual buprenorphine in neonates. The apparent clearance (CL) of buprenorphine was linearly related to body weight and matured with increasing age via two distinct saturated pathways. A typical neonate with NAS (body weight, 2.9 kg; postnatal age; 5.4 days) had a CL of 3.5 L/kg/hour and elimination half-life of 11 hours. Phenobarbital did not affect the clearance of buprenorphine compared to neonates of similar age and weight.This is the first study to investigate the population PK of sublingual buprenorphine in neonatal NAS. To our knowledge, this is also the first report to describe the age-dependent changes of buprenorphine PK in this patient population. No buprenorphine dose adjustment is needed for neonates with NAS treated with buprenorphine and concurrent phenobarbital.
| S-EPMC5119858 | biostudies-literature
Project description:Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety. The time to NAS stabilization was found to decrease with increasing buprenorphine exposure. This pharmacokinetic-pharmacodynamic (PK-PD) relationship was able to be quantified and adequately described with a mathematical model. The findings confirm a previous PK model of buprenorphine and extend the model to describe the PK of norbuprenorphine and to identify a novel PK-PD relationship of buprenorphine in NAS. This model will allow optimization of dosing strategies in future clinical trials.
| S-EPMC5992055 | biostudies-literature
Project description:In utero exposure to drugs of abuse can lead to neonatal abstinence syndrome, a condition that is associated with prolonged hospitalization. Buprenorphine is a partial mu-opioid agonist used for treatment of adult detoxification and maintenance but has never been administered to neonates with opioid abstinence syndrome. The primary objective of this study was to demonstrate the feasibility and, to the extent possible in this size of study, the safety of sublingual buprenorphine in the treatment of neonatal abstinence syndrome. Secondary goals were to evaluate efficacy relative to standard therapy and to characterize buprenorphine pharmacokinetics when sublingually administered.We conducted a randomized, open-label, active-control study of sublingual buprenorphine for the treatment of opiate withdrawal. Thirteen term infants were allocated to receive sublingual buprenorphine 13.2 to 39.0 mug/kg per day administered in 3 divided doses and 13 to receive standard-of-care oral neonatal opium solution. Dose decisions were made by using a modified Finnegan scoring system.Sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to approximately 0.60 ng/mL, which is less than needed to control abstinence symptoms in adults. The ratio of buprenorphine to norbuprenorphine was larger than that seen in adults, suggesting a relative impairment of N-dealkylation. Three infants who received buprenorphine and 1 infant who received standard of care reached protocol-specified maximum doses and required adjuvant therapy with phenobarbital. The mean length of treatment for those in the neonatal-opium-solution group was 32 compared with 22 days for the buprenorphine group. The mean length of stay for the neonatal-opium-solution group was 38 days compared with 27 days for those in the buprenorphine group. Treatment with buprenorphine was well tolerated.Buprenorphine administered via the sublingual route is feasible and apparently safe and may represent a novel treatment for neonatal abstinence syndrome.
| S-EPMC2574639 | biostudies-literature
Project description:BACKGROUND:Our objective was to estimate the association between methadone and neonatal abstinence syndrome compared with buprenorphine using a probabilistic bias analysis to account for unmeasured confounding by severity of addiction. METHODS:We used a cohort of live-born infants exposed in utero to methadone or buprenorphine for maternal opioid maintenance therapy at Magee-Womens Hospital in Pittsburgh, PA, from 2013 to 2015 (n = 716). We determined exposure and outcome status using pharmacy billing claims. We used log-binomial regression models to assess association of treatment with neonatal abstinence syndrome after adjusting for parity, maternal race, age, delivery year, employment, hepatitis c, smoking, marital, and insurance status. We implemented probabilistic bias analysis, informed by an internal validation study, to assess the impact of unmeasured confounding by severity of addiction. RESULTS:Infants exposed to methadone in utero were more likely to experience neonatal abstinence syndrome compared with those exposed to buprenorphine (RR, 1.3; 95% CI, 1.2, 1.5). After adjustment, infants exposed to methadone were more likely (adjusted RR, 1.3; 95% CI, 1.1, 1.5) than infants exposed to buprenorphine to have the syndrome. In the validation cohort (n = 200), severe addiction was more common in methadone- versus buprenorphine-exposed deliveries (77% vs. 32%). However, adjustment for severe addiction in the bias analysis only slightly attenuated the association (RR, 1.2; 95% CI, 1.0, 1.4), supporting conventional analysis. CONCLUSIONS:Methadone is associated with increased risk of neonatal abstinence syndrome compared with buprenorphine in infants exposed in utero. This association is subject to minimal bias due to unmeasured confounding by severity of addiction.
| S-EPMC5792296 | biostudies-literature
Project description:More than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS.Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine.Large, urban, tertiary care hospital.Twenty-four term infants requiring pharmacological treatment for NAS.Outcomes were neonatal safety, length of treatment and length of hospitalization.Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of treatment compared to 38 days for those treated with morphine (P = 0.01), representing a 40% reduction. Length of hospital stay in the buprenorphine group was reduced 24%, from 42 to 32 days (P = 0.05).Sublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine.
| S-EPMC3022999 | biostudies-literature
Project description:To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine-exposed infants.Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined.For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (methadone = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition.Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine-exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine-exposed infants (36 versus 59 hours postnatal, respectively).The profile of neonatal abstinence syndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal abstinence syndrome.
| S-EPMC4165073 | biostudies-literature
Project description:Significant variability has been observed in the development and severity of neonatal abstinence syndrome (NAS) among neonates exposed to prenatal opioids. Since maternal opioid dose does not appear to correlate directly with neonatal outcome, maternal, placental, and fetal genomic variants may play important roles in NAS. Previous studies in small cohorts have demonstrated associations of variants in maternal and infant genes that encode the μ-opioid receptor (OPRM1), catechol-O-methyltransferase (COMT), and prepronociceptin (PNOC) with a shorter length of hospital stay and less need for treatment in neonates exposed to opioids in utero. Consistently falling genomic sequencing costs and computational approaches to predict variant function will permit unbiased discovery of genomic variants and gene pathways associated with differences in maternal and fetal opioid pharmacokinetics and pharmacodynamics and with placental opioid transport and metabolism. Discovery of pathogenic variants should permit better delineation of the risk of developing more severe forms of NAS. This review provides a summary of the current role of genomic factors in the development of NAS and suggests strategies for further genomic discovery.
| S-EPMC5572235 | biostudies-literature