Buprenorphine-naloxone use in pregnancy: a systematic review and metaanalysis.

OBJECTIVE: The goal of this systematic review and metaanalysis is to compare pregnancy outcomes between pregnant women undergoing treatment for opioid use disorder with buprenorphine-naloxone and those undergoing treatment for opioid use disorder with other forms of medication-assisted treatment. STUDY DESIGN: PubMed, Embase, PsycINFO, Cochrane Clinical Trials, and Web of Science were searched to identify studies assessing the relationship between maternal buprenorphine-naloxone use and pregnancy outcomes. Outcomes assessed included neonatal abstinence syndrome diagnosis and treatment, neonatal intensive care unit admission, length of neonatal hospital stay, delivery complications, mode of delivery, labor analgesia, illicit drug use, medication-assisted treatment dosage, gestational age at delivery, breastfeeding status, miscarriage, congenital anomalies, intrauterine fetal demise, birthweight, head circumference, length, and Apgar scores. RESULTS: Overall, 5 studies comprising 6 study groups met the inclusion criteria. Of the 1875 mother-baby dyads available for analysis, medications prescribed as part of the medication-assisted treatment included buprenorphine-naloxone, buprenorphine alone, methadone, or long-acting opioids. There were no serious adverse maternal or neonatal outcomes associated with maternal buprenorphine-naloxone use reported among any of the studies. Women prescribed with buprenorphine-naloxone for delivered neonates who were less likely to require treatment for neonatal abstinence syndrome were compared with pregnant women prescribed with other opioid agonist medications. Of the remaining outcomes assessed, metaanalysis did not detect any statistically significant differences when comparing the groups of women using buprenorphine-naloxone with the groups of women prescribed with other medications as part of the medication-assisted treatment. CONCLUSION: Pregnant women undergoing treatment for opioid use disorder with buprenorphine-naloxone do not experience significantly different pregnancy outcomes than women undergoing treatment with other forms of opioid agonist medication-assisted therapy.

Assessment of the newborn prenatally exposed to drugs: The history.

This paper reviews the history of the development of scoring tools used to assess the occurrence and severity of the Neonatal Abstinence Syndrome. Beginning with the first tools published in 1975, this review describes tools published through 2010; identifies each tool's strengths and weaknesses; and discusses their representation in the literature.

Prenatal Opioid Exposure, Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome, and Later Child Development Research: Shortcomings and Solutions.

: The opioid epidemic has brought with it an increasing focus on the incidence of Neonatal Abstinence Syndrome (NAS) (also known as Neonatal Opioid Withdrawal Syndrome) in neonates prenatally exposed to opioids, and recently, in the putative long-term effects of NAS on child development. The purpose of the present paper is three-fold: (1) outline shortcomings regarding the current research relating NAS to child development; (2) propose solutions to minimize these shortcomings; and (3) recommend an alternative conceptual framework to understanding developmental problems in later childhood presumed to be a result of NAS. The paper focuses on issues regarding definitions of the population of interest, choice of comparison groups, matching practices, statistical analyses, and an implicit single-cause fallacy related to NAS. It offers possible solutions to the problems identified in each of these areas. Use of a NAS or Neonatal Opioid Withdrawal Syndrome diagnosis as a main indicator of adverse developmental outcomes poses potential radiating harm to the child and the family and misses the opportunity to see the complexities of interpersonal, intrapersonal, and environmental factors that contribute to the long-term developmental trajectories of children.

Prenatal exposure to methadone or buprenorphine: Early childhood developmental outcomes.

BACKGROUND: Methadone and buprenorphine are recommended to treat opioid use disorders during pregnancy. However, the literature on the relationship between longer-term effects of prenatal exposure to these medications and childhood development is both spare and inconsistent. METHODS: Participants were 96 children and their mothers who participated in MOTHER, a randomized controlled trial of opioid-agonist pharmacotherapy during pregnancy. The present study examined child growth parameters, cognition, language abilities, sensory processing, and temperament from 0 to 36 months of the child's life. Maternal perceptions of parenting stress, home environment, and addiction severity were also examined. RESULTS: Tests of mean differences between children prenatally exposed to methadone vs. buprenorphine over the three-year period yielded 2/37 significant findings for children. Similarly, tests of mean differences between children treated for NAS relative to those not treated for NAS yielded 1/37 significant finding. Changes over time occurred for 27/37 child outcomes including expected child increases in weight, head and height, and overall gains in cognitive development, language abilities, sensory processing, and temperament. For mothers, significant changes over time in parenting stress (9/17 scales) suggested increasing difficulties with their children, notably seen in increasing parenting stress, but also an increasingly enriched home environment (4/7 scales) CONCLUSIONS: Findings strongly suggest no deleterious effects of buprenorphine relative to methadone or of treatment for NAS severity relative to not-treated for NAS on growth, cognitive development, language abilities, sensory processing, and temperament. Moreover, findings suggest that prenatal opioid agonist exposure is not deleterious to normal physical and mental development.

Impact of Mindfulness-Based Parenting on Women in Treatment for Opioid Use Disorder.

OBJECTIVES: Mothers with opioid use disorder are at high risk for maladaptive parenting. The present observational study aimed to measure the impact of a trauma-informed mindfulness-based parenting (MBP) intervention on quality of parenting behaviors of mothers primarily with opioid use disorders as well as examine associations between exposure to adverse childhood experiences and self-reported mindful parenting. METHODS: A pretest posttest design was used with repeated measures. A total of 160 women were recruited from a substance use treatment program into the 12-week-long group-based intervention comprised didactic and experiential mindfulness activities. The Keys to Interactive Parenting Scale (KIPS) measured quality of parenting behavior, the Adverse Childhood Experiences Tool captured history of exposure to childhood trauma, and the Interpersonal Mindfulness in Parenting (IM-P) scale measured the degree of mindful parenting. Analyses were conducted using multilevel modeling. RESULTS: The MBP intervention resulted in clinically significant improvements in KIPS total and all subscale scores and an IM-P total score. Data showed higher baseline Adverse Childhood Experiences and higher program attendance significantly predicted improved overall quality of parenting behaviors at a greater rate over time. Higher IM-P scores were associated with greater rate of improvement in KIPS total and all subscale scores. CONCLUSIONS: Study findings suggest a trauma-informed MBP intervention for parenting women with opioid use disorders is associated with significant clinical improvements in quality of parenting behavior. Results of this model show promise in supporting parenting of mothers receiving treatment for opioid use disorders to enhance bonding and parenting.

Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome.

BACKGROUND: Current 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: Among 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 .).

Reducing Stress Among Mothers in Drug Treatment: A Description of a Mindfulness Based Parenting Intervention.

Background Parenting women with substance use disorder could potentially benefit from interventions designed to decrease stress and improve overall psychosocial health. In this study we assessed whether a mindfulness based parenting (MBP) intervention could be successful in decreasing general and parenting stress in a population of women who are in treatment for substance use disorder and who have infants or young children. Methods MBP participants (N = 59) attended a two-hour session once a week for 12 weeks. Within-group differences on stress outcome measures administered prior to the beginning of the MBP intervention and following the intervention period were investigated using mixed-effects linear regression models accounting for correlations arising from the repeated-measures. Scales assessed for pre-post change included the Perceived Stress Scale-10 (PSS) and the Parenting Stress Index-Short Form (PSI). Results General stress, as measured by the PSS, decreased significantly from baseline to post-intervention. Women with the highest baseline general stress level experienced the greatest change in total stress score. A significant change also occurred across the Parental Distress PSI subscale. Conclusions Findings from this innovative interventional study suggest that the addition of MBP within treatment programs for parenting women with substance use disorder is an effective strategy for reducing stress within this at risk population.

Neonatal Abstinence Syndrome: Presentation and Treatment Considerations.

This clinical case conference discusses the treatment of a pregnant woman with opioid use disorder in a comprehensive care program that includes buprenorphine pharmacotherapy. The presentation summarizes common experiences that pregnant women who receive buprenorphine pharmacotherapy face, and also what their prenatally opioid-exposed children confront in the immediate postpartum period. It describes the elements of a successful comprehensive care model and corollary neonatal abstinence syndrome treatment regimen. Expert commentary is included on issues that arise in the buprenorphine induction and maintenance throughout the prenatal and postpartum periods and in the treatment of co-occurring mental health problems during both the prenatal and postpartum periods, particularly the treatment of depression. There is also expert commentary on the care of opioid-exposed neonates, with attention to the treatment for neonatal abstinence syndrome.

Neonatal Abstinence Syndrome: Presentation and Treatment Considerations.

The increase in opioid use among the general population is reflected in pregnant women and neonatal abstinence syndrome (NAS) statistics. This increase has produced an unprecedented focus on NAS from both the political-judicial sphere and the medical community. Under the banner of fetal protection, judges and prosecutors have implemented punitive approaches against women who use prescribed and nonprescribed opioids during pregnancy, including arrest, civil commitment, detention, prosecution, and loss of custody or termination of parental rights. Within the medical community, questions have been raised regarding protocols to detect prenatal drug exposure at delivery, NAS treatment protocols, the need for quality-improvement strategies to standardize care and reduce length of stay for mother and infant, and the benefits of engaging the mother in the care of her infant. It is not uncommon for the expression of strong discordant views on these issues both between and among these political-judicial and medical constituencies. Closely examining the issues often reveal a lack of understanding of substance use disorders, their treatment, and the occurrence and treatment of NAS. This study provides an in-depth examination of NAS, including variations in presentation and factors that impact the efficacy of treatment, and also identifying questions that remain unanswered. Finally, 4 key areas on which future research should focus to guide both medical care and public policy are discussed.

Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study.

OBJECTIVE: To provide absolute and relative risk estimates of neonatal abstinence syndrome (NAS) based on duration and timing of prescription opioid use during pregnancy in the presence or absence of additional NAS risk factors of history of opioid misuse or dependence, misuse of other substances, non-opioid psychotropic drug use, and smoking. DESIGN: Observational cohort study. SETTING: Medicaid data from 46 US states. PARTICIPANTS: Pregnant women filling at least one prescription for an opioid analgesic at any time during pregnancy for whom opioid exposure characteristics including duration of therapy: short term (<30 days) or long term (≥ 30 days); timing of use: early use (only in the first two trimesters) or late use (extending into the third trimester); and cumulative dose (in morphine equivalent milligrams) were assessed. MAIN OUTCOME MEASURE: Diagnosis of NAS in liveborn infants. RESULTS: 1705 cases of NAS were identified among 290,605 pregnant women filling opioid prescriptions, corresponding to an absolute risk of 5.9 per 1000 deliveries (95% confidence interval 5.6 to 6.2). Long term opioid use during pregnancy resulted in higher absolute risk of NAS per 1000 deliveries in the presence of additional risk factors of known opioid misuse (220.2 (200.8 to 241.0)), alcohol or other drug misuse (30.8 (26.1 to 36.0)), exposure to other psychotropic medications (13.1 (10.6 to 16.1)), and smoking (6.6 (4.3 to 9.6)) than in the absence of any of these risk factors (4.2 (3.3 to 5.4)). The corresponding risk estimates for short term use were 192.0 (175.8 to 209.3), 7.0 (6.0 to 8.2), 2.0 (1.5 to 2.6), 1.5 (1.0 to 2.0), and 0.7 (0.6 to 0.8) per 1000 deliveries, respectively. In propensity score matched analyses, long term prescription opioid use compared with short term use and late use compared with early use in pregnancy demonstrated greater risk of NAS (risk ratios 2.05 (95% confidence interval 1.81 to 2.33) and 1.24 (1.12 to 1.38), respectively). CONCLUSIONS: Use of prescription opioids during pregnancy is associated with a low absolute risk of NAS in the absence of additional risk factors. Long term use compared with short term use and late use compared with early use of prescription opioids are associated with increased NAS risk independent of additional risk factors.

The relationship between maternal methadone dose at delivery and neonatal outcome: methodological and design considerations.

Compared to untreated opioid dependence, methadone maintenance treatment of opioid-dependent pregnant women has been found to be associated with better maternal and neonatal outcomes. Secondary analysis of data from 73 maternal and neonatal participants in the MOTHER study (H. E. Jones et al., New England Journal of Medicine, 2010) found no relationship between maternal methadone dose at delivery and any of 9 neonatal outcomes--peak neonatal abstinence syndrome (NAS) score, total amount of morphine needed to treat NAS, duration of neonatal hospital stay, duration of treatment for NAS, estimated gestational age at delivery, Apgar score at 5 min, and neonatal head circumference, length, and weight at birth. These results are consistent with a recent systematic review and meta-analysis (B. J. Cleary et al., Addiction, 2010) and extend findings to outcomes other than NAS. Methodological and design issues that might have adversely impacted the ability of researchers to establish the existence or non-existence of these relationships are considered.

Induction of pregnant women onto opioid-agonist maintenance medication: an analysis of withdrawal symptoms and study retention.

BACKGROUND: Induction onto buprenorphine during pregnancy may be more challenging than induction onto methadone. This study explores factors predicting withdrawal intensities and compares trajectories of withdrawal during the induction phase between opioid-dependent women randomly assigned to methadone or buprenorphine. METHODS: A secondary analysis was conducted on data from 175 opioid-dependent pregnant women inducted onto buprenorphine or methadone subsequent to stabilization on morphine sulfate. ANOVA analyses were conducted to determine differences between mean peak CINA scores by medication and completion status. General linear mixed models were fitted to compare trajectories of CINA scores between methadone and buprenorphine conditions, and between study dropouts and completers within the buprenorphine condition. RESULTS: Both buprenorphine and methadone patients experienced withdrawal categorized as minimal by the CINA scoring system. Significant differences in mean peak CINA scores for the first 72 hours of induction were found between the methadone (4.5; SD=0.4) and buprenorphine conditions (6.9; SD=0.4), with buprenorphine patients exhibiting higher mean peak CINA scores [F (3, 165)=9.70, p<0.001]. The trajectory of CINA scores showed buprenorphine patients exhibiting a sharper increase in mean CINA scores than methadone patients [F (1, 233)=8.70, p=0.004]. There were no differences in mean peak CINA scores [F (3, 77)=0.08, p=0.52] or in trajectory of CINA scores [F (1, 166)=0.42, p=0.52] between buprenorphine study dropouts and completers. CONCLUSION: While mean peak CINA score was significantly higher in the buprenorphine condition than the methadone condition, neither medication condition experienced substantial withdrawal symptoms. Further research on factors related to successful induction to buprenorphine treatment in pregnant women is needed.

A comparison of cigarette smoking profiles in opioid-dependent pregnant patients receiving methadone or buprenorphine.

INTRODUCTION: Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients. The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine. Patients were participants in the international, randomized controlled Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. METHODS: A sample of opioid-maintained pregnant patients (18-41 years old) with available smoking data who completed a multisite, double-blind, double-dummy, randomized controlled trial of methadone (n = 67) and buprenorphine (n = 57) between 2005 and 2008. Participants were compared on smoking variables based on opioid agonist treatment condition. RESULTS: Overall, 95% of the sample reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts. Over the course of the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant (ß = -0.08, SE = 0.05, p = .132). CONCLUSIONS: Results support high rates of smoking with little change during pregnancy among opioid-dependent patients, regardless of the type of agonist medication received. These findings are consistent with evidence that suggests nicotine effects, and interactions may be similar for buprenorphine compared with methadone. The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women.

Cigarette smoking in opioid-dependent pregnant women: neonatal and maternal outcomes.

BACKGROUND: The relationship between cigarette smoking and neonatal and maternal clinical outcomes among opioid-agonist-treated pregnant patients is sparse. OBJECTIVES: (1) Is smoking measured at study entry related to neonatal and maternal outcomes in pregnant women receiving opioid-agonist medication? (2) Is it more informative to use a multi-item measure of smoking dependence or a single-item measure of daily smoking? (3) Is the relationship between smoking at study entry and outcomes different between methadone and buprenorphine? METHODS: Secondary analyses examined the ability of the tobacco dependence screener (TDS) and self-reported past 30-day daily average number of cigarettes smoked, both measured at study entry, to predict 12 neonatal and 9 maternal outcomes in 131 opioid-agonist-maintained pregnant participants. RESULTS: Past 30-day daily average number of cigarettes smoked was significantly positively associated with total amount of morphine (mg) needed to treat neonatal abstinence syndrome (NAS), Adjusted Odds Ratio (AOR)=1.06 (95% CI: 1.02, 1.09), number of days medicated for NAS, AOR=1.04 (95% CI: 1.01, 1.06), neonatal length of hospital stay in days, AOR=1.03 (95% CI: 1.01, 1.05), and negatively associated with 1-AOR=.995 (95% CI: .991,.999) and 5-min Apgar scores, AOR=.996 (95% CI: .994,.998). Simple effect tests of the two significant TDS×medication condition effects found TDS was unrelated to non-normal presentation and amount of voucher money earned in the methadone [AORs=.90 (95% CI: .74, 1.08, p>.24) and 1.0 (95% CI: .97, 1.03, p>.9)] but significant in the buprenorphine condition [AORs=1.57 (95% CI: 1.01, 2.45, p<.05) and 1.08 (95% CI: 1.04, 1.12, p<.01)]. CONCLUSIONS: Regardless of prenatal methadone or buprenorphine exposure, heavier cigarette smoking was associated with more compromised birth outcomes.

Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.

AIMS: This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk and longer-term developmental effects. METHODS: Within each outcome area, findings are summarized first for the three randomized clinical trials and then for the 44 non-randomized studies (i.e. prospective studies, case reports and series and retrospective chart reviews), only 28 of which involve independent samples. RESULTS: Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiological suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development. CONCLUSIONS: While buprenorphine produces a less severe neonatal abstinence syndrome than methadone, both methadone and buprenorphine are important parts of a complete comprehensive treatment approach for opioid-dependent pregnant women.