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 after methadone or buprenorphine exposure.

BACKGROUND: Methadone, 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. METHODS: We 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. RESULTS: Treatment 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. CONCLUSIONS: These 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.).

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.

Nonserious adverse events in randomized trials with opioid-dependent pregnant women: direct versus indirect measurement.

BACKGROUND AND OBJECTIVES: How best to measure the occurrence of adverse events during a randomized clinical trial is an issue that has not been adequately examined in the research literature. Focus of this study was on the examination of the relative frequency of occurrence of adverse events directly recorded during the conduct of the trial compared to an indirect determination of adverse events derived from data collected as part of the trial. METHODS: A secondary analysis of nonserious adverse events that occurred in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study was undertaken. MOTHER was a randomized clinical trial of methadone versus buprenorphine in 175 opioid-dependent pregnant women. RESULTS: The two methods of recording adverse events failed to agree on where differences in the frequency of occurrence of adverse events between the medication conditions might exist. Moreover, indirect assessment indicated all participants had experienced at least one adverse event, yet indirect coverage of adverse events was incomplete. CONCLUSIONS: Findings suggest indirect examination of occurrence of adverse events should be cautiously undertaken, because indirect assessment of adverse events makes no distinction between what might be simply typical variation in behavior rather than systematic changes in behavior attributable to study condition, and lacks coverage of the full spectrum of adverse events. SCIENTIFIC SIGNIFICANCE: Contemporaneous direct measurement of adverse events likely yield reasonably valid estimates of the rate of occurrence of the adverse events, while indirect measu-rement of adverse events may not be sufficiently reliable.

Co-occurring psychiatric symptoms in opioid-dependent women: the prevalence of antenatal and postnatal depression.

BACKGROUND: Despite the high prevalence of psychiatric symptoms in substance-dependent women, little evidence is available on postpartum depression in this population. OBJECTIVES: To determine whether demographic variables and prenatal depression predict postpartum depression and select substance abuse treatment outcomes in a sample of pregnant women. METHODS: A retrospective chart review was conducted on 125 pregnant women enrolled in a comprehensive substance abuse treatment program. Data on demographic variables, prenatal care attendance, urine drug screen (UDS) results, and psychiatric symptoms were abstracted from patient medical and substance abuse treatment charts. The Postpartum Depression Screening Scale (PDSS) was administered 6 weeks post-delivery. Multiple linear regression was conducted to identify predictors of prenatal care attendance and total PDSS scores at 6 weeks postpartum. Multiple logistic regression was used to examine predictors of positive UDS at delivery. RESULTS: Nearly one-third (30.4%) of the sample screened positive for moderate or severe depression at treatment entry. Psychiatric symptoms did not predict either prenatal care compliance or UDS results at delivery. Almost half of the sample (43.7%) exhibited postpartum depression at 6 weeks post-delivery. No demographic variables correlated with incidence of postnatal depression. Only antenatal depression at treatment entry predicted PDSS scores. CONCLUSION: Prevalence of antenatal psychiatric disorders and postpartum depression was high in this sample of women seeking substance abuse treatment. Results support prior history of depression as a predictor of risk for developing postpartum depression. SCIENTIFIC SIGNIFICANCE: Routine screening for perinatal and postpartum depression is indicated for women diagnosed with substance abuse disorders.

Cigarette Smoking and Neonatal Outcomes in Depressed and Non-Depressed Opioid-Dependent Agonist-Maintained Pregnant Patients.

AIMS: To investigate whether cigarette smoking and/or depression contribute to neonatal abstinence syndrome (NAS) severity. DESIGN: Cohort study analyzing data from a randomized, controlled trial of methadone versus buprenorphine. SETTING: Seven study sites that randomized patients to study conditions and provided comprehensive addiction treatment to pregnant patients. PARTICIPANTS: 119 of 131 opioid-dependent pregnant patients who completed the MOTHER study. MEASUREMENTS: Smoking data and depression status were obtained from the Addiction Severity Index and Mini International Neuropsychiatric Interview, respectively. Neonatal outcomes (birth weight, preterm delivery and NAS pharmacologic treatment) were collected from the medical charts. Study site was a fixed-effect factor in all analyses. FINDINGS: Cigarette smoking was reported by 94% of participants and depression identified in 35%. Smoking was associated with low birth weight, preterm delivery, and NAS pharmacologic treatment in both depressed and non-depressed participants. The association between smoking and NAS treatment differed significantly between depressed and non-depressed participants. Among non-depressed participants, adjusting for site and illicit drug use, each additional average cigarette per day (CPD) increased the odds of NAS treatment by 12% [95%CI: (1.02-1.23), p=0.02]. Among depressed participants, each additional average CPD did not statistically increase the odds of NAS treatment [OR: 0.94, 95% CI: (0.84-1.04), p=0.23]. CONCLUSIONS: These results are consistent with the hypothesis that NAS expression is influenced by many factors. The relationship between CPD and NAS pharmacologic treatment is attenuated among depressed women in this study for reasons currently unknown. Further investigations are needed to clarify the complex relationships among maternal smoking, depression, and NAS.

Co-occurring psychiatric symptoms are associated with increased psychological, social, and medical impairment in opioid dependent pregnant women.

The interaction of psychiatric symptoms with drug dependence during pregnancy is not well understood. This study examines the relationship of psychiatric symptoms to severity of drug use and drug-related problems among participants in a clinical trial of pharmacologic treatment of opioid dependence during pregnancy (N = 174). A total of 64.6% reported additional psychiatric symptoms (48.6% mood symptoms, 40.0% anxiety symptoms, and 12.6% suicidal thinking). Women who endorsed co-occurring psychiatric symptoms showed more severe impairment on the Addiction Severity Index. Further investigation is warranted to understand the effect of psychiatric symptoms on long-term maternal and neonatal outcomes.

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.

Psychopharmacologic management of opioid-dependent women during pregnancy.

Illicit drug use during pregnancy presents complex clinical challenges, including reducing drug use and treating psychiatric disorders. Pharmacologic treatment of psychiatric disorders in a pregnant woman requires an evaluation of the balance between potential clinical benefit and the risk of potential neonatal consequences. This study describes psychiatric symptoms in 111 opioid-dependent pregnant women and their prescribed psychotropic medications. Hypomania, generalized anxiety disorder and depression were the most common disorders for which psychiatric symptoms were endorsed. Over half of women studied were prescribed some form of psychoactive medication during pregnancy. Pharmacologic vs. non-pharmacologic treatment approaches in this patient population are discussed.

Characteristics of opioid-using pregnant women who accept or refuse participation in a clinical trial: screening results from the MOTHER study.

BACKGROUND: Although concerns arise about the generalizability of results from Randomized Controlled Trials (RCTs), few studies systematically examine this issue. OBJECTIVES: This study compared the characteristics of 427 opioid-using pregnant women who did (n = 208) and did not consent (n = 219) to enrollment in a multicenter clinical trial of agonist medications (i.e., the MOTHER study). METHODS: Logistic regression models were used to compare consenters and non-consenters to examine the effect of screening variables on the likelihood of consenting. RESULTS: Of nine characteristics examined, most differences did not reach statistical significance. Consenting participants were less likely than non-consenting women to be currently enrolled in a methadone maintenance program (74.5% vs. 84.5%, p =.01). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These data show that the recruited sample of drug-dependent pregnant women enrolled in an intensive RCT is representative of the larger population of treated opioid-dependent patients and supports the generalizability of randomized controlled trials in this population.

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.

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.

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.