Hendrée E. Jones

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.

Neonatal outcomes following in utero exposure to methadone or buprenorphine: A National Cohort Study of opioid-agonist treatment of Pregnant Women in Norway from 1996 to 2009

BACKGROUND In Norway, most opioid-dependent women are in opioid maintenance treatment (OMT) with either methadone or buprenorphine throughout pregnancy. The inclusion criteria for both medications are the same and both medications are provided by the same health professionals in any part of the country. International studies comparing methadone and buprenorphine in pregnancy have shown differing neonatal outcomes for the two medications. METHOD This study compared the neonatal outcomes following prenatal exposure to either methadone or buprenorphine in a national clinical cohort of 139 women/neonates from 1996 to 2009. RESULTS After adjusting for relevant covariates, buprenorphine-exposed newborns had larger head circumferences and tended to be heavier and longer than methadone-exposed newborns. The incidence of neonatal abstinence syndrome (NAS) and length of treatment of NAS did not differ between methadone- and buprenorphine-exposed newborns. There was little use of illegal drugs and benzodiazepines during the pregnancies. However, the use of any drugs or benzodiazepines during pregnancy was associated with longer lasting NAS-treatment of the neonates. CONCLUSIONS The clinical relevance of these findings is that both methadone and buprenorphine are acceptable medications for the use in pregnancy, in line with previous studies. If starting OMT in pregnancy, buprenorphine should be considered as the drug of choice, due to more favorable neonatal growth parameters. Early confirmation of the pregnancy and systematic follow-up throughout the pregnancy are of importance to encourage the women in OMT to abstain from the use of tobacco, alcohol, illegal drugs or misuse of prescribed drugs.

Double jeopardy--Drug and sex risks among Russian women who inject drugs: Initial feasibility and efficacy results of a small randomized controlled trial:

BackgroundWith HIV prevalence estimated at 20% among female injecting drug users (IDUs) in St. Petersburg, Russia, there is a critical need to address the HIV risks of this at-risk population. This study characterized HIV risks associated with injecting drug use and sex behaviors and assessed the initial feasibility and efficacy of an adapted Woman-Focused intervention, the Womens CoOp, relative to a Nutrition control to reduce HIV risk behaviors among female IDUs in an inpatient detoxification drug treatment setting.MethodWomen (N = 100) were randomized into one of two one-hour long intervention conditions--the Woman-Focused intervention (n = 51) or a time and attention-matched Nutrition control condition (n = 49).ResultsThe results showed that 57% of the participants had been told that they were HIV-positive. At 3-month follow-up, both groups showed reduced levels of injecting frequency. However, participants in the Woman-Focused intervention reported, on average, a lower frequency of partner impairment at last sex act and a lower average number of unprotected vaginal sex acts with their main sex partner than the Nutrition condition.ConclusionThe findings suggest that improvements in sexual risk reduction are possible for these at-risk women and that more comprehensive treatment is needed to address HIV and drug risks in this vulnerable population.

Predicting Treatment for Neonatal Abstinence Syndrome in Infants Born to Women Maintained on Opioid Agonist Medication

AIM To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero. DESIGN AND SETTING Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters. PARTICIPANTS A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment. MEASUREMENTS Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment and total dose of morphine required for treatment of NAS symptoms. FINDINGS Of the sample, 53% (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin re-uptake inhibitors (SSRIs), vaginal delivery and higher infant birthweight predicted higher peak NAS scores. Higher infant birthweight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS. CONCLUSIONS Maternal weight at delivery, estimated gestational age, infant birthweight, delivery type, maternal nicotine use and days of maternal study medication received and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine.

Neonatal neurobehavior effects following buprenorphine versus methadone exposure

AIM To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior. DESIGN Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this substudy. SETTING Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI and Vienna, Austria. PARTICIPANTS Thirty-nine full-term infants. MEASUREMENTS The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30. FINDINGS While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer stress-abstinence signs (P < 0.001), were less excitable (P < 0.001) and less over-aroused (P < 0.01), exhibited less hypertonia (P < 0.007), had better self-regulation (P < 0.04) and required less handling (P < 0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher self-regulation scores (P < 0.01), and demonstrated the least amount of excitability (P < 0.02) and hypertonia (P < 0.02) on average. Quality of movement was correlated negatively with peak NAS score (P < 0.01), number of days treated with morphine for NAS (P < 0.01) and total amount of morphine received (P < 0.03). Excitability scores were related positively to total morphine dose (P < 0.03). CONCLUSION While neurobehavior improves during the first month of postnatal life for in utero agonist medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure.

Methamphetamine (“tik”) Use and Its Association with Condom Use among Out-of-School Females in Cape Town, South Africa

Background: Little is known about the association between methamphetamine use and sexual risk behaviors among young South African women between 13 and 20 years of age. Objective: To examine the association between methamphetamine use and condom use among out-of-school South African female adolescents. Methods: Black and Coloured female adolescents were interviewed and categorized into methamphetamine user (n = 261) or non-user (n = 188) groups. Results: Methamphetamine use was reported by 58% of the total sample. Higher methamphetamine rates were found among young Coloured females (87%) than among young Black females (11%). In a multiple logistic regression analysis that adjusted for relevant confounders and included an interaction term for race and methamphetamine use, Coloured female methamphetamine users were over six times more likely than other participants to report not using a condom the last time they had sex (OR = 6.21; 95% CI = 1.21, 31.94). Conclusions and Scientific Significance: Efforts are needed to reduce methamphetamine use and related sexual risk among adolescent females in Coloured communities and to prevent the spread of methamphetamine use in Black African communities.

Buprenorphine + Naloxone in the Treatment of Opioid Dependence during Pregnancy—Initial Patient Care and Outcome Data

BACKGROUND AND OBJECTIVES Research has indicated that the buprenorphine-mono product yields maternal outcomes similar to methadone and a less severe neonatal abstinence syndrome. However, maternal and neonatal outcomes following buprenorphine + naloxone exposure during pregnancy have not been documented. METHODS Retrospective chart review identified 10 opioid-dependent pregnant women treated with the buprenorphine + naloxone film product between January, 2010-June, 2011. Seven maternal outcome measures - weight gain, fetal presentation at delivery, Cesarean delivery, analgesia during delivery, urine drug screening results at delivery, number of days of maternal hospital stay, and began breastfeeding following delivery-and eleven neonatal outcome measures-gestational age at delivery, 1- and 5-minute Apgar scores, head circumference, length, and weight at birth, treated for neonatal abstinence syndrome (NAS), total amount of morphine sulfate needed to treat NAS, length of hospital stay for NAS treatment, and length of hospital stay-were extracted from medical records. RESULTS Maternal findings were unremarkable, and comparable with what might be found following treatment with the buprenorphine-mono product. Neonates were full-term with normal birth parameters. Four neonates were treated for NAS, and number of days treated for NAS and number of hospital days were in line with values reported for the buprenorphine-mono product. CONCLUSIONS Findings suggest no obvious significant adverse maternal or neonatal outcomes related to the use of buprenorphine + naloxone for the treatment of opioid dependence during pregnancy. SCIENTIFIC SIGNIFICANCE These initial findings underscore the need for future research to systematically examine the relative safety and effectiveness of buprenorphine + naloxone for mother, fetus, and child.

Maternal Opioid Treatment: Human Experimental Research (MOTHER) – Approach, Issues, and Lessons Learned

AIMS The Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, an eight-site randomized, double-blind, double-dummy, flexible-dosing, parallel-group clinical trial is described. This study is the most current--and single most comprehensive--research effort to investigate the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine. METHODS The MOTHER study design is outlined, and its basic features are presented. CONCLUSIONS At least seven important lessons have been learned from the MOTHER study: (i) an interdisciplinary focus improves the design and methods of a randomized clinical trial; (ii) multiple sites in a clinical trial present continuing challenges to the investigative team due to variations in recruitment, patient populations and hospital practices that, in turn, differentially impact recruitment rates, treatment compliance and attrition; (iii) study design and protocols must be flexible in order to meet the unforeseen demands of both research and clinical management; (iv) staff turnover needs to be addressed with a proactive focus on both hiring and training; (v) the implementation of a protocol for the treatment of a particular disorder may identify important ancillary clinical issues worthy of investigation; (vi) timely tracking of data in a multi-site trial is both demanding and unforgiving; and (vii) complex multi-site trials pose unanticipated challenges that complicate the choice of statistical methods, thereby placing added demands on investigators to effectively communicate their results.

Buprenorphine and Naloxone Compared With Methadone Treatment in Pregnancy

OBJECTIVE: To compare neonatal abstinence syndrome prevalence and characteristics among neonates born to women prescribed buprenorphine and naloxone compared with methadone during pregnancy. METHODS: Retrospective cohort analysis of mother–neonate dyads treated with either buprenorphine and naloxone or methadone during pregnancy. Primary neonatal outcomes included diagnosis of neonatal abstinence syndrome, neonatal abstinence syndrome peak scores, total amount of morphine used to treat neonatal abstinence syndrome (mg), and duration of treatment for neonatal abstinence syndrome (days). Secondary outcomes included head circumference, birth weight, length, preterm birth, neonatal intensive care unit admission, Apgar scores, and overall length of hospitalization. RESULTS: From January 1, 2011, to November 30, 2013, we identified 62 mother–neonate dyads, 31 treated with methadone and 31 treated with buprenorphine and naloxone. Sixteen neonates (51.6%) in the methadone group were diagnosed with neonatal abstinence syndrome compared with eight (25.1%) in the buprenorphine and naloxone group (adjusted odds ratio 2.55, 95% confidence interval [CI] 1.31–4.98, P=.01). The buprenorphine and naloxone-exposed neonates had lower peak neonatal abstinence syndrome scores (9.0±4.4 compared with 10.7±3.7, multivariate-adjusted mean difference=−2.77, 95% CI −4.99 to −0.56, P=.02) and shorter overall hospitalization (5.6±5.0 compared with 9.8±7.4 days, multivariate-adjusted mean difference=−3.90, 95% CI, −7.13 to −0.67, P=.02). We found no other differences in primary or secondary outcomes. CONCLUSION: In a cohort of pregnant patients treated with either methadone or buprenorphine and naloxone in pregnancy, newborns exposed to maternal buprenorphine and naloxone had less frequent neonatal abstinence syndrome. Additionally, neonates exposed to buprenorphine and naloxone had shorter overall hospitalization lengths. LEVEL OF EVIDENCE: II

Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates

AIMS To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine-exposed infants. DESIGN, SETTING AND PARTICIPANTS 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. MEASUREMENTS 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. FINDINGS 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). CONCLUSIONS 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.