Karol Kaltenbach

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.).

OPIOID DEPENDENCE DURING PREGNANCY Effects and Management

This article describes the complex problems associated with opioid dependence during pregnancy. Medical, obstetric, and psychosocial problems are presented. Methadone maintenance for the treatment of opioid dependence is described in this article. Specific issues of appropriate methadone dose during pregnancy, medical withdrawal, and the relationship of methadone dose and the severity of neonatal abstinence also are discussed.

Women in Recovery Their Perceptions of Treatment Effectiveness

Research with chemically dependent women over the past two decades indicates that women substance abusers have special characteristics and needs that warrant gender-sensitive drug-treatment approaches. While the potential benefit of such treatment seems clear, little empirical data is available on how women perceive the effectiveness of gender-sensitive specialized drug treatment. This article presents findings from an exploratory study of the present and past treatment experiences of 24 women in recovery. Results indicate that while some specialized services such as child care and women-only therapy groups are increasingly available, many drug-treatment programs fail to provide these services in a context which supports and promotes women. As a result, women in drug treatment continue to experience negative stereotyping and sexual harassment as their gender-specific needs remain ignored, silenced, or deemed pathological. Major gaps in drug treatment for women are discussed as are implications for the provision of effective gender-sensitive treatment.

Treatment of opioid-dependent pregnant women: clinical and research issues.

This article addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, based on both research evidence and the collective clinical experience of the authors, which include investigators in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, is provided to aid clinical decision making. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article begins with a discussion of appropriate assessment during pregnancy and then addresses clinical management stages including maintenance medication selection, induction, and stabilization; opioid agonist medication management before, during, and after delivery; pain management; breast-feeding; and transfer to aftercare. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are discussed.

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.

Unintended pregnancy in opioid-abusing women

The aim of this study was to estimate the prevalence of unintended pregnancy and its three subtypes (mistimed, unwanted, and ambivalent) among opioid-abusing women. In the general population, 31%-47% of pregnancies are unintended; data on unintended pregnancy in opioid- and other drug-abusing women are lacking. Pregnant opioid-abusing women (N = 946) screened for possible enrollment in a multisite randomized controlled trial comparing opioid maintenance medications completed a standardized interview assessing sociodemographic characteristics, current and past drug use, and pregnancy intention. Almost 9 of every 10 pregnancies were unintended (86%), with comparable percentages mistimed (34%), unwanted (27%), and ambivalent (26%). Irrespective of pregnancy intention, more than 90% of the total sample had a history of drug abuse treatment, averaging more than three treatment episodes. Interventions are sorely needed to address the extremely high rate of unintended pregnancy among opioid-abusing women. Drug treatment programs are likely to be an important setting for such interventions.

Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Trial

OBJECTIVE. 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 μ-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. METHODS. 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 μg/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. RESULTS. Sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to ∼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. CONCLUSIONS. Buprenorphine administered via the sublingual route is feasible and apparently safe and may represent a novel treatment for neonatal abstinence syndrome.

ArticleWomen in recovery: Their perceptions of treatment effectiveness☆

Research with chemically dependent women over the past two decades indicates that women substance abusers have special characteristics and needs that warrant gender-sensitive drug-treatment approaches. While the potential benefit of such treatment seems clear, little empirical data is available on how women perceive the effectiveness of gender-sensitive specialized drug treatment. This article presents findings from an exploratory study of the present and past treatment experiences of 24 women in recovery. Results indicate that while some specialized services such as child care and women-only therapy groups are increasingly available, many drug-treatment programs fail to provide these services in a context which supports and promotes women. As a result, women in drug treatment continue to experience negative stereotyping and sexual harassment as their gender-specific needs remain ignored, silenced, or deemed pathological. Major gaps in drug treatment for women are discussed as are implications for the provision of effective gender-sensitive treatment.

Methadone and buprenorphine for the management of opioid dependence in pregnancy.

This article provides an overview and discussion of the collective maternal, fetal and neonatal outcome research on women maintained on methadone or buprenorphine during pregnancy. Its focus is on an assessment of the comparative effectiveness of methadone and buprenorphine pharmacotherapy, with particular attention given to recent findings from the literature. Recommendations for clinical practice are outlined, and directions for future research are presented.Findings from comparative studies of methadone and buprenorphine underscore the efficacy of both medications in preventing relapse to illicit opioid use in the treatment of opioid-dependent pregnant patients, as well as the simplicity of induction onto methadone and patient retention while receiving such therapy. Fetal monitoring suggests that buprenorphine results in less fetal cardiac and movement suppression than does methadone. The clinical implications of these findings need future exploration. For the neonate, evidence from studies using a wide range of designs, including retrospective chart reviews, prospective observational studies, and randomized clinical trials, show consistent results, with prenatal exposure to buprenorphine resulting in less severe neonatal abstinence syndrome relative to methadone.Any medication given to pregnant women should be prescribed only after considering the risk: benefit ratio for the maternal-fetal dyad. Medication choices for each opioid-dependent patient during pregnancy need to be made on a patient-by-patient basis, taking into consideration the patient’s opioid dependence history, previous and current treatment experiences, medical circumstances and treatment preferences. Moreover, for a full remission of opioid addiction to be sustainable, both post-partum and across the lifespan, treatment providers must not rely solely on medication to treat their patients but should also utilize women-specific comprehensive treatment models that address the underlying multifaceted complexities of their patient’s lives.

Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome.

AIMS 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. DESIGN Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine. SETTING Large, urban, tertiary care hospital. PARTICIPANTS Twenty-four term infants requiring pharmacological treatment for NAS. MEASUREMENTS Outcomes were neonatal safety, length of treatment and length of hospitalization. FINDINGS 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). CONCLUSIONS Sublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine.