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.).

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.

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.

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.

Efficacy of dose and contingency management procedures in LAAM-maintained cocaine-dependent patients.

Opioid- and cocaine-dependent participants (N=140) were randomly assigned to one of the following in a 12-week clinical trial: LAAM (30, 30, 39 mg/MWF) with contingency management (CM) procedures (LC); LAAM (30, 30, 39 mg/MWF) without CM (LY); LAAM (100, 100, 130 mg/MWF) with CM (HC); LAAM (100, 100, 130 mg/MWF) without CM (HY). Urine samples were collected thrice-weekly. In CM, each urine negative for both opioids and cocaine resulted in a voucher worth a certain monetary value that increased for consecutively drug-free urines. Subjects not assigned to CM received vouchers according to a yoked schedule. Vouchers were exchanged for mutually agreed upon goods and services. Groups generally did not differ on retention and baseline characteristics. Overall opioid use was least in the HC and HY groups; opioid use decreased most rapidly over time in the HC group relative to the HY, LC and LY groups. Overall cocaine use was least in the HC group relative to the HY, LC, and LY groups; cocaine use decreased over time most rapidly in the HC and LY groups. Abstinence from both was greatest in the HC group. Opioid withdrawal symptoms decreased most rapidly in the high-dose groups relative to the low-dose groups. These results suggest that an efficacious maintenance dose is necessary for contingencies to be effective in facilitating both opioid and cocaine abstinence.

Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients.

BACKGROUND: Alteration in noradrenergic regulation as well as alteration in the hypothalamic-pituitary-adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms. METHODS: This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol. RESULTS: Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels. CONCLUSIONS: Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. The effect on cortisol supports the above conclusion and is consistent with HPA axis perturbation in opioid dependence as reported in other studies and extends these observations to stable methadone-maintained patients. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients.

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.

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.

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.

Fetal assessment before and after dosing with buprenorphine or methadone.

AIM: To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal wellbeing. DESIGN: A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial. SETTING: Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women. PARTICIPANTS: Eighty-one of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation. MEASUREMENTS: Two fetal assessments were conducted, once before and once after study medication dosing. Measures included mean fetal heart rate (FHR), number of FHR accelerations, FHR reactivity in the fetal non-stress test (NST) and biophysical profile (BPP) score. FINDINGS: Significant group differences were found for number of FHR accelerations, non-reactive NST and BPP scores (all Ps < 0.05). There were no significant group differences before time of dosing. Significant decreases (all Ps < 0.05) occurred from pre- to post-dose assessment for mean FHR, FHR accelerations, reactive NST and fetal movement. The decrease in accelerations and reactive NST were significant only for fetuses in the methadone group, and this resulted in a significantly lower likelihood of a reactive NST compared to fetuses in the buprenorphine group. CONCLUSION: Buprenorphine compared with methadone appears to result in less suppression of mean fetal heart rate, fetal heart rate reactivity and the biophysical profile score after medication dosing and these findings provide support for the relative safety of buprenorphine when fetal indices are considered as part of the complete risk-benefit ratio.

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.

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.

Infections and obstetric outcomes in opioid-dependent pregnant women maintained on methadone or buprenorphine.

AIMS: To characterize infections and compare obstetric outcomes in opioid-dependent pregnant women who participated in a randomized clinical trial comparing agonist medications, methadone and buprenorphine. DESIGN: Incidence of infections was identified as part of the screening medical assessment. As part of a planned secondary analysis, analysis of variance and polytomous logistic regressions were conducted on obstetric outcome variables using treatment randomization condition (maternal maintenance with either methadone or buprenorphine) as the predictor variable, controlling for differences between study sites. SETTING: Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women. PARTICIPANTS: Pregnant opioid-dependent women (n = 131) who delivered while participating in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. MEASUREMENTS: Obstetric, infectious and other maternal medical complications captured by medical records, physical examination, blood tests and self-report. Neonatal medical complications captured by medical records. FINDINGS: Hepatitis C was the most common infection (32.3%), followed by hepatitis B (7.6%) and chlamydia (6.1%) among participants at study enrollment. Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor (P = 0.04) and a significantly higher percentage of signs of respiratory distress in neonates at delivery (P = 0.05). Other medical and obstetric complications were infrequent in the total sample, as well as in both methadone and buprenorphine conditions. CONCLUSIONS: Buprenorphine appears to have an acceptable safety profile for use during pregnancy.

Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication.

AIM: To examine hepatic enzyme test results throughout the course of pregnancy in women maintained on methadone or buprenorphine. DESIGN: Participants were randomized to either methadone or buprenorphine maintenance. Blood chemistry tests, including liver transaminases and hepatitis C virus (HCV) status, were determined every 4 weeks and once postpartum. As part of a planned secondary analysis, generalized mixed linear models were conducted with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) as the dependent variables. SETTING: Six US sites and one European site that provided comprehensive treatment to pregnant opioid-dependent women. PARTICIPANTS: A total of 175 opioid-dependent pregnant women enrolled in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. FINDINGS: ALT, AST and GGT levels decreased for all subjects across pregnancy trimesters, rising slightly postpartum. HCV-positive subjects exhibited higher transaminases at all time-points compared to HCV-negative subjects, regardless of medication (all Ps < 0.05) condition. Both HCV-positive and negative buprenorphine-maintained participants exhibited lower GGT levels than those who were methadone-maintained (P < 0.05). CONCLUSIONS: Neither methadone nor buprenorphine appear to have adverse hepatic effects in the treatment of pregnant opioid-dependent women.

Opioid dependence during pregnancy: relationships of anxiety and depression symptoms to treatment outcomes.

AIMS: To examine the relationship of anxiety and depression symptoms with treatment outcomes (treatment discontinuation, rates of ongoing use of illicit drugs and likelihood of preterm delivery) in opioid-dependent pregnant women and describe their use of psychotropic medications. DESIGN AND SETTING: Secondary data analysis from a randomized clinical trial of treatment for opioid dependence during pregnancy. PARTICIPANTS: A total of 175 opioid-dependent pregnant women, of whom 131 completed treatment. MEASUREMENTS: Symptoms of anxiety and depression were captured with the 15-item Mini International Neuropsychiatric Interview (MINI) screen. Use of illicit drugs was measured by urine drug screening. Preterm delivery was defined as delivery prior to 37 weeks' gestation. Self-reported use of concomitant psychotropic medication at any point during the study was recorded. FINDINGS: Women reporting only anxiety symptoms at study entry were more likely to discontinue treatment [adjusted odds ratio (OR) = 4.56, 95% confidence interval (CI) : 1.91-13.26, P = 0.012], while those reporting only depression symptoms were less likely to discontinue treatment (adjusted OR = 0.14, 95% CI : 0.20-0.88, P = 0.036) compared to women who reported neither depression nor anxiety symptoms. No statistically significant between-group differences were observed for ongoing illicit drug use or preterm delivery. A majority (61.4%) of women reported use of concomitant psychotropic medication at some point during study participation. CONCLUSIONS: Opioid agonist-treated pregnant patients with co-occurring symptoms of anxiety require additional clinical resources to prevent premature discontinuation.

Motivation Enhancement Therapy with pregnant substance-abusing women: does baseline motivation moderate efficacy?

Some evidence suggests that motivational approaches are less efficacious--or even counter-productive--with persons who are relatively motivated at baseline. The present study was conducted to examine whether disordinal moderation by baseline motivation could partially explain negative findings in a previous study [Winhusen, T., Kropp, F., Babcock, D., Hague, D., Erickson, S.J., Renz, C., Rau, L., Lewis, D., Leimberger, J., Somoza, E., 2008. Motivational enhancement therapy to improve treatment utilization and outcome in pregnant substance users. J. Subst. Abuse Treat. 35, 161-173]. Analyses also focused on the relative utility of the University of Rhode Island Change Assessment (URICA) scale, vs. a single goal question as potential moderators of Motivation Enhancement Therapy (MET). Participants were 200 pregnant women presenting for substance abuse treatment at one of four sites. Women were randomly assigned to either a three-session MET condition or treatment as usual (TAU). Generalized Estimating Equations (GEE) revealed no significant moderation effects on drug use at post-treatment. At follow-up, contrary to expectations, participants who had not set a clear quit goal at baseline were less likely to be drug-free if randomized to MET (OR=0.48); participants who did set a clear quit goal were more likely to be drug-free if randomized to MET (OR=2.53). No moderating effects were identified via the URICA. Disordinal moderation of MET efficacy by baseline motivation may have contributed somewhat to the negative results of the [Winhusen, T., Kropp, F., Babcock, D., Hague, D., Erickson, S.J., Renz, C., Rau, L., Lewis, D., Leimberger, J., Somoza, E., 2008. Motivational enhancement therapy to improve treatment utilization and outcome in pregnant substance users. J. Subst. Abuse Treat. 35, 161-173] study, but in the opposite direction expected. A simple question regarding intent to quit may be useful in identifying persons who may differentially respond to motivational interventions. However, moderation effects are unstable, may be best identified with alternate methodologies, and may operate differently among pregnant women.

Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence.

Few studies in community settings have evaluated predictors, mediators, and moderators of treatment success for medically supervised opioid withdrawal treatment. This report presents new findings about these factors from a study of 344 opioid-dependent men and women prospectively randomized to either buprenorphine-naloxone or clonidine in an open-label 13-day medically supervised withdrawal study. Subjects were either inpatient or outpatient in community treatment settings; however not randomized by treatment setting. Medication type (buprenorphine-naloxone versus clonidine) was the single best predictor of treatment retention and treatment success, regardless of treatment setting. Compared to the outpatient setting, the inpatient setting was associated with higher abstinence rates but similar retention rates when adjusting for medication type. Early opioid withdrawal severity mediated the relationship between medication type and treatment outcome with buprenorphine-naloxone being superior to clonidine at relieving early withdrawal symptoms. Inpatient subjects on clonidine with lower withdrawal scores at baseline did better than those with higher withdrawal scores; inpatient subjects receiving buprenorphine-naloxone did better with higher withdrawal scores at baseline than those with lower withdrawal scores. No relationship was found between treatment outcome and age, gender, race, education, employment, marital status, legal problems, baseline depression, or length/severity of drug use. Tobacco use was associated with worse opioid treatment outcomes. Severe baseline anxiety symptoms doubled treatment success. Medication type (buprenorphine-naloxone) was the most important predictor of positive outcome; however the paper also considers other clinical and policy implications of other results, including that inpatient setting predicted better outcomes and moderated medication outcomes.

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.