Methadone and metabolites in hair of methadone-assisted pregnant women and their infants.

INTRODUCTION: Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose-concentration relationship exists between cumulative maternal methadone dose, methadone and metabolite concentrations in maternal hair during pregnancy and whether maternal hair methadone and metabolite concentrations predict neonatal outcomes. MATERIALS AND METHODS: Hair specimens were collected monthly from opioid-dependent mothers enrolled in methadone treatment and 4 of their infants. Hair specimens were segmented (3 cm), washed (maternal hair only), and analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and 2-ethyl-5-methyl-3,3-diphenylpyrroline by liquid chromatography tandem mass spectrometry. RESULTS: There was large intersubject variability and no dose-concentration relationship for cumulative methadone dose and methadone, EDDP, 2-ethyl-5-methyl-3,3-diphenylpyrroline, or total concentrations in hair. For individual women, a positive trend was noted for cumulative methadone dose and methadone and EDDP concentrations in hair. There was a positive linear trend for cumulative methadone dose and EDDP/methadone ratio in maternal hair, perhaps reflecting methadone's induction of its own metabolism. Maternal methadone concentrations were higher than those in infant hair, and infant EDDP hair concentrations were higher than those in maternal hair. Maternal methadone dose, and methadone and EDDP hair concentrations were not correlated with peak infant neonatal abstinence syndrome (NAS) scores, days to peak NAS, duration of NAS, time to NAS onset, birth length, head circumference, or amount of neonatal morphine pharmacotherapy. Maternal cumulative third trimester methadone dose was positively correlated with infant birth weight. CONCLUSIONS: Methadone and EDDP in pregnant women's hair are markers of methadone exposure and do not predict total methadone dose, nor neonatal outcomes from in utero methadone exposure.

Preliminary buprenorphine sublingual tablet pharmacokinetic data in plasma, oral fluid, and sweat during treatment of opioid-dependent pregnant women.

BACKGROUND: Buprenorphine is currently under investigation as a pharmacotherapy to treat pregnant women for opioid dependence. This research evaluates buprenorphine (BUP), norbuprenophine (NBUP), buprenorphine-glucuronide (BUP-Gluc), and norbuprenorphine-glucuronide (NBUP-Gluc) pharmacokinetics after high-dose (14-20 mg) BUP sublingual tablet administration in three opioid-dependent pregnant women. METHODS: Oral fluid and sweat specimens were collected in addition to plasma specimens for 24 hours during gestation weeks 28 or 29 and 34, and 2 months after delivery. Time to maximum concentration was not affected by pregnancy; however, BUP and NBUP maximum concentration and area under the curve at 0 to 24 hours tended to be lower during pregnancy compared with postpartum levels. RESULTS: Statistically significant but weak positive correlations were found for BUP plasma and OF concentrations and BUP/NBUP ratios in plasma and oral fluid. Statistically significant negative correlations were observed for times of specimen collection and BUP and NBUP oral fluid/plasma ratios. BUP-Gluc and NBUP-Gluc were detected in only 5% of oral fluid specimens. In sweat, BUP and NBUP were detected in only four of 25 (12 or 24 hours) specimens in low concentrations (less than 2.4 ng/patch). CONCLUSION: These preliminary data describe BUP and metabolite pharmacokinetics in pregnant women and suggest that, like methadone, upward dose adjustments may be needed with advancing gestation.

Methadone, cocaine, opiates, and metabolite disposition in umbilical cord and correlations to maternal methadone dose and neonatal outcomes.

OBJECTIVES: The purpose was to explore methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) umbilical cord disposition, correlate with maternal methadone dose and neonatal outcomes, and evaluate the window of drug detection in umbilical cord of in utero illicit drug exposure. METHODS: Subjects comprised 19 opioid-dependent pregnant women from 2 clinical studies, one comparing methadone and buprenorphine pharmacotherapy for opioid-dependence treatment and the second examining monetary reinforcement schedules to maintain drug abstinence. Correlations were calculated for methadone and EDDP umbilical cord concentrations and maternal methadone dose, and neonatal outcomes. Cocaine- and opiate-positive umbilical cord concentrations were compared with those in placenta and meconium, and urine specimens collected throughout gestation. RESULTS: Significant positive correlations were found for umbilical cord methadone concentrations and methadone mean daily dose, mean dose during the third trimester, and methadone cumulative daily dose. Umbilical cord EDDP concentrations and EDDP/methadone concentration ratios were positively correlated to newborn length, peak neonatal abstinence syndrome (NAS) score, and time-to-peak NAS score. Methadone concentrations and EDDP/methadone ratios in umbilical cord and placenta were positively correlated. Meconium identified many more cocaine- and opiate-positive specimens than did umbilical cord. CONCLUSIONS: Umbilical cord methadone concentrations were correlated to methadone doses. Also, our results indicate that methadone and EDDP concentrations might help to predict the NAS severity. Meconium proved to be more suitable than umbilical cord to detect in utero exposure to cocaine and opiates; however, umbilical cord could be useful when meconium is unavailable due to in utero or delayed expulsion.

Maternal methadone dose, placental methadone concentrations, and neonatal outcomes.

BACKGROUND: Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadone-maintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs. METHODS: We calculated the correlations of placental methadone and EDDP concentrations and their correlations with maternal methadone doses and neonatal outcomes. Cocaine- and opiate-positive placenta results were compared with the results for meconium samples and for urine samples collected throughout gestation. RESULTS: Positive correlations were found between placental methadone and EDDP concentrations (r=0.685), and between methadone concentration and methadone dose at delivery (r=0.542), mean daily dose (r=0.554), mean third-trimester dose (r=0.591), and cumulative daily dose (r=0.639). The EDDP/methadone concentration ratio was negatively correlated with cumulative daily dose (r=-0.541) and positively correlated with peak neonatal abstinence syndrome (NAS) score (r=0.513). Placental EDDP concentration was negatively correlated with newborn head circumference (r=-0.579). Cocaine and opiate use was detected in far fewer placenta samples than in thrice-weekly urine and meconium samples, a result suggesting a short detection window for placenta. CONCLUSIONS: Quantitative methadone and EDDP measurement may predict NAS severity. The placenta reflects in utero drug exposure for a shorter time than meconium but may be useful when meconium is unavailable or if documentation of recent exposure is needed.

A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients.

BACKGROUND: Cocaine abuse and dependence continue to be widespread. Currently, there are no pharmacotherapies shown to be effective in the treatment of cocaine dependence. METHODS: A 33-week outpatient clinical trial of fluoxetine (60 mg/day, po) for cocaine dependence that incorporated abstinence-contingent voucher incentives was conducted. Participants (N = 145) were both cocaine and opioid dependent and treated with methadone. A stratified randomization procedure assigned subjects to one of four conditions: fluoxetine plus voucher incentives (FV), placebo plus voucher incentives (PV), fluoxetine without vouchers (F), and placebo without vouchers (P). Dosing of fluoxetine/placebo was double blind. Primary outcomes were treatment retention and cocaine use based on thrice-weekly urine testing. RESULTS: The PV group had the longest treatment retention (M = 165 days) and lowest probability of cocaine use. The adjusted predicted probabilities of cocaine use were 65% in the P group, 60% in the F group, 56% in the FV group, and 31% in the PV group. CONCLUSIONS: Fluoxetine was not efficacious in reducing cocaine use in patients dually dependent on cocaine and opioids.

Excretion of methadone in sweat of pregnant women throughout gestation after controlled methadone administration.

Sweat patches (n = 350) were collected throughout gestation from 29 opioid-dependent pregnant women participating in an outpatient methadone-assisted therapy program. Volunteers provided informed consent to participate in institutional review board-approved protocols. Methadone was eluted from sweat patches with sodium acetate buffer, followed by solid-phase extraction and quantification by gas chromatography mass spectrometry (limit of quantification > or = 10 ng/patch). Methadone was present in all weekly patches (n = 311) in concentrations ranging from 10.2 to 12,129.7 nanograms per patch and in 92.3% of short-term patches (n = 39, worn for 12 or 24 hours) in concentrations up to 3303.9 nanograms per patch. Correlation between patch concentrations and total amount of drug administered (r = 0.224), and concentrations and duration of patch wear (r = 0.129) were both weak. Although there were large intra- and intersubject variations in sweat drug concentrations, sweat testing was an effective alternative technique to qualitatively monitor illicit drug use and simultaneously document methadone medication-assisted treatment.

Infant neurobehavior following prenatal exposure to methadone or buprenorphine: results from the neonatal intensive care unit network neurobehavioral scale.

This study examined the neurobehavioral functioning of neonates prenatally exposed to methadone (n = 11) or buprenorphine (n = 10), who underwent the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) examinations on days 3, 5, 7, 10, and 14 post-delivery. Linear mixed model analyses revealed that NNNS scores of arousal and excitability showed significant differences between medications over time. Compared to neonates who did not require medication to treat neonatal abstinence syndrome (NAS), neonates receiving pharmacotherapy for NAS showed differences over time in quality of movement, excitability, and lethargy. Results suggest the NNNS may detect subtle differences over time between both neonates prenatally exposed to methadone or buprenorphine and neonates pharmacologically treated or untreated for NAS.

Maternal buprenorphine dose, placenta buprenorphine, and metabolite concentrations and neonatal outcomes.

Buprenorphine is approved as pharmacotherapy for opioid dependence in nonpregnant patients in multiple countries and is currently under investigation for pregnant women in the United States and Europe. This research evaluates the disposition of buprenorphine, opiates, cocaine, and metabolites in five term placentas from a US cohort. Placenta and matched meconium concentrations were compared, and relationships among maternal buprenorphine dose, placenta concentrations, and neonatal outcomes after controlled administration during gestation were investigated. Buprenorphine and/or metabolites were detected in all placenta specimens and were uniformly distributed across this tissue (coefficient of variation less than 27.5%, four locations), except for buprenorphine in three placentas. In two of these, buprenorphine was not detected in some locations and in the third placenta was totally absent. Median (range) concentrations were 1.6 ng/g buprenorphine (not detected to 3.2), 14.9 ng/g norbuprenorphine (6.2-24.2), 3 ng/g buprenorphine-glucuronide (1.3-5.0), and 14.7 ng/g norbuprenorphine-glucuronide (11.4-25.8). Placenta is a potential alternative matrix for detecting in utero buprenorphine exposure, but at lower concentrations (15- to 70-fold) than in meconium. Statistically significant correlations were observed for mean maternal daily dose from enrollment to delivery and placenta buprenorphine-glucuronide concentration and for norbuprenorphine-glucuronide concentrations and time to neonatal abstinence syndrome onset and duration, for norbuprenorphine/norbuprenorphine-glucuronide ratio and maximum neonatal abstinence syndrome score, and newborn length. Analysis of buprenorphine and metabolites in this alternative matrix, an abundant waste product available at the time of delivery, may be valuable for prediction of neonatal outcomes for clinicians treating newborns of buprenorphine-exposed women.

Confirmatory analysis of buprenorphine, norbuprenorphine, and glucuronide metabolites in plasma by LCMSMS. Application to umbilical cord plasma from buprenorphine-maintained pregnant women.

An LCMSMS method was developed and fully validated for the simultaneous quantification of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine-glucuronide (BUP-Gluc), and norbuprenorphine-glucuronide (NBUP-Gluc) in 0.5mL plasma, fulfilling confirmation criteria with two transitions for each compound with acceptable relative ion intensities. Transitions monitored were 468.3>396.2 and 468.3>414.3 for BUP, 414.3>340.1 and 414.3>326.0 for NBUP, 644.3>468.1 and 644.3>396.3 for BUP-Gluc, and 590.3>414.3 and 590.3>396.2 for NBUP-Gluc. Linearity was 0.1-50ng/mL for BUP and BUP-Gluc, and 0.5-50ng/mL for NBUP and NBUP-Gluc. Intra-day, inter-day, and total assay imprecision (%RSD) were <16.8%, and analytical recoveries were 88.6-108.7%. Extraction efficiencies ranged from 71.1 to 87.1%, and process efficiencies 48.7 to 127.7%. All compounds showed ion enhancement, except BUP-Gluc that demonstrated ion suppression: variation between 10 different blank plasma specimens was <9.1%. In six umbilical cord plasma specimens from opioid-dependent pregnant women receiving 14-24mg/day BUP, NBUP-Gluc was the predominant metabolite (29.8+/-7.6ng/mL), with BUP-Gluc (4.6+/-4.8ng/mL), NBUP (1.5+/-0.8ng/mL) and BUP (0.4+/-0.2ng/mL). Although BUP biomarkers can be quantified in umbilical cord plasma in low ng/mL concentrations, the significance of these data as predictors of neonatal outcomes is currently unknown.

Umbilical cord monitoring of in utero drug exposure to buprenorphine and correlation with maternal dose and neonatal outcomes.

Buprenorphine is under investigation in the U.S. as pharmacotherapy for opioid-dependent pregnant women. Buprenorphine and metabolites were quantified in umbilical cord specimens from women receiving daily buprenorphine doses. Correlations between maternal buprenorphine dose, buprenorphine and metabolite umbilical cord concentrations, and neonatal outcomes were investigated, as well as the ability to identify heroin and cocaine relapse during pregnancy. Umbilical cord concentrations were compared to those of matched umbilical cord plasma and meconium. Buprenorphine metabolites were detected in all cords, but buprenorphine itself was absent. Concentration ranges were 1.2-5.1 ng/g norbuprenorphine, 1.7-4.2 ng/g buprenorphine-glucuronide, and 8.3-23 ng/g norbuprenorphine-glucuronide. Cord concentrations were similar to those in plasma, and lower (16-210-fold), although statistically correlated, than those in meconium. Significant positive correlations were observed for buprenorphine-glucuronide concentrations in umbilical cord and mean maternal BUP daily dose throughout pregnancy and third trimester, but buprenorphine biomarker concentrations did not predict neonatal outcomes. Opiate concentrations were lower (200-fold) in umbilical cord than in meconium, and when cocaine was present in meconium, it was not identified in cord. Umbilical cord can serve as an alternative matrix for identifying prenatal drug-exposure, but is much less sensitive than meconium. Buprenorphine provided a controlled drug administration model for evaluating drug disposition in the maternal-fetal dyad.

Case histories in pharmaceutical risk management.

The development and implementation of programs in the U.S. to minimize risks and assess unintended consequences of new medications has been increasingly required by the Food and Drug Administration (FDA) since the mid 1990s. This paper provides four case histories of risk management and post-marketing surveillance programs utilized recently to address problems associated with possible abuse, dependence and diversion. The pharmaceutical sponsors of each of these drugs were invited to present their programs and followed a similar template for their summaries that are included in this article. The drugs and presenting companies were OxyContin, an analgesic marketed by Purdue Pharma L.P., Daytrana and Vyvanse, ADHD medications marketed by Shire Pharmaceuticals, Xyrem for narcolepsy marketed by Jazz Pharmaceuticals, and Subutex and Suboxone for opioid dependence marketed by Reckitt Benckiser Pharmaceuticals Inc. These case histories and subsequent discussions provide invaluable real-world examples and illustrate both the promise of risk management programs in providing a path to market and/or for keeping on the market drugs with serious potential risks. They also illustrate the limitations of such programs in actually controlling unintended consequences, as well as the challenge of finding the right balance of reducing risks without posing undue barriers to patient access. These experiences are highly relevant as the FDA increasingly requires pharmaceutical sponsors to develop and implement the more formalized and enforceable versions of the risk management term Risk Evaluation and Mitigation Strategies (REMS).

Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument.

INTRODUCTION: The Clinical Opiate Withdrawal Scale (COWS) is an 11-item clinician-administered scale assessing opioid withdrawal. Though commonly used in clinical practice, it has not been systematically validated. The present study validated the COWS in comparison to the validated Clinical Institute Narcotic Assessment (CINA) scale. METHOD: Opioid-dependent volunteers were enrolled in a residential trial and stabilized on morphine 30 mg given subcutaneously four times daily. Subjects then underwent double-blind, randomized challenges of intramuscularly administered placebo and naloxone (0.4 mg) on separate days, during which the COWS, CINA, and visual analog scale (VAS) assessments were concurrently obtained. Subjects completing both challenges were included (N=46). Correlations between mean peak COWS and CINA scores as well as self-report VAS questions were calculated. RESULTS: Mean peak COWS and CINA scores of 7.6 and 24.4, respectively, occurred on average 30 min post-injection of naloxone. Mean COWS and CINA scores 30 min after placebo injection were 1.3 and 18.9, respectively. The Pearson's correlation coefficient for peak COWS and CINA scores during the naloxone challenge session was 0.85 (p<0.001). Peak COWS scores also correlated well with peak VAS self-report scores of bad drug effect (r=0.57, p<0.001) and feeling sick (r=0.57, p<0.001), providing additional evidence of concurrent validity. Placebo was not associated with any significant elevation of COWS, CINA, or VAS scores, indicating discriminant validity. Cronbach's alpha for the COWS was 0.78, indicating good internal consistency (reliability). DISCUSSION: COWS, CINA, and certain VAS items are all valid measurement tools for acute opiate withdrawal.

Urinary excretion of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide in pregnant women receiving buprenorphine maintenance treatment.

BACKGROUND: Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. We investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum. METHODS: We measured BUP, norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. Specimens were analyzed using a fully validated liquid chromatography-mass spectrometry method with limits of quantification of 5 microg/L for BUP and BUP-Gluc and 25 microg/L for NBUP and its conjugated metabolite. We examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy. RESULTS: NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy. CONCLUSIONS: These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation.

Dosing adjustments in postpartum patients maintained on buprenorphine or methadone.

Scant scientific attention has been given to examining the need for agonist medication dose changes in the postpartum period. Study objectives were: 1) to determine the need for medication dose adjustments in participants stabilized on buprenorphine or methadone 3 weeks before and 4 weeks after delivery, and 2) to evaluate the need for methadone dose adjustments during the first 7 days in participants transferred from buprenorphine to methadone at 5 weeks postpartum. Participants were opioid-dependent pregnant women who had completed a randomized, double-blind, double-dummy, flexible dosing comparison of buprenorphine to methadone. Participants received a stable dose of methadone (N = 10) or buprenorphine (N = 8) before and 4 weeks after delivery. Buprenorphine-maintained participants were transferred to methadone at 5 weeks postpartum. There were no significant differences predelivery and/or postdelivery between the buprenorphine and methadone conditions in the mean ratings of dose adequacy, "liking," "hooked," and "craving" of heroin or cocaine. Patient response to the conversion from buprenorphine to methadone seems variable. Buprenorphine-maintained participants required dose changes postpartum only after they transferred to methadone. Regardless of type of medication, postpartum patients should be monitored for signs of overmedication.

QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.

BACKGROUND: Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. METHODS: We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. RESULTS: Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group). CONCLUSION: Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.

Buprenorphine and norbuprenorphine in hair of pregnant women and their infants after controlled buprenorphine administration.

BACKGROUND: Buprenorphine is under investigation as a pharmacotherapeutic agent for treating opioid dependence in pregnant women. We hypothesized that there would be a relationship between the cumulative maternal dose of buprenorphine during pregnancy and the concentration of buprenorphine and norbuprenorphine in maternal and infant hair. METHODS: This study examined buprenorphine and norbuprenorphine concentrations in hair obtained from 9 buprenorphine-maintained pregnant women and 4 of their infants. Specimens were analyzed by liquid chromatography-tandem mass spectrometry with limits of quantification of 3.0 pg/mg. All maternal hair specimens were washed with methylene chloride before analysis, and when sufficient amounts of maternal hair were available, specimens also were analyzed without washing. Infant hair specimens were not washed. RESULTS: Buprenorphine concentrations were significantly greater in unwashed hair than washed hair (P = 0.031). Norbuprenorphine concentrations were significantly greater than buprenorphine concentrations in both maternal (P = 0.0097) and infant hair (P = 0.0033). There were statistically significant associations between the cumulative maternal dose of buprenorphine administered and the concentrations of buprenorphine (washed, P <0.0001; unwashed, P = 0.0004), norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005), and buprenorphine plus norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005) for both washed and unwashed maternal hair specimens. There was a significant positive association between concentrations of buprenorphine and norbuprenorphine in maternal hair (washed, P <0.0001; unwashed, P = 0.0003), a trend for this association in infant hair (P = 0.08), and an association between buprenorphine concentrations in maternal unwashed hair and infant hair (P = 0.0002). The buprenorphine:norbuprenorphine ratio increased in distal segments. CONCLUSION: Buprenorphine treatment during gestation provides an opportunity for monitoring drug disposition in maternal and fetal tissues under controlled conditions.

HIV risk behaviors during pharmacologic treatment for opioid dependence: a comparison of levomethadyl acetate [corrected] buprenorphine, and methadone.

The efficacies of three opioid substitution medications for reducing HIV risk behaviors in opioid-dependent patients were assessed in a randomized double-blind clinical trial comparing levomethadyl acetate [corrected] (LAAM), buprenorphine (BUP), and methadone (METH). Individually optimized flexible dosing was used for each group, with weekly possible doses of 255-391 mg of LAAM, 56-112 mg of BUP, and 420-700 mg of METH. An interview regarding specific HIV risk behaviors, including injecting, equipment sharing, and sexual activity, yielded data for pretreatment and four in-study time points for 137 subjects. Declines in risk behaviors during treatment were evident in all groups for most measures of injecting and equipment sharing. Only the METH group showed consistent declines in measures of sexual behaviors. These results demonstrate that all three medications can be highly effective in decreasing HIV risk behaviors when the dose is optimized. Reductions in sexual behaviors for the METH group are consistent with known METH side effects.

Development of opioid formulations with limited diversion and abuse potential.

Non-medical abuse of prescription opioid medications is not a new phenomenon, but such use has been increasing in recent years. Various methods have been used and continue to be developed in an effort to limit diversion and abuse of opioid medications. A number of these methods will be described for opioid analgesic and addiction treatment formulations using relevant historical examples (e.g. propoxyphene, pentazocine, buprenorphine) as well as examples of formulations currently being considered or under development (e.g. oxycodone plus naltrexone, sustained-release buprenorphine). The focus, though not exclusively, will be on those formulations that represent a combination of an opioid agonist with an antagonist. These methods must take into consideration the pharmacokinetic profile of the agonist and antagonist, the expected primary route of abuse of the medication and the medication combination, the dose of medication that is likely to be abused, the availability of alternative drugs of abuse, and the population of potential abusers that is being targeted with the revised formulation.

Transferring methadone-stabilized pregnant patients to buprenorphine using an immediate release morphine transition: an open-label exploratory study.

A transition from methadone to buprenorphine without intervening withdrawal symptoms is critical for advancing the treatment of opioid-dependent patients. Four pregnant inpatients were transferred from methadone (65-85 mg) to five days of immediate release morphine (IRM) and then to buprenorphine (12-28 mg). Withdrawal scores decreased during the five days of IRM and subsequently increased over the first three days on buprenorphine. The transitional use of IRM appears safe for both mother and fetus. Withdrawal symptoms appeared during buprenorphine induction; however, these data suggest that the intensity of withdrawal symptoms may be lessened by the dose and frequency of buprenorphine administration.