Diaa M. Shakleya

Methadone Maintenance and Breastfeeding in the Neonatal Period

OBJECTIVE. In a sample of methadone-maintained breastfeeding women and a matched group of formula-feeding women, this study evaluated concentrations of methadone in breast milk among breastfeeding women and concentrations of methadone in maternal and infant plasma in both groups. METHODS. Eight methadone-maintained (dose: 50–105 mg/day), lactating women provided blood and breast milk specimens on days 1, 2, 3, 4, 14, and 30 after delivery, at the times of trough and peak maternal methadone levels. Paired specimens of foremilk and hindmilk were obtained at each sampling time. Eight matched formula-feeding subjects provided blood samples on the same days. Infant blood samples for both groups were obtained on day 14. Urine toxicological screening between 36 weeks of gestation and 30 days after the birth confirmed that subjects were not using illicit substances in the perinatal period. RESULTS. Concentrations of methadone in breast milk were low (range: 21.0–462.0 ng/mL) and not related to maternal dose. There was a significant increase in methadone concentrations in breast milk over time for all 4 sampling times. Concentrations of methadone in maternal plasma were not different between groups and were unrelated to maternal dose. Concentrations of methadone in infant plasma were low (range: 2.2–8.1 ng/mL) in all samples. Infants in both groups underwent neurobehavioral assessments on days 3, 14, and 30; there were no significant effects of breastfeeding on neurobehavioral outcomes. Fewer infants in the breastfed group required pharmacotherapy for neonatal abstinence syndrome, but this was not a statistically significant finding. CONCLUSION. Results contribute to the recommendation of breastfeeding for methadone-maintained women.

Chronic Exposure to Nicotine Is Associated with Reduced Reward-Related Activity in the Striatum but not the Midbrain

BACKGROUND The reinforcing effects of nicotine are mediated by brain regions that also support temporal difference error (TDE) processing; yet, the impact of nicotine on TDE is undetermined. METHODS Dependent smokers (n = 21) and matched control subjects (n = 21) were trained to associate a juice reward with a visual cue in a classical conditioning paradigm. Subjects subsequently underwent functional magnetic resonance imaging sessions in which they were exposed to trials where they either received juice as temporally predicted or where the juice was withheld (negative TDE) and later received unexpectedly (positive TDE). Subjects were scanned in two sessions that were identical, except that smokers had a transdermal nicotine (21 mg) or placebo patch placed before scanning. Analysis focused on regions along the trajectory of mesocorticolimbic and nigrostriatal dopaminergic pathways. RESULTS There was a reduction in TDE-related function in smokers in the striatum, which did not differ as a function of patch manipulation but was predicted by the duration (years) of smoking. Activation in midbrain regions was not impacted by group or drug condition. CONCLUSIONS These data suggest a differential effect of smoking status on the neural substrates of reward in distinct dopaminergic pathway regions, which may be partially attributable to chronic nicotine exposure. The failure of transdermal nicotine to alter reward-related functional processes, either within smokers or between smokers and control subjects, implies that acute nicotine patch administration is insufficient to modify reward processing, which has been linked to abstinence-induced anhedonia in smokers and may play a critical role in smoking relapse.

Acute Nicotine Differentially Impacts Anticipatory Valence- and Magnitude-Related Striatal Activity

BACKGROUND Dopaminergic activity plays a role in mediating the rewarding aspects of abused drugs, including nicotine. Nicotine modulates the reinforcing properties of other motivational stimuli, yet the mechanisms of this interaction are poorly understood. This study aimed to ascertain the impact of nicotine exposure on neuronal activity associated with reinforcing outcomes in dependent smokers. METHODS Smokers (n = 28) and control subjects (n = 28) underwent functional imaging during performance of a monetary incentive delay task. Using a randomized, counterbalanced design, smokers completed scanning after placement of a nicotine or placebo patch; nonsmokers were scanned twice without nicotine manipulation. In regions along dopaminergic pathway trajectories, we considered event-related activity for valence (reward/gain vs. punishment/loss), magnitude (small, medium, large), and outcome (successful vs. unsuccessful). RESULTS Both nicotine and placebo patch conditions were associated with reduced activity in regions supporting anticipatory valence, including ventral striatum. In contrast, relative to controls, acute nicotine increased activity in dorsal striatum for anticipated magnitude. Across conditions, anticipatory valence-related activity in the striatum was negatively associated with plasma nicotine concentration, whereas the number of cigarettes daily correlated negatively with loss anticipation activity in the medial prefrontal cortex only during abstinence. CONCLUSIONS These data suggest a partial dissociation in the state- and trait-specific effects of smoking and nicotine exposure on magnitude- and valence-dependent anticipatory activity within discrete reward processing brain regions. Such variability may help explain, in part, nicotines impact on the reinforcing properties of nondrug stimuli and speak to the continued motivation to smoke and cessation difficulty.

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.

Chronic smoking, but not acute nicotine administration, modulates neural correlates of working memory.

RationaleBeyond the amelioration of deprivation-induced impairments, and in contrast to effects on attentional processes, the cognitive-enhancing properties of nicotine on working memory (WM) operations remain unclear.ObjectivesIn an effort to elucidate potential enhancing effects, we explored the impact of transdermal nicotine on neural functioning in minimally deprived smokers and, in addition, assessed differences between smokers and non-smokers using a mixed block/event-related fMRI design that attempted to isolate specific central executive operations (attentional switch events) within general WM function (task blocks).MethodsIn task blocks, participants performed a continuous counting paradigm that required the simultaneous maintenance of, and frequent switching of attentional focus between, two running tallies in WM on some trials. Cigarette smokers (n = 30) were scanned twice, once each with a nicotine and placebo patch, while non-smokers (n = 27) were scanned twice with no patch.ResultsAcross both groups, task blocks were associated with bilateral activation, notably in medial and lateral prefrontal cortex (PFC), anterior insula, and parietal regions, whereas individual attentional switch trials were associated with activation in a similar, but predominantly left-lateralized network. Within the smoker group, although nicotine increased heart rate, altered performance and mood, and reduced tobacco cravings, no acute drug (state-like) effect on brain activity was detected for either the task or switch effects. However, relative to non-smokers, smokers showed greater tonic activation in medial superior frontal cortex, right anterior insula, and bilateral anterior PFC throughout task blocks (trait-like effect).ConclusionsThese data suggest smokers require recruitment of additional WM and supervisory control operations during task performance.

Development and validation of a liquid chromatography mass spectrometry assay for the simultaneous quantification of methadone, cocaine, opiates and metabolites in human umbilical cord.

A liquid chromatography mass spectrometric selected reaction monitoring mode (SRM) method for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine (BE), 6-acetylmorphine, morphine and codeine quantification in human umbilical cord was developed and fully validated. Analytes were extracted from homogenized tissue (1g) by solid phase extraction. Linearity was 2.5-500ng/g, except for methadone (10-2000ng/g). Method imprecision was <12.7%CV with analytical recovery 85.9-112.7%, extraction efficiency >59.2%, matrix effect 4.5-39.5%, process efficiency 48.6-92.6% and stability >84.6%. Analysis of an umbilical cord following controlled methadone administration and illicit drug use contained in ng/g, 40.3 morphine, 3.6 codeine, 442 BE, 186 methadone and 45.9 EDDP.

Relative performance of common biochemical indicators in detecting cigarette smoking

AIMS Many cities have banned indoor smoking in public places. Thus, an updated recommendation for a breath carbon monoxide (CO) cut-off is needed that optimally determines smoking status. We evaluated and compared the performance of breath CO and semiquantitative cotinine immunoassay test strips (urine and saliva NicAlert®) alone and in combination. DESIGN Cross-sectional study. SETTING Urban drug addiction research and treatment facility. PARTICIPANTS Ninety non-treatment-seeking smokers and 82 non-smokers. MEASUREMENTS Participants completed smoking histories and provided breath CO, urine and saliva specimens. Urine and saliva specimens were assayed for cotinine by NicAlert® and liquid chromatography-tandem mass spectrometry (LCMSMS). FINDINGS An optimal breath CO cut-off was established using self-report and LCMSMS analysis of cotinine, an objective indicator, as reference measures. Performance of smoking indicators and combinations were compared to the reference measures. Breath CO ≥5 parts per million (p.p.m.) optimally discriminated smokers from non-smokers. Saliva NicAlert® performance was less effective than the other indicators. CONCLUSIONS In surveys of smokers and non-smokers in areas with strong smoke-free laws, the breath carbon monoxide cut-off that discriminates most effectively appears to be ≥5 p.p.m. rather than the ≥10 p.p.m. cut-off often used. These findings may not generalize to clinical trials, regions with different carbon monoxide pollution levels or areas with less stringent smoke-free laws.

Simultaneous quantification of buprenorphine, norbuprenorphine, buprenorphine-glucuronide and norbuprenorphine-glucuronide in human umbilical cord by liquid chromatography tandem mass spectrometry

A LCMS method was developed and validated for the simultaneous determination of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine-glucuronide (BUP-Gluc) and norbuprenorphine-glucuronide (NBUP-Gluc) in human umbilical cord. Quantification was achieved by selected ion monitoring of precursor ions m/z 468.4 for BUP; 414.3 for NBUP; 644.4 for BUP-Gluc and 590 for NBUP-Gluc. BUP and NBUP were identified by MS(2), with m/z 396, 414 and 426 for BUP, and m/z 340, 364 and 382 for NBUP. Glucuronide conjugates were identified by MS(3) with m/z 396 and 414 for BUP-Gluc and m/z 340 and 382 for NBUP-Gluc. The assay was linear 1-50 ng/g. Intra-day, inter-day and total assay imprecision (%RSD) were <14.5%, and analytical recovery ranged from 94.1% to 112.3% for all analytes. Extraction efficiencies were >66.3%, and process efficiency >73.4%. Matrix effect ranged, in absolute value, from 3.7% to 7.4% (CV<21.8%, n=8). The method was selective with no endogenous or exogenous interferences from 41 compounds evaluated. Sensitivity was high with limits of detection of 0.8 ng/g. In order to prove method applicability, an authentic umbilical cord obtained from an opioid-dependent pregnant woman receiving BUP pharmacotherapy was analyzed. Interestingly, BUP was not detected but concentrations of the other metabolites were NBUP-Gluc 13.4 ng/g, BUP-Gluc 3.5 ng/g and NBUP 1.2 ng/g.

Methadone Maintenance and Breastfeeding in the Neonatal Period: In Reply

We thank the writers for their commentary regarding our article titled “Methadone Maintenance and Breastfeeding in the Neonatal Period.” The writers are correct that we have suggested a positive (but not statistically significant) association between reduced severity of neonatal abstinence syndrome (NAS) and …