morphine and Opioid-Related-Disorders

Buprenorphine and methadone are international gold standards for managing opioid use disorders. Although they are efficacious in treating opioid dependence, buprenorphine and methadone present risks, especially during pregnancy, causing neonatal abstinence syndrome and adverse obstetrical outcomes. Buprenorphine and methadone are also abused during pregnancy, and identifying their use is important to limit unprescribed prenatal exposure. Previous studies have suggested that concentrations of buprenorphine, but not methadone markers in unconventional matrices may predict child outcomes, although currently only limited data exist. We reviewed the literature on concentrations of buprenorphine, methadone, and their metabolites in unconventional matrices to improve data interpretation.. A literature search was conducted using scientific databases (PubMed, Scopus, Web of Science, and reports from international institutions) to review published articles on buprenorphine and methadone monitoring during pregnancy.. Buprenorphine and methadone and their metabolites were quantified in the meconium, umbilical cord, placenta, and maternal and neonatal hair. Methadone concentrations in the meconium and hair were typically higher than those in other matrices, although the concentrations in the placenta and umbilical cord were more suitable for predicting neonatal outcomes. Buprenorphine concentrations were lower and required sensitive instrumentation, as measuring buprenorphine glucuronidated metabolites is critical to predict neonatal outcomes.. Unconventional matrices are good alternatives to conventional ones for monitoring drug exposure during pregnancy. However, data are currently scarce on buprenorphine and methadone during pregnancy to accurately interpret their concentrations. Clinical studies should be conducted with larger cohorts, considering confounding factors such as illicit drug co-exposure.

Topics: Analgesics, Opioid; Buprenorphine; Drug Monitoring; Female; Hair; Humans; Meconium; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Umbilical Cord

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.. 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.. 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.. 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.

Topics: Analgesics, Opioid; Apgar Score; Birth Weight; Body Size; Cephalometry; Cocaine; Female; Gestational Age; Humans; Infant, Newborn; Maternal Exposure; Meconium; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Placenta; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimesters; Pyrrolidines; Tissue Distribution

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.. 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.. 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.. 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.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Cocaine; Dose-Response Relationship, Drug; Female; Humans; Infant, Newborn; Maternal-Fetal Exchange; Meconium; Methadone; Narcotics; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Placenta; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pyrrolidines; Umbilical Cord

For the first time, relationships among maternal buprenorphine dose, meconium buprenorphine and metabolite concentrations, and neonatal outcomes are reported. Free and total buprenorphine and norbuprenorphine, nicotine, opiates, cocaine, benzodiazepines, and metabolites were quantified in meconium from 10 infants born to women who had received buprenorphine during pregnancy. Neither cumulative nor total third-trimester maternal buprenorphine dose predicted meconium concentrations or neonatal outcomes. Total buprenorphine meconium concentrations and buprenorphine/norbuprenorphine ratios were significantly related to neonatal abstinence syndrome (NAS) scores >4. As free buprenorphine concentration and percentage free buprenorphine increased, head circumference decreased. Thrice-weekly urine tests for opiates, cocaine, and benzodiazepines and self-reported smoking data from the mother were compared with data from analysis of the meconium to estimate in utero exposure. Time of last drug use and frequency of use during the third trimester were important factors associated with drug-positive meconium specimens. The results suggest that buprenorphine and metabolite concentrations in the meconium may predict the onset and frequency of NAS.

Topics: Adult; Buprenorphine; Cocaine; Double-Blind Method; Female; Humans; Infant, Newborn; Male; Maternal Behavior; Maternal-Fetal Exchange; Meconium; Methadone; Narcotic Antagonists; Neonatal Abstinence Syndrome; Nicotine; Opiate Alkaloids; Opioid-Related Disorders; Pregnancy; Smoking

This was a prospective longitudinal multisite study of the effects of prenatal cocaine and/or opiate exposure on neurodevelopmental outcome in term and preterm infants at 1 month of age.. The sample included 658 exposed and 730 comparison infants matched on race, gender, and gestational age (11.7% born <33 weeks' gestational age). Mothers were recruited at 4 urban university-based centers and were mostly black and on public assistance. Exposure was determined by meconium assay and self-report with alcohol, marijuana, and tobacco present in both groups. At 1 month corrected age, infants were tested by masked examiners with the NICU Network Neurobehavioral Scale and acoustical cry analysis. Exposed and comparison groups were compared adjusting for covariates (alcohol, marijuana, tobacco, birth weight, social class, and site). Separate analyses were conducted for level of cocaine exposure.. On the NICU Network Neurobehavioral Scale, cocaine exposure was related to lower arousal, poorer quality of movement and self-regulation, higher excitability, more hypertonia, and more nonoptimal reflexes with most effects maintained after adjustment for covariates. Some effects were associated with heavy cocaine exposure, and effects were also found for opiates, alcohol, marijuana, and birth weight. Acoustic cry characteristics that reflect reactivity, respiratory, and neural control of the cry sound were also compromised by prenatal drug exposure, including cocaine, opiates, alcohol, and marijuana and by birth weight. Fewer cry effects remained after adjustment for covariates.. Cocaine effects are subtle and can be detected when studied in the context of polydrug use and level of cocaine exposure. Effects of other drugs even at low thresholds can also be observed in the context of a polydrug model. The ability to detect these drug effects requires a large sample and neurobehavioral tests that are differentially sensitive to drug effects. Long-term follow-up is necessary to determine whether these differences develop into clinically significant deficits.

Topics: Adult; Alcohol Drinking; Analysis of Variance; Child Development; Cocaine-Related Disorders; Female; Humans; Infant, Newborn; Life Style; Longitudinal Studies; Meconium; Nervous System; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Prospective Studies; Smoking

Buprenorphine (Suboxone, Zubsolv, Buprenex, Butrans, etc.) is an opioid drug that has been used to treat opioid dependence on an outpatient basis, and is also prescribed for managing moderate to severe pain. Pregnant women may be prescribed buprenorphine as part of a treatment plan for opioid addiction. This chapter quantitates buprenorphine and norbuprenorphine in meconium by liquid chromatography tandem mass spectrometry (LC-MS/MS).

Topics: Analgesics, Opioid; Buprenorphine; Chromatography, Liquid; Female; Humans; Infant, Newborn; Meconium; Opioid-Related Disorders; Pregnancy; Tandem Mass Spectrometry

Meconium drug testing is a non-invasive method to detect prenatal drug exposure, which can cause severe problems for the infant, indicating the need for follow-up measures to ensure the welfare of the child. Meconium samples for drug testing were collected from 143 infants as part of routine clinical work among addicted mothers. The drug testing findings were combined with medical records including clinical background and follow-up data. The substances screened for included medicinal opioids, 6-monoacetylmorphine (a metabolite of heroin), amphetamines and tetrahydrocannabinolic acid. At least one of the 13 target drugs was detected in 57 (40%) meconium samples. In 21 cases, the findings were unexpected on the basis of clinical data or denied by the mother. Medicinal opioids, especially the opioid substitution treatment drugs buprenorphine and methadone, comprised the majority of the findings of both admitted and unexpected drug misuse. Meconium drug testing methods should target not just traditional illicit drugs but also prescription drugs with misuse potential.

Topics: Female; Follow-Up Studies; Humans; Infant, Newborn; Meconium; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Substance Abuse Detection

In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.

Topics: Analgesics, Opioid; Animals; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Drug Tolerance; Humans; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Opioid-Related Disorders; Pyridines; Radioligand Assay; Receptors, Opioid, mu; Receptors, sigma; Structure-Activity Relationship

Methadone is standard pharmacotherapy for opioid-dependent pregnant women, yet the relationship between maternal methadone dose and neonatal abstinence syndrome (NAS) severity is still unclear. This research evaluated whether quantification of fetal methadone and drug exposure via meconium would reflect maternal dose and predict neonatal outcomes.. Prospective clinical study.. An urban drug treatment facility treating pregnant and post-partum women and their children.. Forty-nine opioid-dependent pregnant women received 30-110 mg methadone daily.. Maternal methadone dose, infant birth parameters and NAS assessments were extracted from medical records. Thrice-weekly urine specimens were screened for opioids and cocaine. Newborn meconium specimens were quantified for methadone, opioid, cocaine and tobacco biomarkers.. There was no relationship between meconium methadone concentrations, presence of opioids, cocaine and/or tobacco in meconium, maternal methadone dose or NAS severity. Opioid and cocaine were also found in 36.7 and 38.8 of meconium specimens, respectively, and were associated with positive urine specimens in the third trimester. The presence of opioids other than methadone in meconium correlated with increased rates of preterm birth, longer infant hospital stays and decreased maternal time in drug treatment.. Methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentrations in meconium did not predict infant birth parameters or NAS severity. Prospective urine testing defined meconium drug detection windows for opiates and cocaine as 3 months, rather than the currently accepted 6 months. The presence of opioids in meconium could be used as a biomarker for infants at elevated risk in the newborn period.

Topics: Adult; Analgesics, Opioid; Cocaine; Cocaine-Related Disorders; Female; Gestational Age; Humans; Infant, Newborn; Length of Stay; Meconium; Methadone; Narcotics; Neonatal Abstinence Syndrome; Opiate Substitution Treatment; Opioid-Related Disorders; Predictive Value of Tests; Pregnancy; Pregnancy Complications; Premature Birth; Prenatal Exposure Delayed Effects; Prospective Studies; Substance Abuse Detection; Young Adult

A novel liquid chromatography tandem mass spectrometry method for quantification of buprenorphine, norbuprenorphine, and glucuronidated conjugates was developed and validated. Analytes were extracted from meconium using buffer, concentrated by solid-phase extraction and quantified within 13.5 min. In order to determine free and total concentrations, specimens were analyzed with and without enzyme hydrolysis. Calibration was achieved by linear regression with a 1/x weighting factor and deuterated internal standards. All analytes were linear from 20 to 2000 ng/g with a correlation of determination of >0.98. Accuracy was >or=85.7% with intra-assay and interassay imprecisionor=85.0%. There was suppression of ionization by the polar matrix; however, this did not interfere with sensitivity or analyte quantification due to inclusion of deuterated internal standards. Analytes were stable on the autosampler, at room temperature, at 4 degrees C, and when exposed to three freeze/thaw cycles. This sensitive and specific method can be used to monitor in utero buprenorphine exposure and to evaluate correlations, if any, between buprenorphine exposure and neonatal outcomes.

Topics: Buprenorphine; Calibration; Chromatography, Liquid; Female; Glucuronides; Humans; Infant; Meconium; Mothers; Opioid-Related Disorders; Pregnancy; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

To compare the sensitivity and specificity of maternal interview, maternal hair analysis, and meconium analysis in detecting perinatal exposure to cocaine, opiate, and cannabinoid.. The use of cocaine, opiate, and cannabinoid during pregnancy was determined prospectively in 58 women by 3 methods: structured maternal interview, maternal hair analysis, and meconium analyses. The results of the 3 methods were compared with one another.. The maternal interview showed the lowest sensitivity in detecting cocaine and opiate exposures (65% and 67%, respectively), but it had the highest sensitivity in detecting cannabinoid exposure (58%). Both hair and meconium analyses had high sensitivity for detecting cocaine or opiate exposures. Hair analysis had a sensitivity of 100% for cocaine and 80% for opiate detection. However, it had a false-positive rate of 13% for cocaine and 20% for opiate, probably as a result of passive exposure. Meconium analysis had a sensitivity of 87% for cocaine and 77% for opiate detection, but unlike hair analysis, it had no false-positive test results for cocaine. Both hair and meconium analyses had low sensitivity in detecting cannabinoid exposure (21%-22.7%), most probably because of the sporadic use of cannabinoid.. Meconium and hair analyses had the highest sensitivities for detecting perinatal use of cocaine and opiate, but not for cannabinoid. The principal drawback of hair analysis is its potential for false-positive test results associated with passive exposure to drugs. Maternal interview is a time-consuming test of low sensitivity. The high sensitivity of meconium analysis and the ease of collection make this test ideal for perinatal drug screening.

Topics: Adult; Cocaine-Related Disorders; Female; Hair; Humans; Infant, Newborn; Interviews as Topic; Marijuana Abuse; Meconium; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; Prospective Studies; Sensitivity and Specificity; Substance Abuse Detection; Substance-Related Disorders

Topics: Animals; Aorta, Thoracic; Cocaine; Cyclic AMP; Electric Stimulation; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Mice; Muscle, Smooth; Opioid-Related Disorders; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Serotonin; Substance-Related Disorders

The relationship of maternal illicit drug use to congenital syphilis was studied in a population of newborn infants (N = 1012) who were screened for intrauterine exposure to illicit drugs by meconium analysis and whose mothers were screened for syphilis by the rapid plasmin reagin fluorescent treponemal antibody, absorbed (RPR/FTA-ABS) test. The result of the meconium drug screening was positive in 449 (44.3%) infants: 401 (39.6%) screening results were positive for cocaine, 71 (7%) positive for opiate, and 31 (3.1%) positive for cannabinoid. The maternal RPR/FTA-ABS result was positive in 72 (7.1%) women, and congenital syphilis was diagnosed in 46 (4.5%) infants on the basis of Centers for Disease Control and Prevention definitions. The incidence of positive RPR/FTA-ABS result (10.5% vs 4.4%) and congenital syphilis (7% vs 2.5%) was significantly higher (p < 0.01) among infants with positive results compared with those with negative drug screening results. Similarly, the incidence of positive RPR/FTA-ABS (11% vs 4.6%) and congenital syphilis (8% vs 2.3%) was significantly (p < 0.01) higher among infants with cocaine-positive results compared with those with cocaine-negative results. We conclude that maternal illicit drug use, specifically cocaine, is significantly related to the resurgence of congenital syphilis among newborn infants.

Topics: Adult; Cocaine; Female; Fluorescent Treponemal Antibody-Absorption Test; Humans; Incidence; Infant, Newborn; Male; Marijuana Abuse; Meconium; Opioid-Related Disorders; Risk Factors; Syphilis, Congenital

To determine the mortality rate, during the first 2 years of life, in infants who were exposed to cocaine, opiate, or cannabinoid during gestation.. For a period of 11 months, a large group of infants were enrolled and screened at birth for exposure to cocaine, opiate, or cannabinoid by meconium analysis. Death outcome, within the first 2 years after birth, was determined in this group of infants using the death registry of the Michigan Department of Public Health.. A total of 2964 infants was studied. At birth, 44% of the infants tested positive for drugs: 30. 5% positive for cocaine, 20.2% for opiate, and 11.4% for cannabinoids. Compared to the drug negative group, a significantly higher percentage (P < .05) of the drug positive infants had lower weight and smaller head circumference and length at birth and a higher percent of their mothers were single, multigravid, multiparous, and had little to no prenatal care. Within the first 2 years of life, 44 infants died: 26 were drug negative (15.7 deaths per 1000 live births) and 18 were drug positive (13.7 deaths per 1000 live births). The mortality rate among cocaine, opiate, or cannabinoid positive infants were 17.7, 18.4, and 8.9 per 1000 live births, respectively. Among infants with birth weight

Topics: Birth Weight; Cannabinoids; Cannabis; Cocaine; Confidence Intervals; Data Interpretation, Statistical; Female; Humans; Infant; Infant Mortality; Infant, Newborn; Male; Meconium; Narcotics; Neonatal Screening; Odds Ratio; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Registries; Sudden Infant Death