Deuterium labeled methadone and deuterium labeled metabolites were synthesized to use in gas chromatography mass spectrometry (GCMS) studies of the metabolic pathways of metha-done in rats. These compounds were also useful to develop sensitive and selective analytical methods to study the pharmacokinetics and disposition of methadone. Synthesis of the deuterium labeled compounds was mainly achieved by using known procedures with special treatments required to provide label enrichment. Using the labeled and unlabeled derivatives, mass fragmentation processes that are common to methadone and its metabolites were defined. Aryl ring migration was observed in a fragmentation process for 2-ethylidene-l,5-dimethyl-3,3-diphenyl pyrrolidine (EDDP). This aryl ring migration was not a favorable process for ring substituted EDDP analogs. Various aspects regarding the optimization of the selected ion monitoring (SIM) analysis of methadone and its metabolites in biological fluids are described. The SIM analysis using deuterium labeled compounds as internal standards generally proved to be selective but not as sensitive as expected using electron impact ionization (EI) conditions of GCMS. One advantage of using SIM over GC analysis was described in terms of ratio analysis. Quantitation of methadone in human plasma and saliva using SIM gave a lower limit of sensitivity of 20 ng/0.5 ml of sample by monitoring the base peak, m/e 72. The mean methadone ratios of saliva to plasma for two patients were 0.55 ± 0.15 (standard deviation) and 0.48 ± 0.10 (standard deviation). Methadone metabolism studies emphasized the detection of minor metabolites using special extraction methods for rat bile and using labeled and unlabeled compounds. Comparison of the mass spectra from total ion current (TIC) profiles of metabolites from unlabeled compounds with those from labeled compounds run as separate experiments gave GCMS evidence for methadone nitrone (N-methylene-l-methyl-3,3-diphenyl-4-oxo-hexanamine-oxide). Possibilities for the metabolic formation of N-hydroxynormethadone and the pharmacological significance of the detection of methadone nitrone were described. A proposal for metabolic studies to examine the potential formation of other methadone metabolites resulting from metabolic oxidation of nitrogen was presented. Structural evidence for the methadone nitrone molecule was obtained indirectly by chemical oxidation studies of metha done metabolites. m-Chloroperbenzoic acid treatment of EDDP perchlorate gave three products: methadone nitrone, 4,4-diphen yl-2,5-heptanedione (diketone), and 2-acetyl-5-methyl-3,3-di-phenyl-l-pyrroline. These compounds were identified from their IR, NMR and mass spectral data. Mass fragmentation processes were defined for the methadone nitrone. Possible mechanisms for the formation of methadone nitrone and diketone from chemical oxidation of EDDP are proposed. Since diazepam is a drug widely abused by methadone maintenance patients, methadone-diazepam interaction studies were designed to analyze metabolites using deuterium labeled authentic compounds as internal standards. Metabolites in the conjugated fraction of rat bile were analyzed using deuterium labeled biosynthetic internal standards. Diazepam (5 mg/kg) was given to rats through a cannulated jugular vein and a subcutaneous dose of methadone (10 mg/kg) was given. Bile was collected through the cannulated bile duct over a period of 24 hours. The deuterium label was found to be stable even under severe conditions of incubation temperature and time. SIM analysis of bile sample extracts showed that concomitant administration of diazepam with methadone did not affect biliary excretion of EDDP nor the conjugated metabolites. This indicates that diazepam does not interact with methadone at the hepatic metabolism level and with transport of the metabo-: lites by the biliary excretion route. Application of the use of a biosynthetic internal standard to drug metabolism and pharmacokinetic studies by means of ratio analysis was described with examples. / Pharmaceutical Sciences, Faculty of / Graduate

Cette étude permet d'étudier la toxicité de la méthadone (les ingestions accidentelles pédiatriques, les mésusages,les conduites suicidaires et les symptômes reportés chez des patients traités) à l'aide des bases de données des Centres antipoisons et également de l'étude Méthaville. Elle permet de souligner la gravité des intoxications pédiatriques à la méthadone, et de confirmer que la forme gélule ne paraît pas entraîner plus de risque que la forme sirop, qui est commercialisée depuis 1995. Nous avons pu également retrouver de nombreuses différences significatives entre les 2 types d’exposition à la méthadone permettant de définir des profils de patients bien distincts. L'étude des symptômes rapportés par les patients traités par méthadone nous permet d'identifier des facteurs de risques à prendre en compte pour une meilleure prise en charge globale. / This study investigates the toxicity of methadone (accidental pediatric ingestions, misuses, suicidal behaviours and reported symptoms in treated patients) using Poison Center databases and also the Methaville study. It highlights the severityof pediatric methadone poisoning, and confirms that the capsule form does not appear more dangerous than the syrup form, which exists since 1995 in France. We also found many significant differences between the 2 types of methadone exposure to define distinct patient profiles. The study of symptoms reported by patients treated with methadone allows us to identify risk factors to consider for a better medical management.

Background: Methadone maintenance treatment (MMT) is a commonly prescribed therapy for patients with opioid use disorder, yet inter-individual variability in terms of treatment response is evident. Given the high prevalence of cannabis use in this population, this thesis aims to elucidate the association between cannabis use and MMT outcomes. Methods: We conducted a systematic review and meta-analysis to comprehensively evaluate the literature and quality of evidence, as well as to identify gaps in the literature to inform future research. We then conducted a cross-sectional study investigating sex differences in the association between cannabis use and illicit opioid use in MMT patients. We employed a multivariable logistic regression analysis to assess the influence of any cannabis use as well as heaviness of cannabis use within men and women. Results: The systematic review included 22 observational studies. Results revealed the low quality of available evidence as well as substantial heterogeneity among studies. We identified several limitations in the evidence base including reliance on crude measures of cannabis use and inadequate consideration of confounding variables. Our cross-sectional study included a sample of 777 patients on MMT. Consistent with previous research, we found cannabis use to be unrelated to illicit opioid use in the entire sample. However when we stratified the analysis by sex, we found cannabis use was associated with increased odds of having concurrent illicit opioid use. Conclusion: Results of this thesis suggest certain populations within MMT patients may be at higher risk of experiencing adverse effects of cannabis in terms of treatment outcomes. Future work can build on the results of these studies to identify unique risk factors for patients in order to inform the use of tailored treatment options to improve MMT effectiveness. / Thesis / Master of Science (MSc)

ABSTRACT Introduction. Research from the early 1980s indicates that there are different neurodevelopmental differences between methadone-exposed and non-exposed infants. However, the extent to which these difficulties translate to later problems in the domain areas of physical health, social-emotional adjustment, approaches to learning, language, and cognition for children born to mothers maintained on methadone during pregnancy, is largely unknown. Accordingly, this research aimed to compare school readiness outcomes between children prenatally exposed to methadone and comparison children at age 4.5 years across five key developmental domains. A secondary aim was to assess the impact of known neonatal, and socio-familial risk factors associated with this population on school readiness outcomes of methadone-exposed children at age 4.5 years. Research Methods. Sixty seven children born to mothers maintained on methadone and 81 comparison children were followed prospectively from birth to age 4.5 years. At age 4.5 years, all children underwent a comprehensive school readiness assessment of health and physical development; social-emotional skills; approaches to learning; language; and cognition. A score < 1SD below the comparison group mean was used to classify children as unready in any one domain. Measures of socio-familial risk were collated from aspects of the maternal interview at the term assessments, based on risk indices used in the research of other at-risk populations. Results. Methadone-exposed children performed worse than comparison children across all school readiness domains. They also had higher odds of being classed as “unready” in each school readiness domain, relative to the control group. They were also iii more likely to have multiple readiness problems (p =<.0001). The most common pattern of comorbidity identified, was among children classified as unready in terms of cognition and general knowledge. However, after controlling for confounding and selection factors, methadone-exposure was not significantly associated with school readiness at age 4.5 years. Maternal smoking during pregnancy, maternal benzodiazepine use during pregnancy, and socio-familial risk were significant covariates of low school readiness at age 4.5 years, independent of group. Discussion. By age 4.5 years, a larger proportion of methadone-exposed than control children were experiencing school readiness difficulties across five key developmental domains. Prenatal methadone exposure alone was not a sufficient explanation for these problems. Findings suggest that readiness outcomes were largely explained by a range of confounding and selection factors, including the extent of socio-familial risk, and poly-drug use during pregnancy. The results raise concerns for the later school performance of methadone-exposed children and emphasise the importance of early and targeted intervention services prior to school entry for this population.

Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The current study aimed to assess the efficacy and safety of buprenorphine maintenance for the treatment of illicit opioid dependence during pregnancy. Parameters investigated assessed pregnancy progression and Neonatal Abstinence Syndrome (NAS) compared to methadone maintenance and non-opioid exposed control pregnancies. This is the first study to present results comparing the two treatment groups to a control population. The trial was a prospective, non-randomised, open-label, flexible dosing study (n=25 for each group). Women were recruited up to a gestational age of 28 weeks and their infants observed postnatally for 4 weeks. Methadone and buprenorphine doses did not change significantly from recruitment to delivery and were 48.40±5.95 mg.day⁻¹ and 7.46±O.84 mg.day⁻¹ respectively at delivery. Both subjective and objective measures of maternal withdrawal were significantly lower for buprenorphine compared to the methadone group (p<O.Ol and p<O.05, respectively) at the sub-optimal does observed in this study. Direct drug effects were similar between methadone and buprenorphine groups and did not change over the course of pregnancy. Additional substance use during pregnancy was significantly higher for methadone and buprenorphine groups compared to controls but was not significantly different between each other. Patterns of maternal symptom complaints during pregnancy were higher for methadone and buprenorphine compared to controls but were not significantly different to each other and raised several issues regarding maternal health, and re-dosing in the antenatal period. Obstetric complications in the antenatal period and during labour and delivery were similar between the three groups. There was no significant difference between the three groups for infant gestational age at delivery or their Apgar scores. However, methadone exposed infants were significantly smaller than control infants (birth weight p<O.05, body length p<O.05, head circumference p<O.05) while buprenorphine exposed infants did not differ to controls. There was no significant difference between methadone and buprenorphine exposed infants for the percentage of infants who required pharmacological treatment to control NAS (methadone 60%, buprenorphine 48%). However, significantly less morphine was required to control NAS in buprenorphine compared to methadone exposed infants (methadone: 40.07 ± 3.95 mg, buprenorphine: 22.77 ± 4.29 mg; p<0.05) and may have been due to reduced placental transfer of buprenorphine. The current study observed buprenorphine to be at least as efficacious as methadone for the treatment of opioid dependence during pregnancy while minimising NAS. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1259912 / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2006

Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The current study aimed to assess the efficacy and safety of buprenorphine maintenance for the treatment of illicit opioid dependence during pregnancy. Parameters investigated assessed pregnancy progression and Neonatal Abstinence Syndrome (NAS) compared to methadone maintenance and non-opioid exposed control pregnancies. This is the first study to present results comparing the two treatment groups to a control population. The trial was a prospective, non-randomised, open-label, flexible dosing study (n=25 for each group). Women were recruited up to a gestational age of 28 weeks and their infants observed postnatally for 4 weeks. Methadone and buprenorphine doses did not change significantly from recruitment to delivery and were 48.40±5.95 mg.day⁻¹ and 7.46±O.84 mg.day⁻¹ respectively at delivery. Both subjective and objective measures of maternal withdrawal were significantly lower for buprenorphine compared to the methadone group (p<O.Ol and p<O.05, respectively) at the sub-optimal does observed in this study. Direct drug effects were similar between methadone and buprenorphine groups and did not change over the course of pregnancy. Additional substance use during pregnancy was significantly higher for methadone and buprenorphine groups compared to controls but was not significantly different between each other. Patterns of maternal symptom complaints during pregnancy were higher for methadone and buprenorphine compared to controls but were not significantly different to each other and raised several issues regarding maternal health, and re-dosing in the antenatal period. Obstetric complications in the antenatal period and during labour and delivery were similar between the three groups. There was no significant difference between the three groups for infant gestational age at delivery or their Apgar scores. However, methadone exposed infants were significantly smaller than control infants (birth weight p<O.05, body length p<O.05, head circumference p<O.05) while buprenorphine exposed infants did not differ to controls. There was no significant difference between methadone and buprenorphine exposed infants for the percentage of infants who required pharmacological treatment to control NAS (methadone 60%, buprenorphine 48%). However, significantly less morphine was required to control NAS in buprenorphine compared to methadone exposed infants (methadone: 40.07 ± 3.95 mg, buprenorphine: 22.77 ± 4.29 mg; p<0.05) and may have been due to reduced placental transfer of buprenorphine. The current study observed buprenorphine to be at least as efficacious as methadone for the treatment of opioid dependence during pregnancy while minimising NAS. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1259912 / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2006

Thesis (B.A.)--Haverford College, Dept. of Religion, 2007. / Includes bibliographical references.

Thesis (M.S.W.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 81-92).

Thesis (M.S.W.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 81-92) Also available in print.

Previous research into the subsequent effects of prenatal methadone exposure has primarily focused on neurological changes and short term physical development. While there have been some studies of behavioural development, only short term effects have been investigated. The present research therefore aimed to assess longer term behavioural development of offspring exposed to methadone gestationally, lactationally or both. Methadone was provided in the drinking water of drug-treated rat dams during gestation (2.39mg/kg/day) and lactation (2.86mg/kg/day). The four conditions were: non-exposure/control (N = 24), gestational-exposure (N = 20), lactational-exposure (N = 24), and combined-exposure (N = 21). As well as several measures of pregnancy characteristics, offspring postnatal physical development was assessed at 30, 60 and 120 days after birth. Behavioural assessments were also made at these ages by means of an open-field, Y maze and emergence apparatus. There were no significant differences in physical development. Maternal methadone exposure during gestation reduced the number of rat dams that became (or remained) pregnant. In the offspring, there was increased activity in lactationally-exposed rats through into adulthood. Anxiety was increased in the combined-exposure condition, primarily in adolescent males. The significant longer term effects of earlier methadone on the rats’ behavioural development supported the need for more research into this hitherto relatively neglected area. More information about effects of methadone exposure on anxiety and activity, as well as on social functioning and motor coordination could be useful for understanding potential risk factors in the ever growing methadone-exposed population, and thus suggesting best practice for methadone maintenance programmes.