Esta dissertação teve como objetivo determinar parâmetros farmacocinéticos da metadona utilizada por via oral em diferentes formas farmacêuticas. A metadona foi administrada i.v. e v.o. (líquido e comprimido) (0,5 mg/kg) em cães da raça Cocker Spaniel Inglês. Foi também utilizada metadona comprimido (0,5 mg/kg) associada a cetoconazol (10 mg/kg, duas doses). As concentrações séricas resultantes foram determinadas por LC-MS/MS, empregando-se metodologia validada. Os perfis plasmáticos individuais foram avaliados por abordagem não compartimental e compartimental, utilizando os softwares Excel® 2003 e Scientist® 2.01, respectivamente, para a determinação dos parâmetros farmacocinéticos, que foram comparados estatisticamente pelo teste Wilcoxon Rank-Sum e Kruskal-Wallis (α = 0,05). Os perfis plasmáticos da metadona i.v. foram descritos pelo modelo de dois compartimentos e o da metadona oral, pelo modelo de um compartimento. Após a administração da metadona oral, todos os grupos apresentaram concentrações séricas, com exceção do grupo que utilizou o comprimido de metadona isoladamente. O grupo que utilizou solução de metadona apresentou concentrações significativamente superiores ao grupo que recebeu comprimido de metadona isolado, com detecção de níveis do fármaco aos 5 min. O grupo associado ao cetoconazol apresentou o fenômeno de duplo pico plasmático sérico. Estes resultados nos permitem sugerir que a utilização de comprimido de metadona apresenta reduzida absorção, alcançando níveis séricos não quantificáveis pela metodologia empregada. No entanto, quando co-administrada com cetoconazol ou como solução, concentrações séricas foram detectadas, o que nos permite concluir que a utilização de metadona em solução se apresenta como uma boa alternativa para a administração oral deste fármaco em cães. / To determine pharmacokinetic parameters of methadone used in different formulations and routes of administration in dogs. Methadone alone was administered iv, bucal, esophagic and v.o. (liquid and tablet) (0.5 mg/kg) in dogs English Cocker Spaniel. It was also used methadone tablet (0.5 mg/kg) associated with ketoconazole (10 mg/kg, two doses). The resulting serum concentrations were determined by LC-MS/MS, using a validated methodology. The serum concentrations were evaluated by noncompartmental and compartmental model using the software Excel ® Scientist ® 2003 and 2.01, respectively, to determine the pharmacokinetic parameters, which were statistically compared using the Wilcoxon Rank-Sum and Kruskal-Wallis ( α=0.05). The plasma profiles of methadone i.v. are described by the compartmental model and the oral methadone for a noncompartimental model. After administration of methadone, all groups presented serum concentrations but the group that used the pill alone. The group using the methadone solution had significantly higher concentrations when compared with the group that received methadone isolated v.o., and the drug was detected in 5 min. The group associated with ketoconazole showed the phenomenon of double peak plasma. The tablet formulation of methadone reduced the absorption to values not measurable by the method used, however, when co-administered with ketoconazole or as a liquid formulation, serum concentrations were detected. The liquid formulation is presented as a potential alternative to oral administration of methadone in dogs.

Esta dissertação teve como objetivo determinar parâmetros farmacocinéticos da metadona utilizada por via oral em diferentes formas farmacêuticas. A metadona foi administrada i.v. e v.o. (líquido e comprimido) (0,5 mg/kg) em cães da raça Cocker Spaniel Inglês. Foi também utilizada metadona comprimido (0,5 mg/kg) associada a cetoconazol (10 mg/kg, duas doses). As concentrações séricas resultantes foram determinadas por LC-MS/MS, empregando-se metodologia validada. Os perfis plasmáticos individuais foram avaliados por abordagem não compartimental e compartimental, utilizando os softwares Excel® 2003 e Scientist® 2.01, respectivamente, para a determinação dos parâmetros farmacocinéticos, que foram comparados estatisticamente pelo teste Wilcoxon Rank-Sum e Kruskal-Wallis (α = 0,05). Os perfis plasmáticos da metadona i.v. foram descritos pelo modelo de dois compartimentos e o da metadona oral, pelo modelo de um compartimento. Após a administração da metadona oral, todos os grupos apresentaram concentrações séricas, com exceção do grupo que utilizou o comprimido de metadona isoladamente. O grupo que utilizou solução de metadona apresentou concentrações significativamente superiores ao grupo que recebeu comprimido de metadona isolado, com detecção de níveis do fármaco aos 5 min. O grupo associado ao cetoconazol apresentou o fenômeno de duplo pico plasmático sérico. Estes resultados nos permitem sugerir que a utilização de comprimido de metadona apresenta reduzida absorção, alcançando níveis séricos não quantificáveis pela metodologia empregada. No entanto, quando co-administrada com cetoconazol ou como solução, concentrações séricas foram detectadas, o que nos permite concluir que a utilização de metadona em solução se apresenta como uma boa alternativa para a administração oral deste fármaco em cães. / To determine pharmacokinetic parameters of methadone used in different formulations and routes of administration in dogs. Methadone alone was administered iv, bucal, esophagic and v.o. (liquid and tablet) (0.5 mg/kg) in dogs English Cocker Spaniel. It was also used methadone tablet (0.5 mg/kg) associated with ketoconazole (10 mg/kg, two doses). The resulting serum concentrations were determined by LC-MS/MS, using a validated methodology. The serum concentrations were evaluated by noncompartmental and compartmental model using the software Excel ® Scientist ® 2003 and 2.01, respectively, to determine the pharmacokinetic parameters, which were statistically compared using the Wilcoxon Rank-Sum and Kruskal-Wallis ( α=0.05). The plasma profiles of methadone i.v. are described by the compartmental model and the oral methadone for a noncompartimental model. After administration of methadone, all groups presented serum concentrations but the group that used the pill alone. The group using the methadone solution had significantly higher concentrations when compared with the group that received methadone isolated v.o., and the drug was detected in 5 min. The group associated with ketoconazole showed the phenomenon of double peak plasma. The tablet formulation of methadone reduced the absorption to values not measurable by the method used, however, when co-administered with ketoconazole or as a liquid formulation, serum concentrations were detected. The liquid formulation is presented as a potential alternative to oral administration of methadone in dogs.

Made available in DSpace on 2014-06-11T19:27:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-25Bitstream added on 2014-06-13T19:56:09Z : No. of bitstreams: 1 pignaton_w_me_botfm.pdf: 442901 bytes, checksum: 4b1a350341437029cdd0ac39e0be3074 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Apesar de doses relativamente elevadas de opioides produzirem maior intensidade de efeito analgésico, tais doses também estão associadas a efeitos adversos que podem limitar seu emprego em equinos. No presente estudo, hipotetizou-se que uma dose baixa de metadona (0,2 mg/kg), a qual não produz analgesia consistente quando administrada isoladamente em modelos de dor experimental, potencializaria a analgesia induzida pela detomidina, sem resultar em efeitos adversos como excitação/depressão cardiorrespiratória importante ou potencializar a hipomotilidade intestinal induzida pelo agonista α2-adrenérgico. Seis equinos (415 ± 20 kg) receberam dois tratamentos intravenosos com intervalo mínimo de uma semana em um delineamento aleatorizado duplo-cego: 0,01 mg/kg de detomidina administrada isoladamente (tratamento DET) ou em associação a 0,2 mg/kg de metadona (tratamento DET/MET). A analgesia foi avaliada através dos limiares nociceptivos térmico (LNT) e elétrico (LNE). O LNT consistiu no tempo para retirada do membro torácico em resposta à lâmpada de projeção de calor aplicada sobre a banda coronária. O LNE consistiu na voltagem (aplicada via eletrodos sobre a banda coronária) mais elevada capaz de induzir a retirada do membro torácico. A sedação foi avaliada pela distância queixo-solo e pelo interesse por alimento (feno de alfafa). A analgesia, sedação e parâmetros cardiorrespiratórios (eletrocardiografia, pressão arterial e gasometria arterial) foram avaliados antes e durante 120 min após os a administração dos tratamentos. Os escores de auscultação intestinal foram determinados durante 12 horas após a administração dos tratamentos. Tanto o LNE como o LNT se elevaram significativamente em relação aos valores basais durante 15 min após a DET. No tratamento DET/MET, a administração dos fármacos resultou em elevação significativamente... / Although relativelly high doses of opioids result in greater analgesic effect, these doses also cause adverse effects that may limit its clinical usefullness in horses. In the present study it was hipothesized that a dose of methadone that does not induce a consistent analgesic effect when administered alone (0.2 mg/kg) in experimental pain models would potentialize detomidine’s analgesic effect without resulting in adverse side effects such as excitation / important cardiorespiratory depression or potentialization of the intestinal hypomotility induced by the alpha-2 agonist. A total of six horses (415 ± 20 kg) received 2 intravenous treatments in a randomized double-blinded study design: 0.01 mg/kg of detomidine administered alone (DET treatment) or combined with 0.2 mg/kg of methadone (DET/MET treatment). The analgesia was evaluated by assessing the thermal (TNT) and electrical nociceptive thresholds (ENT). The TNT was assessed by measuring time for limb withdrawal (thoracic limb) in response to a heat projection lamp applied to the coronary band. The ENT was recorded as the highest voltage (applied via electrodes placed in the coronary band of the thoracic limb) that induced limb withdrawal. Sedation was assessed by the chin-to-floor distance and by the interest for food (alfalfa hay). The nociceptive testing, sedation and cardiorespiratory data (electrocardiography, direct arterial pressures, and arterial blood gases) were recorded before and during 120 minutes after drug injection. The intestinal auscultation scores were recorded for 12 hours after treatment administration.Both the ENT and the TNT significantly increased from baseline during 15 minutes after DET. In the DET/MET treatment, drug injection resulted in significantly greater and more prolonged (30 minutes increases in ENT and TNT in comparison to the DET treatment. The chin-to-floor distance was significantly... (Complete abstract click electronic access below)

Esta dissertação teve como objetivo determinar parâmetros farmacocinéticos da metadona utilizada por via oral em diferentes formas farmacêuticas. A metadona foi administrada i.v. e v.o. (líquido e comprimido) (0,5 mg/kg) em cães da raça Cocker Spaniel Inglês. Foi também utilizada metadona comprimido (0,5 mg/kg) associada a cetoconazol (10 mg/kg, duas doses). As concentrações séricas resultantes foram determinadas por LC-MS/MS, empregando-se metodologia validada. Os perfis plasmáticos individuais foram avaliados por abordagem não compartimental e compartimental, utilizando os softwares Excel® 2003 e Scientist® 2.01, respectivamente, para a determinação dos parâmetros farmacocinéticos, que foram comparados estatisticamente pelo teste Wilcoxon Rank-Sum e Kruskal-Wallis (α = 0,05). Os perfis plasmáticos da metadona i.v. foram descritos pelo modelo de dois compartimentos e o da metadona oral, pelo modelo de um compartimento. Após a administração da metadona oral, todos os grupos apresentaram concentrações séricas, com exceção do grupo que utilizou o comprimido de metadona isoladamente. O grupo que utilizou solução de metadona apresentou concentrações significativamente superiores ao grupo que recebeu comprimido de metadona isolado, com detecção de níveis do fármaco aos 5 min. O grupo associado ao cetoconazol apresentou o fenômeno de duplo pico plasmático sérico. Estes resultados nos permitem sugerir que a utilização de comprimido de metadona apresenta reduzida absorção, alcançando níveis séricos não quantificáveis pela metodologia empregada. No entanto, quando co-administrada com cetoconazol ou como solução, concentrações séricas foram detectadas, o que nos permite concluir que a utilização de metadona em solução se apresenta como uma boa alternativa para a administração oral deste fármaco em cães. / To determine pharmacokinetic parameters of methadone used in different formulations and routes of administration in dogs. Methadone alone was administered iv, bucal, esophagic and v.o. (liquid and tablet) (0.5 mg/kg) in dogs English Cocker Spaniel. It was also used methadone tablet (0.5 mg/kg) associated with ketoconazole (10 mg/kg, two doses). The resulting serum concentrations were determined by LC-MS/MS, using a validated methodology. The serum concentrations were evaluated by noncompartmental and compartmental model using the software Excel ® Scientist ® 2003 and 2.01, respectively, to determine the pharmacokinetic parameters, which were statistically compared using the Wilcoxon Rank-Sum and Kruskal-Wallis ( α=0.05). The plasma profiles of methadone i.v. are described by the compartmental model and the oral methadone for a noncompartimental model. After administration of methadone, all groups presented serum concentrations but the group that used the pill alone. The group using the methadone solution had significantly higher concentrations when compared with the group that received methadone isolated v.o., and the drug was detected in 5 min. The group associated with ketoconazole showed the phenomenon of double peak plasma. The tablet formulation of methadone reduced the absorption to values not measurable by the method used, however, when co-administered with ketoconazole or as a liquid formulation, serum concentrations were detected. The liquid formulation is presented as a potential alternative to oral administration of methadone in dogs.

We examined internal consistency and test-retest reliability of a measure of dispositional optimism, the Life Orientation Test-Revised, in 121 opiate-dependent patients seeking methadone treatment. Internal consistency was adequate at baseline (α=.69) and follow-up (α=.72). Low socioeconomic status and being on disability were significantly associated with reduced internal consistency; ethnic and educational differences approached significance. Test-retest reliability was good (ICC=.72), varying across gender, race, ethnicity, education, employment and income (ICC Range=.24-.85). Criterion validity was strong; the LOT-R was significantly negatively correlated with hopelessness (r=-.65, p<.001) and depression (r=-.60, p<.001). Findings support the use of this measure of optimism and pessimism to assess positive cognitive and emotional attributes and improve treatment strategies for opiate-dependent individuals. Future research should address the measurement and significance of optimism in minority, low socioeconomic status and poorly-educated individuals.

An alternative analgesic to morphine is methadone, which is used to control chronic pain and is used in opioid rehabilitation treatment programs due to methadone having a long half-life and being relatively inexpensive as compared to extended-release forms of morphine. Despite its benefits, methadone accumulates in adipose tissue due to being lipophilic, binds strongly to plasma proteins, and is metabolized in the liver by the cytochrome P450 system causing methadone levels to be variable and subject to influence according to the individual body compositions and concurrent use of cytochrome P450 inhibitors. In addition to methadone being able to cause both respiratory and central nervous system depression, methadone can also prolong the QT interval and cause potentially life-threatening arrhythmias including torsades de pointes. The susceptibility of unintentional overdosing of methadone due to its varied pharmacologic properties and potentially fatal induction of arrhythmias may cause the risks of methadone use to outweigh its benefits and therefore must be closely monitored.

Abstract Introduction and Background: Methadone, Buprenorphine and other opioid management therapies are being put into effect to help pregnant women who have abused opioids in the months prior to getting pregnant and continued the abuse during pregnancy. Purpose Statement: The purpose of this research was to determine if opioid maintenance therapies would have lasting effects on infants in their growth development. The population in the studies were derived from women who had or were currently abusing opioids during their pregnancy. The interventions taken were to prescribe women with a specific opioid maintenance treatment and measure the outcome on the infant such as birth weight, head circumference, ability to eat, etc. Literature Review: The East Tennessee State University Sherrod Library database was used to search for articles pertaining to the research. The method includes searching for key terms such as opioids on fetal development and ways to improve fetal development with opioid addiction within the years of 2017 to 2022 from peer reviewed journal articles. Findings: The researchers in each study were able to come to a consensus that there were no more effects put into fetal development with the opioid therapy and the subjects that were not given therapy during pregnancy. Conclusion: In the end, some studies showed minor effects that infants would have with getting opioid maintenance therapy in utero but concluded that infants would not experience any more damage to their development by receiving the treatment over infants who did not receive the treatment in utero.

Methadone is a mu-opioid agonist used in the treatment of patients with an opioid use disorder in an outpatient addiction treatment clinic. A recognized knowledge gap exists among nurses managing overweight and obese patients in an outpatient methadone treatment center in the northeastern United States. The goal of this project was to develop a weight management toolkit to assist nurses in the identification, evaluation, and management of overweight and obese patients receiving methadone treatment at the center. The evidence-based weight management toolkit incorporated practice guidelines from the American Heart Association, American Association of Clinical Endocrinologists, America College of Cardiology, and the Obesity Medical Association. The project was evaluated by 8 content experts in primary care and addiction medicine. A 5-point Likert-scale survey was used to measure experts' responses. The survey evaluated the relevance of the weight management educational toolkit in relation to nurses' preparedness to assess, identify, and manage patients on methadone treatment with negative weight gain. Results indicated that toolkit content was beneficial in guiding nurses on the use of evidence-based guidelines to promote weight management treatment for patients on methadone. The toolkit supports social change by providing nurses with the tools necessary to increase their knowledge and skills to manage patients' weight gain on methadone, thus promoting improved patient outcomes.

Background: Social adversities are prevalent among those with psychiatric disorders and may be involved in poor outcomes among patients receiving treatment. Identification of social risk factors influencing outcomes will help provide targeted interventions for at-risk patients. This thesis explored the role of social and behavioural factors in relation to adverse psychiatric outcomes, specifically relapse to substance use and attempted suicide. Methods: We used scoping study methodology to perform a comprehensive review to identify the gaps in the literature examining social functioning and MMT outcomes. This review informed our primary cohort study examining the association between social factors and continued opioid use in MMT. Lastly, we conducted a case-control study to identify risk factors for suicide attempts by comparing psychiatric patients with and without suicide attempt history (cases and controls, respectively). Multivariable logistic regression analyses were conducted in both primary studies to examine the association between predictors and outcomes. Results: The review included 101 observational studies and determined the need for further research on social factors and MMT outcomes among a current sample of Canadian patients. Our cohort study included 1043 participants (mean age=38.4 years, standard deviation [SD]=11.06); 45.8% women) to investigate this and found that unemployment, criminal activity and interpersonal conflict with friends significantly increased odds of illicit opioid use. In examining risk factors for suicide attempts, we recruited 146 cases (mean age=45.18 years, SD=14.70 years; 55% female) and 104 control participants (mean age=45.01 years, SD=14.23 years; 50% female). No sociodemographic differences existed between groups, however higher impulsivity and borderline personality symptoms significantly increased odds of attempted suicide. Conclusions: Findings from these studies may indicate the need for structured monitoring of at-risk psychiatric patients. It may be important to develop tools to measure social and behavioural factors in clinical settings and promote further integration of social services in treatment settings. / Thesis / Master of Science (MSc)

Background: The consequences of continued opioid abuse among patients treated with opioid substitution therapy (OST) are serious and can result in abnormal cardiovascular function, overdose, and mortality. Conflicting evidence exists that both implicates and refutes the role of chronic non-cancer pain (CNCP) as a major risk factor for continued opioid abuse within the addiction treatment setting. This thesis aims to 1) evaluate the impact of chronic pain on the treatment outcomes of patients with opioid addiction receiving OST, 2) determine whether a clinical or inflammatory profile exists to distinguish pain in this population, 3) explore the sources of heterogeneity in previous studies examining this question, 4) determine the best therapy for patients with chronic pain, and 5) evaluate the most effective treatment for opioid addiction. We anticipate chronic pain to be an important predictor of continued opioid abuse such that patients with comorbid pain will require careful consideration when managed on OST. Methods: We systematically reviewed the literature to determine the impact of pain in opioid addiction patients receiving methadone maintenance treatment (MMT). We determined the clinical and inflammatory profile of MMT patients using data from the Genetics of Opioid Addiction (GENOA) research collaborative between the Canadian Addiction Treatment Centres (CATC) and the Population Genomic Program. GENOA is a prospective cohort study aimed to determine the genetic, biological, and psychosocial determinants of treatment prognosis for opioid addiction patients receiving MMT. GENOA recruits patients ≥ 18 years of age meeting the DSM-IV criteria for opioid dependence. All GENOA participants are receiving MMT for the management of opioid addiction. Baseline data from the GENOA pilot study (n=235) were used to evaluate the impact of pain on illict opioid use behaviour and determine the clinical and inflammatory profile of patients with comorbid pain. We explored sources of heterogeneity in previous studies using data from the full-phase GENOA study (n=444), examining the prognostic value of different pain measures for predicting illicit opioid use. We then performed a multiple treatment comparison of all opioid substitution and antagonist therapies in efforts to determine the best intervention for improving treatment outcomes for patients with comorbid pain. We lastly determined the most effective treatment for opioid addiction by performing a network meta-analysis using data from a systematic review of opioid maintenance therapy trials. Results: Our initial systematic review confirmed a lack of consensus in the literature, whereby some studies suggest pain increases risk for illicit opioid use and other studies suggest pain has no effect on substance use behaviour. Findings from the analysis of GENOA pilot data confirmed chronic pain to be an important predictor of sustained opioid abuse and also showed patients with pain to have elevated Interferon-Gamma. Using data from the GENOA prospective cohort study we determined the Brief Pain Inventory (a commonly used pain measurement in pervious studies) to be highly sensitive with poor prognostic value. Our final reviews propose 1) there is limited evidence to suggest any OST is superior for managing patients with comorbid pain, and 2) heroin and high-dose methadone are the most effective treatments for improving treatment retention. The final systematic review and network meta-analysis in this thesis also highlights a major problem in the treatment of opioid use disorders, primarily the lack of consensus as to what outcomes matter for determining success in patients with addiction. Conclusion: Patients with comorbid pain and addiction are at high-risk for continued opioid abuse and should be managed closely by clinicians administering OST. Contention in the previous literature likely resulted from the use of pain measurements with poor prognostic value. No OST demonstrated superiority for managing patients with chronic pain. While our findings indicate heroin is the most effective treatment across multiple endpoints, we use this thesis to provide readers with 1) a sense of the feasibility issues associated with heroin administration, 2) a summary of the limitations of this evidence base, and 3) recommendations for how to improve the addiction trials’ design for future research. / Thesis / Doctor of Philosophy (PhD)