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Orientador: Paulo Sergio Patto dos Santos / Resumo: Objetivou-se com este trabalho avaliar os efeitos na hemodinâmica, respiração, motilidade ruminal e sedação, da associação de detomidina e nalbufina em ovinos. Foram utilizados 8 ovinos hígidos, jovens, fêmeas ou machos, pesando 54,85 ± 20,31kg. Foi instalado na veia jugular esquerda um introdutor e, posteriormente, posicionado um cateter de Swan-Ganz com a extremidade distal alocada no lumen da artéria pulmonar. Foi administrado pela via intramuscular detomidina (10μg/kg) associado a nalbufina (0,1mg/kg). Foram avaliadas FC, PAS, PAD, PAM, PVC, PAPm, IC, IS, IRVS, FR, pH, PaO2, PaCO2, HCO3, TC, sedação e motilidade ruminal antes do início da administração dos fármacos (MB) e a cada quinze minutos após a aplicação durante sessenta minutos (M15, M30, M45 e M60). Houve redução do IC, FR e aumento da PAS, PAPm, temperatura central, PaCO2 e HCO3 após administração dos fármacos. A sedação foi considerada satisfatória durante 45 minutos. Com os resultados obtidos neste estudo, conclui-se que a neuroleptoanalgesia promovida pela associação de detomidina e nalbufina em ovinos, nas doses utilizadas, promove sedação satisfatória. As alterações hemodinâmicas, respiratórias e na motilidade ruminal observadas podem ser bem toleradas por animais sadios. / Abstract: The aim of this study was to evaluate the effects on hemodynamics, respiration, ruminal motility and sedation of the combination of detomidine and nalbuphine in sheep. Were used eight healthy young, female or male sheep, weighing 54.85 ± 20.31kg. A Percutaneous Sheath Introducer was placed in the left jugular vein and then a Swan-Ganz catheter was positioned with the distal port allocated to the lumen of the pulmonary artery. Association of detomidine (10µg/kg) and nalbuphine (0,1mg/kg) was administered intramuscular. HR, SAP, DAP, MAP, CVP, MPAP, CI, SI, SVRI, RR, pH, PaO2, PaCO2, HCO3, CT, sedation and ruminal motility before drug administration (MB) and at each fifteen minutes after application for sixty minutes (M15, M30, M45 and M60). There was a reduction in CI, RR and increase in SAP, mPAP, CT, PaCO2 and HCO3 after drug administration. Sedation was considered satisfactory for 45 minutes. The results of this study allowed us to conclude that neuroleptoanalgesia promoted by the association of detomidine and nalbuphine in sheep at the doses used, promotes satisfactory sedation for short procedures. The hemodynamic, respiratory and ruminal motility changes observed can be well tolerated by healthy animals. / Mestre

This thesis critically investigates how female and male opioid users are represented in local newspapers in Ohio, one of the states which has been most severely affected by the ongoing ‘opioid crisis’ in the United States. Through an analysis of 20 articles from the The Plain Dealer and The Columbus Dispatch, the study aims to highlight how women and men who use opioids are portrayed, and what ideologies are hidden in the texts. Guided by Fairclough’s framework for critical discourse analysis and van Dijk’s sociocognitive approach, the analysis was performed on three levels: text-level, whereby journalists’ word choices, contextualisation and linguistic emphasis were studied; discursive level, which focused on processes involved in the production and consumption of the news pieces, and; sociocultural level, which entailed analysing historical and current developments of drug policy locally and nationally. The study finds that journalists downplay the seriousness of (white) male opioid use by calling men by their nicknames, by portraying them as ‘mischievous’ and by using jokey undertones when referring to their drug use. Female opioid use is constructed as abnormal by use of words such as ‘erratic’ and ‘unruly’ and women are discursively penalised for failing in their roles as caregivers to children. This thesis exemplifies how language use by local journalists’ in Ohio reinforces societal perceptions of male and female opioid users, which may influence counteractive measures by authorities.

Orientador: Paulo Sergio Patto dos Santos / Resumo: A nalbufina é um opioide agonista-antagonista com propriedades analgésicas adequadas e poucos efeitos depressores no sistema respiratório. Sua utilização na medicina veterinária é limitada pois muitos veterinários desconhecem suas vantagens. Além disso, seus efeitos na função cardíaca são pouco estudados. Portanto, com o estudo objetivou-se avaliar os efeitos da infusão contínua de nalbufina na função sistólica e diastólica do ventrículo esquerdo em cães saudáveis anestesiados com sevofluorano. Foram utilizados dezoito cães fêmeas de diversas raças ou sem raça definida, com idade média de 2 ± 1 anos e peso médio de 9,9 ± 3,8 kg. Os cães foram aleatoriamente submetidos a dois grupos denominados: nalbufina (GN) e controle (GC), com nove animais para cada grupo. Os animais foram induzidos e mantidos sob anestesia com sevofluorano (2V%). No GN foi administrado bolus intravenoso de nalbufina (0,3 mg/kg), seguido de infusão continua (0,4 mg/kg/h). O GC recebeu solução salina (NaCl 0,9%), em volumes idênticos em bolus e infusão ao GN. As variáveis ecocardiográficas de função sistólica e diastólica e os parâmetros hemodinâmicas foram determinadas no momento basal (antes do bolus) e 20, 40, 60 e 80 minutos após o início da infusão contínua. Não houve diferença entre os grupos para os parâmetros de função sistólica e diastólica ventricular esquerda derivados da ecocardiografia convencional e speckle tracking bidimensional. Do mesmo modo, as variáveis hemodinâmicas não apresentaram dife... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Nalbuphine is an agonist-antagonist opioid with adequate analgesic properties and few depressant effects on the respiratory system. Its use in veterinary medicine is limited due to the unknown of its effects on cardiac function. The aim of this study was to assess the effects of a continuous rate infusion (CRI) of nalbuphine on left ventricular systolic and diastolic function of healthy sevoflurane-anesthetized dogs. Were used eighteen mixed-breed bitches ageging 2 ± 1 years and weighing 9.9 ± 3.8 kg. Dogs were randomly assigned to one of two groups: nalbuphine (GN, n=9); and control (GC, n=9). Anesthesia was induced and maintained with sevoflurane (2V%) followed by an intravenous (IV) bolus of nalbuphine (0.3 mg/kg) or 0.9% NaCl at equal volume, then CRI of nalbuphine (0.4 mg/kg/h) or 0.9% NaCl at equal infusion rate. Echocardiographic and hemodynamic variables were determined at baseline and 20, 40, 60 and 80 minutes following start of CRI. No differences were found between groups for left ventricular systolic and diastolic variables obtained through conventional echocardiography and two-dimensional speckle tracking. Likewise, hemodynamic variables did not differ between groups. The E′/A′ ratio significantly increased at 20 minutes compared to baseline only in GN. Nalbuphine given at a CRI does not influence left ventricular systolic and diastolic function in healthy sevoflurane-anesthetized dogs. / Doutor

The prevalence of opioid use has increased in many populations including pregnant women, which has led to a substantial rise in infants born dependent on opioids due to in utero exposure. Many women use multiple substances aside from opioids during pregnancy, and their infants therefore present with a variety of symptoms. With increasing legalization and changing perception of marijuana, it has become one of the most commonly used substances during pregnancy. Few studies have evaluated concomitant use of marijuana and opioids in pregnancy despite both being implicated in adverse newborn outcomes. The primary aim of this study was to determine the association between marijuana use and pregnancy outcomes in opioid-exposed pregnancies. The secondary aim was to identify, in a sample of women already using opioids, maternal characteristics associated with marijuana use during pregnancy. A retrospective chart review was conducted from July 2011 to June 2016 of all births from 6 delivery hospitals in South-Central Appalachia to determine pregnancy and neonatal outcomes of pregnancies exposed to any form of opioid and positive urine drug screen for marijuana at the time of delivery. 2375 pregnancies met the inclusion criteria with 108 pregnancies positive for marijuana. Student t-test and Chi-Square test were used for group comparison for presence and absence of marijuana. Logistic regression was done for significant confounding variables to find aOR for marijuana exposure for neonatal abstinence syndrome diagnosis, premature birth, and low birth weight. Among opioid using women, marijuana positive women were more likely to be unmarried, nulliparous, and use tobacco and benzodiazepines. Infants born to the marijuana users were likely to be of earlier gestational age (3 days), lower birth weight, and preterm; with preterm birth and low birth weight (mean difference = 265 gms) increased two fold even after controlling for parity, marital status, tobacco and benzodiazepine use with aOR of 2.35 (1.30-4.23) and 2.02 (1.18-3.47) respectively. Ultimately, prenatal use of marijuana in opioid-exposed pregnancies carries significant risk of prematurity and low birth weight. For pregnant women continuing their American College of Obstetricians and Gynecologists recommended medical assisted treatment for opioid use disorder, providers should counsel women to abstain from marijuana during pregnancy.

During the course of human evolution, being a member of a group has been more beneficial for survival than being alone. Food gathering, protection from predators, cooperation, and care for offspring are distributed among group members, increasing the likelihood for survival. It is as if there is an interplay between agent and environment that interprets being socially cooperative as pleasurable and being left out as painful. Studies have been dedicated to examine how our social life is one of the most important aspects of health and well-being, particularly social relationships. Since this link has been demonstrated, it would be interesting to incorporate the field of neuroscience to understand the involvement of the human brain in our social experiences, specifically the experience of social connection. The current state of neuroscience does not allow researchers to examine this kind of subjective experiences, simply because of the lack of proper tools and knowledge. Research in this field has come a long way since the early stages, and studies have indicated on significant results regarding the involved neural regions. The dorsal anterior cingulate cortex (dACC) and the anterior insula (AI) are active when threats to social connection is experienced. They are also active in situations were survival is threatened. An experience of social connection evokes a feeling of (social) safety, in part because it activates regions of the brain associated with physical safety, such as the ventromedial prefrontal cortex (VMPFC). In similar fashion, a sense of social closeness ("warmth") activates the ventral striatum (VS), which is associated with physical warmth and studies have shown that social and physical warmth share overlapping neural activity in VS. Finally, Mu-opioids have been shown to be responsible for social bonding; while using an opioid antagonist such as naltrexone, decreases the feeling of social connection. Studies in this field are few; one should take their results with caution. The field continues to grow, and the studies that have been done to date give exciting hints of the influence of social relationships on physical health and mental well-being.

La bronchopneumopathie chronique obstructive (BPCO) est une des maladies chroniques les plus fréquentes et constitue une des premières causes de mortalité dans le monde avec un impact sociétal majeur et des couts de santé considérables. La BPCO est aujourd’hui considérée comme une maladie multi-systémique dont le pronostic est lié en grande partie à ses comorbidités et à la survenue d’exacerbations. Les exacerbations qui vont ponctuer l’évolution de la BPCO précipitent le déclin de la fonction respiratoire et favorisent la décompensation des comorbidités et la survenue d’événements cardiovasculaires comme des infarctus du myocarde ou des accidents vasculaires cérébraux. La prise en charge moderne de la BPCO est basée sur la mise en place d’un soin intégré incluant la prise en charge des comorbidités et une meilleure détection et gestion des exacerbations.Dans ce travail de thèse nous abordons l’atteinte hépatique (stéatopathie hépatique non alcoolique - NAFLD) dans la BPCO comme une comorbidité sous-estimée (publication 1) alors qu’elle a probablement des implications pronostiques importantes (publication 2). La BPCO s'accompagne également de symptômes non respiratoires tel que des douleurs, dont les variations et localisations sont peu connues pendant et après l'exacerbation (publication 3). Le traitement de ces douleurs par des opiacés pourrait avoir un effet spécifiquement délétère dans cette population (publication 5). Les enjeux de réforme du système de santé avec une optimisation cout-efficacité incitent à développer et valider de nouvelles méthodes de prise en charge ambulatoire des exacerbations (publication 6).Dans une première partie de la thèse nous explorons les liens épidémiologiques entre BPCO et NAFLD. Nous explorerons également les conséquences d’une telle association sur le devenir cardiovasculaire des patients à moyen terme. Dans une deuxième partie, nous cherchons à définir les caractéristiques des douleurs avant et après exacerbation au cours de la BPCO, le lien entre douleur, anxiété et dépression chez ces patients et la sécurité d'emploi des morphiniques dans cette population fragile. Dans une dernière partie, nous aborderons la stratification du risque lié à une exacerbation de BPCO, et la possibilité d’une prise en charge ambulatoire extrahospitalière pour les exacerbations de sévérité modérée. / Chronic Obstructive Pulmonary Disease (COPD) is one of the most common chronic diseases and is one of the leading causes of death in the world with major societal impact and considerable health costs. COPD is now considered a multi-systemic disease whose prognosis is largely related to its comorbidities and the occurrence of exacerbations. The exacerbations that punctuate the evolution of COPD precipitate the decline of respiratory function and promote the decompensation of comorbidities and the occurrence of cardiovascular events such as myocardial infarction or cerebrovascular accidents. The modern management of COPD is based on the implementation of integrated care including the management of comorbidities and better detection and management of exacerbations.In this thesis we address liver injury (non-alcoholic fatty liver disease - NAFLD) in COPD as an underestimated comorbidity (publication 1), although it probably has important prognostic implications (publication 2). COPD is also associated with non-respiratory symptoms such as pain, the variations and locations of which are poorly known during and after exacerbation (publication 3). Treatment of this pain with opiates may have a specifically deleterious effect in this population (publication 5). The challenges of health system reform with cost-effectiveness optimization encourage the development and validation of new methods of outpatient management of exacerbations (publication 6).In a first part of the thesis we explore the epidemiological links between COPD and NAFLD. We will also explore the consequences of such an association on the cardiovascular outcome of patients in the medium term. In a second part, we seek to define the characteristics of pain before and after exacerbation during COPD, the link between pain, anxiety and depression in these patients and the safety of opioids in this fragile population. In the last part, we will discuss the stratification of the risk linked to an exacerbation of COPD, and the possibility of outpatient care for exacerbations of moderate severity.

Mu-opioid receptor (MOR) agonists are effective agents for pain management, but are also limited by a number of undesirable effects. One approach to enhance the therapeutic effects and minimize the undesirable effects of MOR agonists may be to combine MOR agonists with an adjunct targeting a different receptor system. This targeted medical approach, known as “combination therapy”, aims to augment the desired effects of the MOR agonist (i.e. antinociception) and/or diminish the undesirable deleterious side effects of the MOR agonist. This dissertation investigated the utility of this approach in an assay of thermal nociception and schedule-controlled responding in male rhesus monkeys with three aims. One aim determined the utility of N-methyl D-aspartate (NMDA) receptor antagonists to selectively enhance MOR agonist antinociception. A second identified the pharmacological determinants of antinociceptive interactions between a nociceptin opioid peptide (NOP) receptor agonist and MOR agonists. A third aim investigated the potential for fixed-proportion mixtures of a competitive MOR antagonist and MOR agonist to manipulate antinociceptive efficacy. Experimental results did not support the utility of NMDA antagonists as adjuncts to selectively enhance MOR agonist antinociception. Furthermore, the antinociceptive interactions between a NOP agonist and MOR agonists were modest and occurred under a narrow range of conditions. Finally, fixed proportion MOR antagonist-agonist mixtures were effective in manipulating antinociceptive in vivo efficacy. In conclusion, this dissertation does not provide strong empirical evidence that a combination therapy approach will result in clinically effective and selective enhancement of MOR agonist analgesia. The dissertation concludes with proposed strategies and novel preclinical methods to enhance preclinical-to-clinical translation of effective candidate analgesics.

The mortality in drug related deaths has increased in many countries, calling it an epidemic. Overdose caused by opioids have contributed to the increasing drug related deaths. This study aims to examine and compile which methods and strategies have shown to reduce the mortality in drug related deaths. Using a systematic review and no limitation to countries a mix of methods and strategies was found. Some Ministries of Health department list them as important in reducing damages and risk behavior related to addiction. The repressive approach that was historically dominated has shown less successful. Individuals own strengths and access to treatments and strategies are momentous. It is also of great importance that governments and health care applies the listed methods and strategies. Blood diseases have decreased with needle exchange programs as a result of having implemented the method. Medications for addiction treatment are improving living conditions for people with opioid addiction. Still there are problems and difficulties with access to addiction treatment and harm reduction strategies. Stigma and the historical perception of drug use and addiction are some of the reasons for the inaccessibility and lack of harm reduction strategies.

The United States (U.S.) government has been attempting to combat the growing opioid epidemic ravaging the nation. The opioid epidemic has had a significant impact on public health and forensic science laboratories. Moreover, this epidemic has moderate to fatal health consequences for expectant mothers with substance use disorder and their child who may develop Neonatal Abstinence Syndrome (NAS), otherwise known as Neonatal Opioid Withdrawal Syndrome (NOWS). The objective of this thesis is to emphasize that further research is needed for the identification and quantification of opioids in human breast milk. This topic has public health implications such as discussing the information gaps as it relates to a highly vulnerable group, women, and infants, affected by the opioid epidemic. Furthermore, there are implications in forensic science connected to postmortem toxicology and pathology when determining the cause of death and contributing factors in pediatric cases. This emphasis on the need for greater research will be accomplished by highlighting the opioid epidemic, its impact and further understanding of the addictive drug class known as opioids. The history of the crisis, effects on society as well as pharmaceutical knowledge of opioids will assist in development of plans to suppress growth and provide care for the afflicted. Furthermore, this thesis will attempt to demonstrate the need for further research involving opioids will be of significant value for public health and forensic science. As the forensic laboratories and various medical facilities are at the forefront of the opioid epidemic, there is a need for more robust, validated, inexpensive, and fast drug detection methodologies. Increasing rates of new designer drugs, addiction, and opioid-related deaths has caused a backlog in the forensic laboratories due to the great number of cases. While, the higher instances of maternal substance use disorder (SUD)/ opioid use disorder (OUD) with parallel increases in cases of NAS incidences are a few of the issues that need to be managed by public health leaders. Additionally, this thesis will examine current methodologies for drug quantification of opioids in human breast milk. The valid methodologies developed as well as the findings by the few available studies allowed for the current recommendations related to the acceptability of mothers in MAT programs, using methadone and buprenorphine during pregnancy and postpartum, being able to breastfeed their infant. By examining these studies and the findings, standardization criteria for the development of study designs for new methodologies relating to drug determination in human breast milk could be developed. The establishment of standardization criteria and acknowledging information gaps in current knowledge will be significant as these findings could influence policies, guidelines and procedures relating to maternal SUD/OUD, NAS/NOWS, and pediatric death determination as well as postmortem toxicology.