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Agradecemos a compreensão. on 2017-05-08T16:42:03Z (GMT) / Submitted by MARIA EULÁLIA BALEOTTI null (mabaleotti@yahoo.com.br) on 2017-05-09T02:13:09Z No. of bitstreams: 1 Maria Eulalia Baleotti - Unesp - Dissertação versão final _M1_ _T1_.pdf: 1404968 bytes, checksum: ed93838350a715d82b43c32074f22275 (MD5) / Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-05-10T17:49:28Z (GMT) No. of bitstreams: 1 baleotti_ma_me_assis.pdf: 1404968 bytes, checksum: ed93838350a715d82b43c32074f22275 (MD5) / Made available in DSpace on 2017-05-10T17:49:28Z (GMT). No. of bitstreams: 1 baleotti_ma_me_assis.pdf: 1404968 bytes, checksum: ed93838350a715d82b43c32074f22275 (MD5) Previous issue date: 2017-03-07 / Fármacos antidepressivos como os inibidores seletivos de recaptação de serotonina (ISRSs; exemplos: fluoxetina e escitalopram) são drogas de primeira escolha no tratamento dos Transtornos de Ansiedade Generalizada (TAG) e do Transtorno do Pânico (TP). No entanto, apesar de eficazes na terapêutica, esses fármacos apresentam limitações no seu uso, tais como: os efeitos desejados ocorrem somente após administração crônica, em torno de 3 a 4 semanas após o início do tratamento; a proporção relativamente alta de pacientes que não respondem à medicação e o frequente aumento nos níveis de ansiedade desse pacientes no início do tratamento, levando à descontinuidade do uso destas drogas. Nesse sentido, há grande interesse na busca de novas estratégias de tratamento, identificando outros sistemas de neurotransmissão que possam estar relacionados à etiologia e, consequentemente, ao tratamento desses transtornos de ansiedade. Estudos prévios apontaram o envolvimento de opioides endógenos na modulação da ansiedade. Mais especificamente em relação ao TP, já se constatou que mecanismos opioides favorecem a atividade inibitória da serotonina em neurônios da Substância Cinzenta Periaquedutal Dorsal (SCPD) que modulam a fuga/pânico, possivelmente por meio da formação de heterodímeros entre receptores 5-HT1A e μ-opioide. Com base em tais aspectos, o presente estudo teve por objetivo investigar o efeito da Buprenorfina, um agonista parcial de receptores µ-opioide e antagonista de receptores κ-opioide, sobre a manifestação de comportamentos defensivos relacionados com o TAG e com o TP. O uso de agonistas parciais justifica-se pela possibilidade de atenuar efeitos adversos sobrevindos do uso contínuo de agonistas plenos para os receptores µ-opioide, tais como a euforia, a tolerância e a dependência. Para isto, foram conduzidos dois experimentos utilizando ratos Wistar, seguindo-se em cada um deles dois tipos de avaliação: Teste de analgesia, como parâmetro da eficácia do fármaco e testes comportamentais Labirinto em T Elevado (LTE), Campo Aberto e Transição Claro-Escuro. No primeiro experimento foi implantado cirurgicamente um adesivo de Buprenorfina (5mg) entre a pele e o tecido subcutâneo, cujas avaliações foram conduzidas 27 horas após o implante. No segundo experimento utilizou-se um extrato liofilizado da Buprenorfina a partir dos adesivos, em 3 doses diferentes: 1,5 mg/kg; 3,0 mg/kg; 6,0 mg/kg. Todas as avaliações ocorreram 10 minutos após as injeções intraperitoneais. Os resultados mostraram que a Buprenorfina nas doses e vias estudadas desinibiu o comportamento de esquivas inibitórias no LTE e o comportamento motor dos ratos no Teste do Campo Aberto, mas não afetou as fugas no LTE e nem outras manifestações comportamentais no Teste de Transição Claro-Escuro, exceto no implante do adesivo, quando se observou ansiólise nesse teste. Na administração por via IP, esses resultados ocorreram em todos os testes, mas somente na reexposição, 24 horas após a primeira avaliação comportamental. Em conclusão, a Buprenorfina nas doses e vias estudadas apresentou efeito analgésico e desinibiu o comportamento de esquivas e o comportamento motor dos ratos, mas não afetou as fugas, o que indica seu envolvimento na modulação de comportamentos defensivos apenas relacionados com a manifestação da ansiedade generalizada. Nesta dissertação, para maior aprofundamento do tema, foi inicialmente apresentada uma fundamentação teórica geral sobre as variáveis sob foco de investigação. Na sequência, foi exposto um artigo contendo uma fundamentação teórica mais específica, a descrição metodológica, bem como a análise e discussão dos resultados dos experimentos realizados. / Antidepressant drugs such as the selective serotonin reuptake inhibitors (SSRI; examples: fluoxetine and escitalopram) are first choice drugs for treating Generalized Anxiety Disorders (GAD) and Panic Disorder (PD). However, in spite of being therapeutically effective, such drugs present use limitations, such as: the desired effects occur only after chronic administration, within 3 to 4 weeks after the beginning of treatment; a relatively high proportion of patients who do not respond to the drug and the frequent increase of anxiety levels of such patients at the beginning of the treatment, leading to discontinuity in the use of such drugs. Along these lines, there is a great interest in the search of new treatment strategies, identifying other neurotransmission systems which may be related to the etiology and, consequently, to the treatment of such anxiety disorders. Previous studies pointed to the involvement of endogenous opioids in anxiety modulation. More specifically in relation to PD, one has found out that opioid mechanisms favor the inhibitory activity of serotonin in periaqueductal grey matter (dPAG) neurons which modulate escape/panic, probably by means of the formation of heterodimers between 5-HT1A and μ-opioide receptors. Based on such features, this study was carried out aiming at investigating buprenorfine effects, a partial μ-opioide receptor agonist and κ- opioidereceptor antagonist, on the manifestation of defensive behaviors related to GAD and PD. The use of partial agonists is justified by the possibility of attenuating adverse effects occurred after the continuous use of full agonists for μ- opioidereceptors, such as euphoria, tolerance and dependence. Therefore, two experiments werecarread out using Wistar rat, each one followed by two assessment types: analgesia test, as efficiency parameter of the drug and behavioral tests the elevated T-maze (ETM), Open Field and Light-Dark Transition. In the first experiment was surgically implanted a buprenorfine patch (5 mg) between the skin and the subcutaneous tissue, whose assessments were carried out 27 hours after the implantation. In the second experiment was used a buprenorfine extract based on the patches, with three different doses: 1.5 mg/kg; 3.0 mg/kg; 6.0 mg/kg. All the assessments were carried out 10 minutes after the intra-peritoneal injections. The results showed that buprenorfine administered in the studied doses and means uninhibited the inhibiting escape behavior in LTE and the motor behavior of rat in the Open Field Test, but did not affect escapes in LTE nor in other behavioral manifestations in the Light-Dark Transition Test, with the exception of the patch implant, when we were observed anxiolysis in this test. In the IP administration, such results occurredin all the tests, but only in the re-exposure, 24 hours after the first behavioral assessment. In conclusion, buprenorfine administered in doses and methods produced analgesic effect and impaired of the avoidance, but did not affected the escapes, which shows the involvement of this drug in the modulation of defensive behaviors only related whit manifestation of generalized anxiety. In this dissertation, presented a general theoretical foundation on the variables focused on the investigation and afterwards, a paper with a more specific theoretical foundation, the methodological description, as well as the analysis and discussion of the results yielded in the conducted experiments.

Abstract The study mapped various aspects of buprenorfine (Subutex \regm{}, herein S) abuse among opiate-dependent community. It analyses three sources of data, questionnaires distributed in general problem drug-users community ({\clq}non-substitution sample{\crq}, n = 64), questionnaires distributed among patients of buprenorphine substitution treatment ({\clq}substitution sample{\crq}, n = 42), and semi-structured moderated interviews conducted with S users attending low-threshold contact centre in Ceske Budejovice (n = 15). Prevalence of non-commissioned S abuse was 57% of the non-substitution sample and 21% of the sample claimed S as their primary drug. Illicit market prices range from prescription price to its multiple of eight, are higher in small towns and during weekends, and lower in case of close relationships between the seller and buyer. There are no regular big dealers in the community, and the contracts are rather based on close acquaintance among baseline users. The user view S price and availability as worse/higher than in case of marihuana, comparable with hallucinogens and ecstasy, and better/cheaper than metamphetamine and heroin. The main driver for buying was occasional abuse over the prescription dose, the main incentive to sell was to help a friend. Illicit S users view substitution treatment as a chance how to reduce their drugrelated expenses and stabilise their life, but some are repelled by strict treatment rules. Both licit and illicit users displayed comparably high (over 90%) prevalence of injection use; they typically understand the risks, but explain the injection use by their psychological attachment to the injection ritual. An indisputably positive aspect of substitution treatment is lower total number of drugs abused by individual patients, compared to general drug-abusing population. Illicit S market bears only marginal societal risks and its existence is rather positive with respect to harm reduction philosophy, as it supplies the community of illicit drug users with cheaper and safer alternative to street opiates.

La disponibilité des médicaments analgésiques est limitée en médecine vétérinaire féline. Le but de cette étude était d'investiguer les propriétés anti-nociceptiques d'une nouvelle formule de buprénorphine (Simbadol, 1.8 mg ml-1) et tapentadol chez les chats. Six chats étaient inclus dans deux études différentes, les deux étant prospectives, randomisées, croisées, et aveuglées. Dans la première étude, Simbadol (1.8 mg mL-1) a été administré par voies sous-cutanée (SC;0.24 mg kg-1), intraveineuse (IV; 0.12 mg kg-1) et buccale (OTM; 0.12 mg kg-1) et les seuils thermiques ont été comparés avec ceux d'un groupe contrôle contenant de la saline (SAL; saline SC). Les concentrations plasmatiques de buprénorphine et norbuprénorphine ont été mesurées jusqu'à 72 heures suivant chaque traitement de buprénorphine. Un modèle pharmacocinétique-pharmacodynamique adapté à 2 substances et 3 voies d'administration a été utilisé. Dans la deuxième étude, les seuils thermiques ont été comparés entre les chats recevant de la buprénorphine (0.02 mg kg−1, IM), un placébo (50 mg de dextrose oral) et deux doses de tapentadol oralement (dose réduite: 25 mg; dose élevée: 50 mg) L'administration sous-cutanée de Simbadol a provoqué une anti-nociception thermique de longue durée (≥ 24 heures). Ces effets étaient prolongés comparativement aux traitements intraveineux (8 heures) et buccal (12 heures). Le modèle conjoint de pharmacocinétique/pharmacodynamique a démontré des concentrations plasmatiques prolongée pour la voie sous-cutanée. Les deux doses de tapentadol ont augmenté l'antinociception thermique chez les chats. La dose élevée de tapentadol a produit une durée d'antinociception similaire à celle de la buprénorphine (2 heures) et deux fois plus longue que la dose réduite. La palatabilité de la médication représente une limite significative de la voie d'administration. Simbadol et tapentadol produisent une antinociception thermique comparée à la saline. Des investigations cliniques supplémentaires seront nécessaires. / Analgesic drug availability is limited in feline practice. The aim of these studies was to investigate the antinociceptive properties of a novel formulation of buprenorphine (Simbadol, 1.8 mg ml-1) and tapentadol in cats. In two separate studies, six healthy cats (each) were included in a prospective, randomised, blinded, crossover study. In study I, Simbadol (1.8 mg mL-1) was administered by various routes: subcutaneous (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) route of administration and thermal thresholds (TT) were compared with a saline group (SAL; saline SC). Plasma buprenorphine and norbuprenorphine concentrations were measured up to 72 hours following each buprenorphine treatment. A bespoke pharmacokinetic-pharmacodynamic model fitted data from two analytes/three routes of administration. In study II, thermal thresholds were compared among cats receiving buprenorphine (0.02 mg kg−1, IM), placebo (50 mg oral dextrose) and two doses of oral tapentadol (low-dose 25 mg; high-dose 50 mg). Subcutaneous administration of Simbadol provided long-lasting thermal antinociception (≥ 24 hours). These effects are prolonged compared with the IV (8 hours) and OTM (12 hours) treatments. Joint pharmacokinetic-pharmacodynamic modelling demonstrated prolonged plasma concentrations for the SC route. Both doses of tapentadol increased thermal antinociception in cats. The high-dose of tapentadol produced similar duration of antinociception as intramuscular buprenorphine (2 hours) and twice as long as the low-dose. Palatability presented a significant limitation to the drug’s administration. Simbadol and tapentadol produced thermal antinociception when compared with saline. Additional investigation is necessary to determine if this translates to the clinical setting.

Background: In many countries, the opioid agonists, buprenorphine and methadone, are licensed for maintenance treatment of opioid dependence. Many short-term studies have been performed, but little is known about long-term effects. Therefore, this study described over 6 years (1) mortality, retention and abstinence rates and (2) changes in concomitant drug use and somatic and mental health. Methods: A prevalence sample of n = 2,694 maintenance patients, recruited from a nationally representative sample of n = 223 substitution doctors, was evaluated in a 6-year prospectivelongitudinal naturalistic study. At 72 months, n = 1,624 patients were assessed for outcome; 1,147 had full outcome data, 346 primary outcome data and 131 had died; 660 individuals were lost to follow-up. Results: The 6-year retention rate was 76.6%; the average mortality rate was 1.1%. During follow-up, 9.4% of patients became “abstinent” and 1.9% were referred for drug-free addiction treatment. Concomitant drug use decreased and somatic health status and social parameters improved. Conclusions: The study provides further evidence for the efficacy and safety of maintenance treatment with opioid agonists. In the long term, the number of opioid-free patients is low and most patients are more or less continuously under opioid maintenance therapy. Further implications are discussed.

Les opioïdes peuvent être responsables, en cas d’intoxication, d’une dépression respiratoire mortelle. Deux opioïdes ont un profil de toxicité particulier. La buprénorphine, seule, a des effets respiratoires plafonnés alors qu’administrée avec des benzodiazépines elle peut être à l’origine d’une dépression respiratoire mortelle. Le tramadol, dans un contexte d’intoxication aigue, entraine dans 20% des cas des convulsions. Les mécanismes de ces toxicités sont inconnus.L’objectif de cette thèse était d’étudier de façon multimodale les mécanismes impliqués dans ces deux types de toxicité en incluant des données pharmacodynamiques et neuropharmacocinétiques in vivo. Pour la buprénorphine, nous avons montré que la dépression respiratoire observée avec le diazépam ne résultait pas d’une interaction neuropharmacocinétique/réceptologique centrale (imagerie TEP 11C- buprénorphine). En revanche, les données physiologiques respiratoires (pléthysmographie, gaz du sang, électromyographie) et leur réversion par les antagonistes des récepteurs opioïdes et de l’acide γ-aminobutyrique (GABA) étaient en faveur d’une interaction pharmacodynamique. Pour le tramadol, nous avons montré que les convulsions n’impliquaient pas les systèmes noradrénergiques, dopaminergiques, sérotoninergiques ou opioïdergiques. Le tramadol agissait comme un modulateur allostérique négatif du site de liaison des benzodiazépines des récepteurs GABA-A (imagerie TEP 11C-flumazénil). Par cette approche multimodale in vivo chez le rat, nous avons pu déterminer que les interactions entre les opioïdes et le système GABAergique jouent un rôle majeur dans les profils de toxicité spécifique de la buprénorphine et du tramadol. / Opioids overdose may be responsible for respiratory depression. Nevertheless, two molecules exhibit particular toxicity patterns. Buprenorphine induces ceiling respiratory effects even at high doses. However, several deaths have been reported, mainly when buprenorphine was co-administered with benzodiazepines. Tramadol is a µ-opioid receptor agonist that induces seizures in 20% of poisoning cases. The exact mechanisms involved in both toxicity remain poorly understood. The aim of our investigation was to study the mechanisms involved in these two types of toxicity using a multimodal approach including pharmacodynamic data and in vivo brain neuropharmacokinetics. Regarding buprenorphine, we have shown that respiratory depression with diazepam does not result from neuropharmacokinetic/receptologic interaction (11C-buprenorphine PET imaging) Conversely, the study of respiratory parameters (plethysmography, blood gas, electromyogram) and their antagonization by opioid and gamma-aminobutyric acid (GABA) receptors antagonists supported interactions mediated by the addition of the pharmacodynamic effects of each molecule. Regarding tramadol, we showed that seizures did not involve the noradrenergic, dopaminergic, serotoninergic or opioidergic systems. Conversely, they involve the GABA-ergic system; tramadol acts as negative allosteric modulator of the benzodiazepine site of the GABA-A receptor (11C-flumazenil PET imaging). Using a multimodal in vivo approach in the rat, we have been able to determine that the interactions between opioids and the GABAergic system play a major role in mechanisms of toxicity of buprenorphine and tramadol.

Background: In many countries, buprenorphine and methadone are licensed for the maintenance treatment (MT) of opioid dependence. Despite many short-term studies, little is known about the long-term (12-month) effects of these treatments in different settings, i.e. primary care-based (PMC) and specialized substitution centers (SSCs). Objectives: To describe over a period of 12 months: (1) mortality, retention and abstinence rates; (2) changes in concomitant drug use, somatic and mental health; and (3) to explore differences between different types of provider settings. Methods: 12-Month prospective-longitudinal naturalistic study with four waves of assessment in a prevalence sample of N= 2694 maintenance patients, recruited from a nationally representative sample of N= 223 substitution physicians. Results: The 12-month retention rate was 75%; the mortality rate 1.1%. 4.1% of patients became “abstinent” during follow-up. 7% were referred to drug-free addiction treatment. Concomitant drug use decreased and somatic health status improved. No significant improvements were observed for mental health and quality of life. When controlling for initial severity, small PMC settings revealed better retention, abstinence and concomitant drug use rates. Conclusion: The study underlines the overall 12-month effectiveness of various forms of agonist MT. Findings reveal relatively high retention rates, low mortality rates, and improvements in most 12-month outcome domains, except for mental health and quality of life. PMC settings appear to be a good additional option to improve access to MTs.

Background Buprenorphine is a semi-synthetic opioid used for the treatment of opioid dependence. Opioid use, including buprenorphine, has been increasing in recent years, in the general population and in pregnant women. Consequently, there has been a rise in frequency of neonatal abstinence syndrome (NAS), associated with buprenorphine use during pregnancy. The purpose of this study was to investigate correlations between buprenorphine and buprenorphine-metabolite concentrations in cord blood and onset of NAS in buprenorphine exposed newborns. Methods Nineteen (19) newborns who met inclusion criteria were followed after birth until discharge in a double-blind non-intervention study, after maternal consent. Cord blood and tissue samples were collected and analyzed by liquid chromatography–mass spectrometry (LC–MS) for buprenorphine and metabolites. Simple and multiple logistic regressions were used to examine relationships between buprenorphine and buprenorphine metabolite concentrations in cord blood and onset of NAS, need for morphine therapy, and length of stay. Results Each increase in 5 ng/ml level of norbuprenorphine in cord blood increases odds of requiring treatment by morphine 2.5 times. Each increase in 5 ng/ml of buprenorphine-glucuronide decreases odds of receiving morphine by 57.7 %. Along with concentration of buprenorphine metabolites, birth weight and gestational age also play important roles, but not maternal buprenorphine dose. Conclusions LC–MS analysis of cord blood concentrations of buprenorphine and metabolites is an effective way to examine drug and metabolite levels in the infant at birth. Cord blood concentrations of the active norbuprenorphine metabolite and the inactive buprenorphine-glucuronide metabolite show promise in predicting necessity of treatment of NAS. These finding have implications in improving patient care and reducing healthcare costs if confirmed in a larger sample.

The United States experiences opioid addiction at epidemic levels. In 2012, the National Institute of Drug Abuse reported that 23.1 million Americans were in need of addiction treatment services, although only 2.5 million were enrolled in treatment. Following an amendment to the Drug Addiction Treatment Act of 2000 (Public Law 106-310), advanced practice nurses were qualified as providers who could bridge the healthcare gap in treatment access. The purpose of this project was to determine the interest of advanced practice nurses in (a) prescribing buprenorphine and (b) establishing guidelines that would allow them to do so. This quantitative project used a 10-question Internet-based survey with a convenience sample of 95 nurses (recruited online) who were currently practicing in advanced nursing roles. Social media platforms, including Facebook, were used to recruit participants. The survey included questions about expanding the scope of practice in addiction treatment and establishing guidelines that would allow nursing knowledge and expertise to be used in outpatient opiate addiction treatment. Critical social theory and Kingdon's theory of policy analysis were applied to support the project. The Survey Monkey data analysis tool was used to generate descriptive statistics, which demonstrated respondents' support for an expanded scope of practice. If the recommendations of this project are adopted by national legislation, increased accessibility to addiction treatment services will save millions of dollars in justice system, healthcare system, employment, and societal costs. Nursing policy advocates nationally can apply these results to support efforts to expand scope of practice to include prescribing buprenorphine.

Background: Patients engaged in evidence-based opioid use disorder (OUD) treatment can obtain prescriptions for buprenorphine containing products from specially trained physicians that are subsequently dispensed by community pharmacists. Despite the involvement of physicians and community pharmacists in buprenorphine prescribing and dispensing, respectively, our understanding of their interactions in this context is limited. Objective: To qualitatively describe the communication and collaborative experiences between Drug Addiction Treatment Act 2000 (DATA)-waivered physicians and community pharmacists from the perspective of the physician. Methods: Ten key informant interviews were conducted with DATA-waivered physicians practicing in Northeast Tennessee. A semi-structured interview guide was used to explore communication and collaborative experiences between the physicians and community pharmacists. Interviews were audio recorded and transcribed verbatim. A coding frame was developed using concepts from the scientific literature and emerging codes from physician interviews. Interviews were coded using NVivo 11, with the data subsequently organized and evaluated for themes. Results: Four themes were identified: (1) mechanics of communication; (2) role specification and expectations; (3) education and understanding; and (4) climate of clinical practice. Physician-pharmacist communication primarily occurred indirectly through patients or staff and perceived challenges to collaboration included; lack of trust, stigma, and fear of regulatory oversight. Physicians also indicated the two professionals may lack clear roles and responsibilities as well as common expectations for treatment plans. Conclusions: Communication between DATA-waivered physicians and community pharmacists is influenced by multiple factors. Further research is warranted to improve physician-community pharmacist collaboration (PCPC) in the context of OUD pharmacotherapy and addiction treatment.

Opioid use disorder (OUD) impacts 5.6 million people in the US. Buprenorphine (BUP) is a commonly prescribed opioid medication used to treat OUD, including in pregnant women. However, opioid use during pregnancy is associated with poorer infant outcomes including reduced fetal growth, neurodevelopmental deficits, and neonatal opioid withdrawal syndrome (NOWS). Recent clinical data suggests that providing mothers with a lower dose of BUP may result in fewer negative outcomes in infants. Here, a preclinical rodent model of low-dose perinatal BUP exposure was used to study offspring health outcomes in the neonate, juvenile, and adolescent offspring. Dams were given clinically relevant doses of BUP prior to and throughout gestation, and continuing through weaning to mimic human doses and exposure. Although the lowest BUP dose still elicited signs of NOWS in offspring, there were fewer negative effects on overall brain morphology across the early lifespan than that of the higher BUP dose compared to controls.