Objetivou-se comparar os efeitos de duas doses de nalbufina em relação ao tramadol após infusão contínua de fentanil durante cirurgia de osteotomia de nivelamento de platô tibial. Realizou-se estudo clínico encoberto com 28 cães (idade 5,6±1,2 anos e peso 34,7±4,2 kg), pré-medicadas com acepromazina (0,03 mg/kg, IM), induzidas com propofol (4 mg/kg, IV), mantidas com isofluorano (EtISO 1,3 V%) e fentanil (bólus de 3 &micro;g/kg, seguido por 0,3 &micro;g/kg/min, IV), randomizados ao final da cirurgia nos grupos: NAL 0,1: 0,1 mg/kg de nalbufina (n=9), NAL0,3: 0,3 mg/kg de nalbufina (n=9) ou TRA: 3 mg/kg de tramadol, (n=10). Avaliou-se os parâmetros fisiológicos, escores de sedação e de dor (Colorado, Glasgow e VAS) a cada 30 minutos após a administração dos tratamentos, por seis horas ou até o resgate (tramadol 4 mg/kg e dipirona 30 mg/kg, quando VAS &ge; 4, Glasgow &ge; 5 e/ ou Colorado &ge; 2). Coletas de sangue para mensuração para gasometria arterial foram realizadas. Avaliou-se ainda os tempos de extubação (TE), recuperação da respiração espontânea (TRE) e decúbito esternal (TDE). Os tempos de recuperação foram avaliados por meio de ANOVA, com pós-teste de Tukey, enquanto as escalas foram avaliadas pelos testes de Friedman e Kruskal-Wallis, seguidos por pós-teste de Dunn quando necessário, com nível de significância de 95%. Os animais que receberam tramadol apresentaram maior grau de sedação em todos os momentos avaliados (p < 0,05), além de maior TE, TRE e TDE que NAL0,1 e NAL0,3 (p<0,001). Quando comparado ao momento basal, o grupo TRA apresentou redução significativa do pH do HCO3 e elevação da PaCO2 em T 30. Na comparação entre grupos, o grupo TRA apresentou menor pH em T30 quando comparado a NAL 0,1 e NAL 0,3. Na escala de avaliação de dor de Glasgow, Colorado e na EAV, o grupo NAL 0,1 apresentou média &#177;DP significativamente mais alta do que NAL 0,3 (p<0,05) e TRA (p<0,001) em T60, T120 e T180. O tempo para administração do resgate foi de 133&#177;50 minutos no grupo NAL0,1, 220&#177;30 minutos no NAL0,3 e 360 minutos no grupo TRA. Com os dados obtidos conclui-se que a administração de nalbufina reduz o tempo de recuperação anestésica, necessitando, porém, de resgate analgésico mais precocemente que o tramadol / The aim of this study was to compare the effects of two nalbuphine doses versus tramadol after fentanyl continuous infusion during tibial plateau leveling osteotomy surgery. A clinical study with 28 dogs (5.6&#177;1.2 years old and 34.7&#177;4.2 kg), pre-medicated with acepromazine (0.03 mg/kg, IM), followed by propofol induction (4 mg/kg, IV), isoflurane (EtISO 1.3 V%) and fentanyl (bolus of 3 &micro;g/kg, following 0,3 &micro;g/kg/min, IV) maintenance; were randomized distributed in the following groups: NAL0.1: 0.1 mg/kg of nalbuphine (n=9), NAL0.3: 0.3 mg/kg of nalbuphine (n=9) or TRA: 3 mg/kg of tramadol (n=10). Physiological parameters, sedation and pain scale (Colorado, Glasgow and VAS) were evaluated every 30 minutes after treatment administration, during six hours, or until rescue medication (tramadol 4 mg/kg and dipyrone 30 mg/kg, when VAS &ge; 4, Glasgow &ge; 5 and/or Colorado &ge; 2). Arterial blood gas sampling were collected. Furthermore, time of extubation (TE), spontaneous respiration recovery (TRE) and sternal decubitus (TDE) were registered. Recovery periods were analyzed using ANOVA, followed by Tukey test, while the pain scales were evaluated using Friedman and Kruskal-Wallis, followed by Dunn&#39;s test, when necessary, with significance level of 95%. Animals that received tramadol exhibited higher sedation score in all evaluated moments (p < 0.05), and also higher TE, TRE and TDE than NAL0.1 and NAL0.3 (p<0.001). TRA group showed significate pH of HCO3 reduction when comparing to baseline and PaCO2 elevation in T30. When comparing between groups, TRA showed significate smaller pH in T30 than NAL0.1 e NAL0.3. Considering Glasgow, Colorado and EAV pain scale, NAL0.1 group produced average &#177;SD significant higher than NAL0.3 (p<0.05) and TRA (p<0.001) in T60, T120 and T180.Rescue pain medication time was 133&#177;50 minutes in NAL0.1 group, 220&#177;30 minutes in NAL0.3 group and 360 minutes in TRA group. The results of this investigation shows that nalbuphine administration decreases anesthesia recovery time, requiring, however, early rescue pain medication than tramadol

Opioid addiction has reached an all-time high in America, partially because there is no federally approved, affordable, available alternative for chronic pain. This paper examines the role of medical cannabis in the opioid crisis by exploring the effect of medical cannabis laws on opioid prescription rates in an OLS regression. I found that medical cannabis laws produce a statistically significant decrease in opioid prescription rates. I discuss the specific policy components that would allow medical cannabis policy to be most effective nationwide.

Despite its numerous side effects, morphine and the opioids derived from this drug, belong among the only effective options for treatment of pain linked to oncological illness. The effect of opioids on the efficiency of cytostatics in vitro has been the subject of many papers but the results are often contradictory, which could be probably caused by the great variability of experimental models and approaches. Some recent studies indicate that the consequences of activation of opioid signaling in astrocytes display certain differences from other cell types. Glioblastoma multiforme, the tumor derived from astrocytes, belong among those with the worst prognosis, mostly for the frequent resistance to cytostatics. In this thesis we focused on the effect of morphine, methadone and DADLE on the efficiency of cytostatics of temozolomide, doxorubicin and vincristine on the cell lines C6 and CCF-STTG1 derived from glioblastomas. Also, we examined the effect of the above mentioned opioids on the level of oxidative cellular stress and using N-acetylcysteine, a ROS scavenger, we verified the role of oxidative stress in cellular systems activated by the effect of the mentioned opioids on the efficiency of cytostatics. We also assessed opioid receptors and the receptor TLR4 in the examined cell lines. The...

Over the past ten years, there has been a consistent increase in opioid use, which has resulted in an increase in enrolment in methadone maintenance therapy [MMT]. With retention in MMT being a key factor, in order to understand the process of retention, it is important to gain an understanding of individual perceptions and experiences. No research in Ottawa, Ontario has addressed the perspective of MMT from people enrolled in MMT; therefore, nursing based research was undertaken. The objective was to understand the process and experiences associated with MMT from the perspective of persons who are enrolled in treatment. Twelve participants were engaged in semi-structured interviews. These participants described that, although MMT can positively affect the people who use such a treatment option, it continues to have a negative impact that repeatedly affects MMT initiation and delivery. The theoretical framework of Hardt and Negri’s “Triple Imperative of Empire” was used to analyze the research participants’ interviews within the current MMT program, to help develop a more inclusive healthcare service that addressed the current barriers hindering access and retention in treatment. The integration of this framework can help engage persons in treatment, tailor treatment to patient specific needs, and as a result increase access and retention in MMT programs.

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This thesis describes the synthesis of novel analogs of the unique opioid receptor modulator mitragynine along with pharmacological and behavioral studies of a subset of its novel analogs. In Chapter 1, a general overview of opioid receptors and the importance of the mu opioid receptor (MOR) for the treatment of pain is provided. The rise of the opioid epidemic is discussed which brings into attention the need to develop safer opioid therapeutics for the treatment of pain. In this regard the Mitragyna indole alkaloids, isolated from kratom leaves are of great interest as they are considered to be “atypical” opioid ligands and represent novel molecular scaffolds for the development of safer opioid receptor modulators. The introductory chapter includes a brief description of the pharmacological profile of mitragynine as a prelude to the work that follows – examining unexplored positions on the alkaloid by devising new methodology and synthetic routes to synthesize novel analogs to study its structure-activity relationship (SAR) at the opioid receptors. Chapter 2 describes the development of a new synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering). The method takes advantage of an indole-ethylene glycol adduct as a key intermediate which can undergo subsequent iridium-catalyzed borylation at the desired position. This late-stage C(sp2)-H functionalization approach provides a practical route to novel C11-analogs of mitragynine and related scaffolds starting from the natural product, thus allowing a systematic SAR exploration of the C11 position. Chapter 3 directly builds on Chapter 2, summarizing the neuropharmacological and behavioral studies on the C11 analogs of 7-hydroxymitragynine (7OH) and mitragynine ethylene glycol (MG-EG). Through these studies we discover that the C11 position represents a key locant for fine-tuning opioid receptor signaling efficacy. We also discuss that the parent 7-hydroxymitragynine (7OH), a low efficacy agonist, is transformed to an even lower efficacy agonist by introducing a fluorine substituent at the C11 position (11-F-7OH). This is demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid therapeutics with mitigated side effects. Thus, this section concludes with the identification 11-F-7OH as lead compound for future investigation. Chapter 4 describes our attempts towards the functionalization of another unexplored and vital position for the activity of mitragynine at the mu opioid receptor (MOR) – the ethyl group at the C20 position. This chapter illustrates our extensive efforts towards the late-stage functionalization of the ethyl group in the C20 position of mitragynine via directed C(sp3)-H activation. Various strategies including using the mitragynine ethylene glycol (MG-EG) as a bidentate ligand or manipulating the acrylate ester group on mitragynine as a directing group are discussed in the chapter. Also described are all the screened reaction conditions using palladium catalysts and various ligands starting from pyridine-based to mono-protected amino acid-based ligands. The outcomes and hypotheses for the failures of each strategy employed are also presented in the chapter. Chapter 5 describes our efforts towards the de novo synthesis of the C20 analogs, as an alternative strategy to the failed late-stage functionalization from Chapter 4. We present a strategy to synthesize the C20 analogs through a diversification strategy from a common intermediate. We further discuss the results of our efforts towards the formal synthesis of this common intermediate. The chapter concludes with a discussion of an alternate strategy for the synthesis of the C20 analogs.

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Depuis plus de 30 ans, les progrès thérapeutiques ont permis de réduire la morbi-mortalité liée à l’infarctus du myocarde. La reperfusion est une étape essentielle dans la prise en charge des patients, mais est également à l’origine de lésions tissulaires cardiaques. Plusieurs travaux ont montré que le conditionnement ischémique ou pharmacologique du coeur permet de réduire ces lésions de reperfusion, mais que cet effet bénéfique reste limité dans un contexte de diabète.Dans ce travail, nous avons tout d’abord étudié l’impact du diabète de type 2 sur la fonction mitochondriale. Les études ont été réalisées sur des trabécules d’oreillette humaine, et dans deux sous-populations mitochondriales, les mitochondries sous-sarcolemmales (SSM) et interfibrillaires (IFM), par des approches polarographique, spectrophotométrique et protéomique. Alors que des différences sont observées en termes d’activité enzymatique et d’expression protéique entre SSM et IFM, nous n’avons pas observé d’effet lié au diabète sur la fonction mitochondriale.Dans un second temps, nous avons développé un modèle d’étude des lésions d’ischémie reperfusion chez la souris en utilisant la technique de Langendorff. Nous avons étudié les effets sur la fonction cardiaque et sur le volume de nécrose, du post-conditionnement pharmacologique par différents agonistes et antagonistes opioïdes (morphine, [D-Pen2,D-Pen5]-enkephaline (DPDPE), naloxone, naltrindole) après une ischémie globale. Chacune des molécules testées réduit le volume de nécrose. La fonction cardiaque était également améliorée après 60 minutes de reperfusion en présence de morphine seule, de naloxone seule, et des associations morphine-naloxone et DPDPE-naltrindole. Les mécanismes moléculaires impliqués dans ces effets cardioprotecteurs nécessitent d’être mieux compris avant d'envisager une application chez l’Homme, en particulier chez le patient diabétique, afin de limiter les lésions de reperfusion dans un contexte d’infarctus du myocarde. / The morbidity and the mortality of the heart stroke have been reduced over the last 30 years and it was related to an improvement of patient care. The early reperfusion of the heart is an essential step, but is responsible for ischemia-reperfusion injuries. Both ischemic and pharmacological conditionings were shown to increase heart function, but these beneficial effects are reduced in a context of diabetes mellitus.First, we studied the effect of type 2 diabetes mellitus on mitochondrial function. Studies were performed on heart trabeculae, and in subsarcolemmal (SSM) or interfibrillar (IFM) mitochondria extracted from human atrial appendages using polarographic, spectrophotometric and proteomic analyses. Whereas differences on enzymatic activities and in protein expression were observed between SSM and IFM, we did not find any deleterious effect of diabetes mellitus on mitochondrial function. Second, using a Langendorff’s apparatus, we developed an experimental model in mouse to study ischemia-reperfusion injuries. Pharmacological post-conditioning was tested by using various opioid agonists and antagonists, including morphine, [D-Pen2,D-Pen5]-enkephalin (DPDPE), naloxone, and naltrindole. The effects were observed on heart function and the volume of necrosis. All treatments were effective to reduce the necrosis in the heart compared to control condition. After 60 minutes of reperfusion, cardiac function was also improved with morphine, naloxone, and the association of morphine-naloxone, and DPDPE-naltrindole. A better understanding of the molecular mechanisms is needed to improve pharmacological post-conditioning in patients, particularly in diabetics, presenting with heart stroke.

Over 1.4 million people are diagnosed with cancer annually. Of those people, 70-90% experience some form of pain. Numerous efforts have been made to educate nurses in the management of pain, yet 30-50% of cancer patients report that their pain is poorly managed. It is not clear whether nurses who obtain certification in Oncology are better equipped to manage this patient population regarding their pain issues. This study compared the knowledge of Oncology Certified Nurses (OCN) and Non-Certified Oncology Nurses (NCON) regarding pain management. The sample of 41 oncology nurses included 19 who were certified in oncology and 22 who were not certified in oncology from two Oncology Nursing Society Chapters in West Central Florida. The nurses sampled were predominately Caucasian (n=35), females (n=38), with a mean age of 48.9 years, all caring for patients in an oncology setting. The participants completed a brief demographic form and the Pain Management Principles Assessment Test (PMPAT). Results of the study showed that the Oncology Certified Nurses scored significantly higher (mean = 71%; SD = 2.9) on the PMPAT than did the Non-Certified Oncology Nurses (mean = 62%; SD = 3.6). Although the sample size was small and limited in geographic location, the results are adequate in providing meaningful results (p = .007). Findings suggest that there is benefit to oncology certification, allowing nurses to provide more comprehensive care for cancer patients in pain.