It is increasingly recognised that chronic exposure to opioids has been associated with neuropsychological impairment during both active use and following a period of abstinence. The overall objective of this thesis was to review the relevant prior literature in a systematic manner and subsequently to describe the effects of chronic exposure to prescribed and illicit opioids using an ambispective cohort study design. A systematic literature review was conducted to identify if chronic (defined as a period for more than 3 months) exposure to opioids (prescribed and/or illicit) was associated with measurable neuropsychological deficits. This review was conducted accordingly to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. The results were subsequently described within three cognitive domains of intelligence, executive function and memory and learning. Out of a total of 905 articles extracted between 1964 and 2009, 49 articles were considered appropriate for selection and review. Studies of current and abstinent chronic opioid users (illicit heroin users, patients prescribed methadone for illicit opioid dependence and patients taking opioids as part of the management of chronic pain) have identified performance deficits in measures of executive functioning and memory. These have included impairments within the domains of cognitive and motor impulsivity, strategic planning, cognitive flexibility, attention and memory. However other studies found no clear deficits when comparing the performance of healthy controls. The literature suggested that these neuropsychological deficits may be subject to at least partial recovery following initiation of methadone or total withdrawal from any opioids.This review also highlighted several methodological issues that affect the reliability, validity and clinical relevance of the results obtained. Subsequently a two year ambispective cohort design study was conducted which tested representative opioid exposed participants and healthy controls. Cohorts of participants with validated histories of illicit heroin use (HEROIN, n=24), stabilised methadone maintenance (METHADONE, n=29), chronic opioid prescriptions for pain (CHRONIC PAIN, n=28) and controls (HEALTHY CONTROL, n=28) were recruited. The study was designed to test neuropsychological performance in the HEALTHY CONTROL and CHRONIC PAIN groups on one occasion; and for the HEROIN and METHADONE groups on three and two occasions respectively. The intention was to describe neuropsychological performance in the HEROIN group under conditions of stable illicit heroin use, in controlled opioid withdrawal and when subsequently stabilised on methadone. For the METHADONE group, participants were tested twice, six months apart, to test for changes induced by chronic exposure to methadone. Eligible, screened and consented individuals were tested on nine tests from the CANTAB test battery. Data were analysed using univariate or repeated measures ANCOVA with a between subjects factor of GROUP. Further a priori subgroup analyses were conducted using (1) a two-group factor reflecting DEPENDENCE status and (2) a two-group factor reflecting INJECTING status separately as between subject factors. The homogeneity of variance across groups in repeated-measures design ANCOVAs was assessed by the Mauchly Sphericity Test. NART, age in years, SIMD, total Fagerström score, years in education and past alcohol use in years were used as covariates. A significance level of p<0.01 was applied due to multiple testing, in addition to the post-hoc Bonferroni correction procedure. On the Cambridge Gambling Task (CGT), HEROIN users placed higher bets earlier and risked more. They also showed increased motor impulsivity, impaired strategic planning and visuospatial memory on the Affective Go-NoGo (AGN), Stockings of Cambridge (SOC), and Delayed Matching to Sample(DMS) respectively. METHADONE users deliberated longer and placed higher bets earlier on the CGT, but did not show a tendency to risk more. METHADONE users were also more inattentive and demonstrated poor strategic planning and visuospatial memory on the Spatial Span (SSP) task. The CHRONIC PAIN participants did not exhibit significant impairment in neuropsychological performance on all the CANTAB tasks. Participants from the HEROIN, METHADONE and CHRONIC PAIN groups did not present with impaired cognitive flexibility. Chronic opioid dependence is associated with neuropsychological impairment reflected in altered performance on measures of risk taking and strategic planning. These data support the hypothesis that these neuropsychological impairments reflect an underlying trait vulnerability to drug taking and/or dependence rather than an effect of chronic exposure to opioids. Notably, motor impulsivity and visuo-spatial memory in HEROIN users improved after three weeks stability with methadone. Methadone use seems to confer improvement in some aspects of neuropsychological performance following cessation of heroin and sustains other deficits during long term stable methadone treatment. Dependence and injecting status do not contribute to the causation or deterioration of the identified neuropsychological impairments. Further long term longitudinal studies to help elucidate cognitive endophenotypes responsible for the components in the initiation, continuation and deterioration of neuropsychological deficits present in an opioid dependent population is necessary.

The purpose of this study was to determine whether therapeutic music affects the patient’s perception of pain, postoperative day 1 after knee replacement surgery in an inpatient hospital. In addition to the patient’s pain levels, the study was an analysis of the quantity of opioids the patient was requested, the length of stay, and the physiological parameters, which included blood pressure, heart rate, respiratory rate, and oxygen saturation. Sixty knee replacement patients were randomly placed in the music group or the quiet group. The Faces Pain Scale Revised with Numeric Rating Scale was used to measure pain levels. Statistical analysis between the music group and the quiet group indicated a significant difference in patient’s pain levels (F = .298; p = .037). Study results support music decreasing patient’s perception of pain. Nurses can suggest music intervention to decrease pain with this patient population knowing evidence based practice supports the efficiency of music.

In my senior year at ETSU I produced a documentary about opioid abuse in East Tennessee. In 2016, two local health care providers and a university collaborated on a project that would bring an opioid treatment center to Gray, Tennessee. The center includes a methadone clinic, an addition that piqued the concern of many citizens living in Gray. The film evaluates the concerns citizens had about the clinic and explores the issue of opioid abuse in East Tennessee.

Opioids, such as oxycodone, morphine, and fentanyl, are commonly used medications in the treatment of moderate to severe pain. In spite of their efficacious analgesic properties, their increased prescribing rates by physicians and inherent abuse-related effects have led to the ongoing opioid epidemic. Their clinical utility is limited by the risk of adverse dose-dependent side effects, such as constipation and respiratory depression, and the development of tolerance and dependence. Opioid-sparing adjunctive therapies are sought to address these issues by reducing the dose of opioid needed to achieve analgesia through alternative non-opioidergic mechanisms and as a result, reduce the incidence of the previously mentioned side effects. Serotonin type-2C receptor agonists have demonstrated antinociceptive efficacy in preclinical models of chronic pain. Lorcaserin is a selective 5-HT2C receptor agonist and was reported to attenuate the abuse-related effects of oxycodone. The antinociceptive properties of 5-HT2C receptor agonists and their potential to alter the abuse-related effects of commonly abused drugs suggest that lorcaserin may be a potential opioid-sparing therapeutic. The goal of these studies was to evaluate the utility of lorcaserin, in combination with opioids, in a preclinical model of acute pain. Based on previous studies demonstrating the antinociceptive activity of 5-HT2C agonists, the hypotheses for these studies were that lorcaserin would increase the acute antinociceptive effects of opioids and would attenuate the development of tolerance associated with chronic opioid consumption. The results demonstrate that the acute antinociceptive effects and the time-course of activity of opioids were enhanced by doses of lorcaserin. These effects were mediated through activation of the 5-HT2C receptor and were not blocked by administration of naloxone. Additionally, the acute effects of lorcaserin to increase opioid potency and time course was not mediated through changes in opioid distribution in the blood or central tissues. Opioid tolerance was evaluated in vivo, and tolerance was developed using two methods of treatment: an acute (single dose administration) model of tolerance and a multiple-injection model. Testing the effect of lorcaserin in these models was important because current research suggests that the mechanisms that underlie both models of tolerance are distinct from one another. The results demonstrate that lorcaserin significantly blocked the development of acute tolerance in the whole animal and on a single cell level in dorsal root ganglion cell cultures. In the multiple-day tolerance model, lorcaserin partially attenuated the development of opioid antinociceptive tolerance. Chronic administration of an opioid is associated with desensitization of the MOR, and the effect of lorcaserin on opioid tolerance may be mediated through changes in MOR functional activity. Upon further investigation using agonist-stimulated [35S]GTPyS, the results showed that lorcaserin altered basal binding of [35S]GTPyS but not agonist-stimulated binding in mice that received chronic opioid treatment. These data suggest that the effect of lorcaserin on opioid tolerance, in the multiple-injection model, is not mediated through changes in MOR functional activity. Collectively, the tolerance studies suggest that the effect of 5-HT2C receptor activation by lorcaserin has differential effects on the stages of opioid tolerances and further supports the notion that the mechanisms that underlie the stages of opioid tolerance are distinct. Given the efficacy of lorcaserin to increase the acute antinociceptive effects of opioids and its ability to impair the development of opioid tolerance, collectively, these data suggest that lorcaserin may be a useful opioid-sparing adjunctive therapy.

Opioid therapy is widely used to treat veterans with chronic noncancer pain (CNCP) despite evidence indicating patient safety concerns with the treatment. Although there is a place for opioid therapy in chronic pain management, opioids are not recommended as the first line of treatment for CNCP because of the risk for accidental overdose and death. The purpose of this project was to examine alternative practices for managing CNCP through a systematic review of the literature guided by the conceptual model of the Joanna Briggs Institute method for systematic reviews (JBIM-SR). A critical appraisal of the literature was conducted, and data were extracted and analyzed to identify evidence-based alternatives to opioids for managing CNCP in veterans. Using Cochrane, CINAHL, Joanna Briggs, and PubMed databases for the search, 116 articles were initially identified and through exclusion of duplicates and those not consistent with the study purpose, the review was narrowed to 16 articles. A 2nd reviewer completed an identical search using the exclusion criteria and databases confirming the search results of the primary reviewer. The 16 peer-reviewed research studies published between 2006 and 2016 selected for the analysis were graded using the JBIM-SR grading chart. Educational programs were seen as positive for improving providers' use of alternative therapies for CNCP. Complementary and alternative therapies such as yoga, peer support, injection therapy, cognitive behavioral therapy and acceptance commitment therapy provided improvement in pain perceptions, and coping abilities. Results of this project can promote positive social change as the findings are shared with providers in the practice site and as Veterans receive safe alternatives to opioid therapy.

Ineffective pain management in the post anesthesia care unit (PACU) increases patients' risk of adverse effects including decreased mobility, infection, chronic pain, depression, cardiopulmonary complications, increased length of stay, insomnia, fatigue, and overall decrease in quality of life. The PACU in a community hospital did not provide an evidence-based pain management guideline for nurses treating postoperative patients, resulting in nurses' concerns about providing pain management. The purpose of this project was to translate evidence on pain management into an evidence-based guideline for improved nursing practice in a PACU. Evidence was obtained from a detailed literature search using multiple databases and professional organizations' guidelines. Nursing practice guidelines were developed and evaluated by 3 expert panelists using the Agree II guidelines. The panelists selected included; Two anesthesiologists, one who is trained in pain management and is also a pharmacist. The third expert is a practicing nurse practitioner in an acute setting who is also a surgical first assist and the associate director of robotics. The panel endorsed the guidelines for advancement through the hospital's review committees. Implementation of the evidence-based pain management guideline in the PACU might provide nurses with tools to guide their interventions and improve patient outcomes. Social changes resulting from the use of evidence-based pain management guidelines include decreased time to opiate administration, decreased adverse effects, improved assessment of pain, and an increase in the number of patients who receive proper pain management.

Osteoarthritis is a common degenerative disorder that affects joints. Despite recent therapeutic advances, osteoarthritis continues to be a challenging health problem, and elderly population is particularly at risk. Pain is the most unbearable symptom experienced by osteoarthritic patients. Currently, several pharmacological medications are available to manage osteoarthritic pain. Opioids, potent analgesics, have shown extraordinary ability to reduce intense pain in many osteoarthritic clinical trials. Although many clinical trials have investigated the efficacy and safety of opioids in osteoarthritic patients, there is an increased need for a study to integrate the reported outcomes and utilize them to achieve a better understanding of efficacy and safety profiles of opioids. Therefore, in our present study, efficacy, safety, and tolerability profiles of opioid compounds used to manage osteoarthritic pain were assessed and compared using a model-based meta-analysis (MBMA). To achieve our goal, a comprehensive database consisting of pain relief compounds with information on summary-level of efficacy over time, adverse events and dropout rates was compiled from multiple sources. MBMA was conducted using nonlinear mixed-effects modeling approach. The results showed that the selected models successfully captured the observed data, and primary efficacy endpoint estimations indicated that the ED50 of oxycodone, oxymorphone, and tramadol were 47, 84, and 247 mg per day, respectively. Efficacy-time course analysis showed that opioids had rapid time to efficacy onset, suggesting potential powerful pain relief effects. Also, it was found that gastrointestinal adverse events were the most opioid-associated and dose-dependent adverse effects. In addition, the analysis revealed that opioids are well-tolerable at low to moderate doses. The results presented here provided clinically meaningful insights into the efficacy and safety of oxycodone, oxymorphone, and tramadol. In addition, the presented framework analysis has a clinical impact on drug development where it can help in optimizing the dose of opioids to manage osteoarthritic pain, making precise key decisions for positioning of new drugs, and designing more efficient clinical trials.

Placebo treatments are inert but are known to alleviate symptoms across numerous clinical conditions. One of the most studied placebo effects is placebo analgesia, which is a placebo effect limited to pain relief. This thesis aims to introduce the current state of research regarding the neuroscience of placebo analgesia and specifically to present research findings regarding the neurotransmission. Studies have demonstrated that placebo analgesia can be elicited through two separate processes interacting with each other; manipulation of expectations and through conditioning. These processes seem to affect neurotransmission in different ways. Many brain areas have been found to be correlated to placebo analgesia. Besides the pain-processing brain areas, studies point to that the prefrontal cortex can have a vital role in the placebo analgesic effect. Known neurotransmitters that have shown to be involved in placebo analgesia are endogenous opioids, cholecystokinin (CCK), and endocannabinoids. Studies point to that endogenous opioids are involved in the placebo analgesic effect when elicited by expectation or conditioned by an opioid drug. CCK act on placebo analgesia by affecting the release of endogenous opioids and endocannabinoids seem to be involved in placebo analgesia while it occurs due to conditioning with non-opioid drugs. Getting a better understanding of placebo analgesia and find ways to apply this knowledge in the clinical context could powerfully develop the whole medical society.

Uma das alterações comuns na sepse são os distúrbios microcirculatórios podem ocorrer mesmo com parâmetros macro hemodinâmicos normais. Vários protocolos são indicados para a anestesia de paciente em sepse. Um fármaco geralmente utilizado em pacientes críticos em humanos é a dexmedetomidina, um potente e seletivo alfa 2 agonista com propriedade sedativas, analgésicas e relaxante muscular que promove aumento de pressão arterial e vasoconstrição periférica. O objetivo do presente estudo é avaliar comparativamente a infusão contínua da dexmedetomidina versus fentanil em cadelas sépticas no que diz respeito a três parâmetros relacionados a microcirculação, parâmetros hemodinâmicos e metabólicos. Foram avaliadas 33 cadelas com piometra submetidas à cirurgia terapêutica de OSH, e triadas pelo score quick SOFA. Os animais foram randomizados em duplo estudo de infusão contínua de 3 &micro;g/kg/hora de dexmedetomidina ou 5 &micro;g/kg/hora de fentanil, durante anestesia com isofluorano e em ventilaçao mecânica. Parâmetros hemodinâmicos, microcirculatórios, ventilatórios e metabólicos foram utilizados para comparação entre grupos. Esses foram coletados antes da indução anestésica, durante e pós a anestesia. Os dados foram submetidos a teste de normalidade e variâncias iguais, para então avaliar comparativamente os grupos pelo test t student ou Wilcoxon não pareado quando necessário. Todas as variáveis referentes à microcirculação não apresentaram diferença significativa entre os grupos. A infusão contínua de dexmedetomidina apresentou melhores resultados de pressão arterial e clearance de lactato, sugerindo não comprometer o transporte de oxigênio da periferia e perfusão de órgãos, quando comparado com o uso de fentanil, e ainda com semelhantes desfechos clínicos como mortalidade, tempo de extubação e ocorrências de hipotensão ou bradiarritmia. Os valores semelhantes de microcirculação e superiores de pressão arterial demonstram que a dexmedetomidina não compromete a microcirculação em relação ao fentanil, mas mantém a macrohemodinâmica com valores superiores. / One of the common changes in sepsis is microcirculatory disorders can occur even with normal hemodynamic macro parameters. Several protocols are indicated for sepsis anesthesia. A drug commonly used in critically ill patients in humans is dexmedetomidine, a potent and selective alpha 2 agonist with proprietary sedatives, analgesics and muscle relaxant that promotes increased blood pressure and peripheral vasoconstriction. The objective of the present study is to compare the continuous infusion of dexmedetomidine versus fentanyl in septic dogs using three parameters related to microcirculation, hemodynamic parameters and metabolic parameters. Thirty - three bitches with pyometra submitted to OSH therapeutic surgery, and triaged by the quick SOFA score, were evaluated. The animals were randomized into a double study using continuous rate infusion of 3 &micro;g/kg/h dexmedetomidine or 5 &micro;g/kg/h of fentanyl, during isoflurane anesthesia and under mechanical ventilation. Hemodynamic, microcirculatory, ventilatory and metabolic parameters were used for comparison between groups. These were collected prior to anesthetic induction, during and after anesthesia. The data were submitted to normality test and the same variances, and then comparatively evaluate the groups by the unpaired Wilcoxon test t student or when necessary. All variables related to microcirculation did not present significant difference between the groups. The continuous infusion of dexmedetomidine presented better blood pressure and lactate clearance results, suggesting that it did not compromise peripheral oxygen transport and organ perfusion when compared to fentanyl, and with similar clinical outcomes such as mortality, extubation time and occurrences of hypotension or bradyarrhythmia. Similar values of microcirculation and higher blood pressure demonstrate that dexmedetomidine does not compromise microcirculation over fentanyl, but maintains macrohemodynamics with higher values.

It is well accepted that both inherent and environmental factors influence the pathogenesis of alcohol dependence. This thesis investigates the role of the opioid system in the initiation and maintenance of high ethanol intake. Ethanol-preferring C57BL/6J mice differ from ethanol-avoiding DBA/2J mice in that they exhibit lower basal levels of the opioid peptides dynorphin B and Met-enkephalin-Arg6Phe7 (MEAP) in the nucleus accumbens, which may contribute to their divergent drug-taking behaviour. Chronic ethanol intake in C57BL/6J mice and repeated ethanol administration in Sprague-Dawley rats induce time-specific changes in dynorphin B and MEAP levels in regions, such as the nucleus accumbens and the ventral tegmental area, associated with reinforcing effects of drugs of abuse. Daily neonatal handling for 15 min (H15) and maternal separation for 360 min (MS360) during postnatal day 1-21 were used as models for environmental manipulation early in life. H15 in male rats results in decreased anxiety-like behaviour, whereas MS360 increases anxiety-like behaviour. Both H15 and MS360 induce changes in dynorphin B and MEAP levels especially in regions related to the hypothalamic-pituitary-adrenal (HPA) axis. In female rats, regions related to the HPA axis are unaffected by H15. This suggests a gender-specific involvement of opioids in the HPA axis response to stress. More rats in the MS360 group initiate ethanol consumption and have a higher ethanol intake later in life than the H15 group. The H15 group has particularly low ethanol intake and also differs with regard to neurochemistry compared to both MS360 and control groups, suggesting that H15 can induce long-term changes, protective against high ethanol intake. Specific changes in opioid receptor density are observed after chronic ethanol consumption, such as an increased κ-receptor density in several brain areas, as well as changes in δ-receptor density in the frontal cortex and the nucleus accumbens. Altogether, these results suggest that the opioid system plays an important role in the mechanisms underlying the initiation and maintenance of high ethanol intake.