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1
Sawyer, Molly K. "Generation Opioid: Teacher Perspectives of Students Affected by Opioids." Miami University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=miami1588195607758498.
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Fundytus, Marian Elaine. "Central nervous system and peripheral signs of opioid abstinence." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=56639.
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It was hypothesized that a metabolite of morphine, morphine-3-glucuronide (M3G), contributes to the expression of symptoms seen during withdrawal from morphine. To test this hypothesis, the behaviors observed during precipitated withdrawal from morphine and sufentanil were compared. Sufentanil was chosen because, like morphine, it acts primarily at the mu opioid receptor, but has different metabolites. Differences in the abstinence syndromes produced by the two drugs may therefore be attributable to the actions of metabolites, rather than the primary opioid actions of morphine and sufentanil. Although there were some differences in the occurrence of symptoms, morphine and sufentanil withdrawal were very similar. Therefore, the evidence was inconclusive as to the contribution of metabolites during withdrawal.<br>Systemic administration of M3G alone and in combination with morphine produced no withdrawal-like behaviors. However, when these drugs were given centrally, withdrawal-like behaviors were observed in conjunction with seizures. The seizures were not attenuated by naloxone (but were alleviated by an anti-convulsant), indicating that they were not mediated by opioid receptors. The behaviors resembled those seen by previous investigators following high doses of morphine. The results suggest that M3G may play a role in the toxic effects of high doses of morphine.
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Raehal, Kirsten M. "Opioid-induced side effects in beta-arrestin2 and G protein-coupled receptor kinase knockout mice." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1236884585.
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Seeberg, Jaclin Dee. "Opioids: Implementation of Opioid Prescribing Education and Policy in a Primary Care Center." Diss., North Dakota State University, 2020. https://hdl.handle.net/10365/31759.
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Many healthcare providers report not feeling confident when prescribing opioids, which represents an educational gap in the clinical setting that must be addressed to improve patient care and outcomes (Dowell, Haegerich, & Chou, 2016b). Healthcare providers attribute this lack of confidence in opioid prescribing to insufficient training on the tools provided to them to ensure safe prescribing habits. Thus, healthcare providers do not feel confident in managing patients’ chronic pain. A healthcare provider’s time spent with their patient is limited and therefore, needs to be utilized efficiently. In order to achieve effective time management, healthcare providers need to be experts on chronic pain management and self-assured with their practice in relation to opioids.
This practice improvement project focused on increasing healthcare providers’ knowledge and confidence when prescribing opioids for chronic pain and managing chronic pain. An educational intervention with health professionals working in federally qualified health centers in North Dakota was implemented via Skype. The intervention allowed healthcare providers to be up-to-date on the most recent evidence-based literature and guidelines regarding this topic. Throughout this practice improvement project, healthcare providers were educated on the latest Centers for Disease Control (CDC) and Prevention Guideline for Prescribing Opioids for Chronic Pain, provided resources for their clinical practice, and given an opportunity to evaluate their own knowledge and confidence.
The implementation of the practice improvement project was comprised of an educational session. To assess the participants’ knowledge, a pre-test was provided prior to the educational session and a post-test was given following the educational session. Furthermore, a self-confidence evaluation survey was administered, which utilized a Likert scale. Lastly, the clinic’s policies and pain agreements related to pain and opioids were reviewed and discussed.
The results of the project indicated an overall increase in the participants’ knowledge and self-confidence. In addition, the project promoted awareness of the clinic’s current pain agreement and the likelihood of a future implementation of a policy regarding chronic pain management. The educational session was beneficial in promoting the use of evidence-based research and guidelines in the primary care setting.
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Odunayo, Adesola DeClue Amy. "Immunomodulatory effects of opioids." Diss., Columbia, Mo. : University of Missouri-Columbia, 2010. http://hdl.handle.net/10355/.
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The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on July 13, 2010). Thesis advisor: Amy DeClue. "May 2010" Includes bibliographical references.
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Nandi, L. Reema S. N. "The developmental neurobiology of opioids." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413159.
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Österlund, Modalen Åsa. "Opioids and regulation of breathing /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-123-7/.
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Striefel, Kelsey Leigh. "Opioids: A Reason for Concern." Diss., North Dakota State University, 2018. https://hdl.handle.net/10365/27894.
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The opioid epidemic has drawn increasing attention as opioid prescribing rates and opioid related deaths continue to rise. Opioid prescribing by health care providers has quadrupled over the past 18 years and is directly proportionate to opioid-related overdoses. Primary care providers initiate chronic opioid pain management and frequently fail due to the multifaceted nature of chronic pain. A rural North Dakota health care system implemented strategies to improve chronic opioid pain management. Strategies were based on the 2016 Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain. Interventions were directed at improving opioid prescribing practices for chronic non-cancer pain management of primary care providers and reducing risks of long term opioid use. Providing clinicians with education and a quick-reference sheet on current evidence-based recommendations and accepted best practices developed their knowledge to complete remaining interventions. Chart audits identified patients on chronic opioid therapy, patients with a signed pain contract, and those with daily opioid doses meeting or exceeding recommended upper daily morphine milligram equivalence. Provider notification of identified patients allowed for further recommended interventions. Chart flagging allowed providers to easily identify patients currently on a pain contract, patients eligible for a pain contract, and patients receiving the upper daily morphine milligram equivalence limits. Evaluation was performed four months after initiation of the project. Results showed the education provided increased clinicians? knowledge and comfort in the evidence-based guidelines for managing chronic pain with opioids. Recommended monitoring strategies were improved after providers received education. Evaluation found the prescription drug monitoring program review and documentation had improved from 0 to 18. Annual urine drug screens increased from 9 to 15. Eighty-five percent of pain contract eligible patients were enrolled in a pain contract. Evaluation of patients prescribed daily morphine milligram equivalence ? 50 and ? 90 that had appropriate recommended interventions were 57% and 50% respectively. Forty-five pain management patients were identified at the time of evaluation and flagged in the electronic health record. Overall, each intervention implemented showed improvement upon comparison of pre-implementation and post-implementation data.
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Munro, Gordon. "Oxytocin neurone adaptations to opioids." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/21439.
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Systemic administration of sulphated cholecystokinin octapeptide (CCK8S) activates central noradrenergic pathways (including possibly the A6 cell group of the locus coeruleus which projects to the SON) and this stimulus to oxytocin secretion into the blood measured by radioimmunoassay was dose-dependently inhibited by the α<SUB>2</SUB>-adrenergic agonist clonidine and by morphine; α<SUB>2</SUB>- and μ-receptor mediated effects may converge on the same post-receptor mechanism. Cells of the locus coeruleus also show tolerance and dependence to opioids. Withdrawal hypersecretion of oxytocin was significantly attenuated by clonidine, possibly by pre-synaptically blocking the noradrenergic input from the A6 cell group although activation of this pathway by CCK8S alone did not initiate withdrawal. Thus withdrawal excitation of supraoptic oxytocin neurones may involve an excitatory noradrenergic input from the A6 cell group which may become more active during dependence. Tolerance to opioids on excitatory inputs to the SON and within the SON itself may increase the expression of several components excitatory to oxytocin neurones such as endogenous CCK function. An amplification in release of noradrenaline within the SON after removal of central morphine inhibition by naloxone, may then excite oxytocin neurones directly by increasing a voltage dependent Ca<SUP>2+</SUP><I> </I>conductance. Co-release of oxytocin and CCK would feed back onto the oxytocin neurones and sustain the withdrawal process, whilst the increase in synaptic drive from the A6 cell group and locally within the SON would continue until release of oxytocin and CCK or a pool of readily available Ca<SUP>2+</SUP> had become depleted thereby bringing the withdrawal process to an end.
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Rutten, Mikal R. "Post treatment with the novel Deltorphin-E, a delta2 opioid receptor agonist, increases recovery and survival following severe hemorrhagic shock in behaving rats." Laramie, Wyo. : University of Wyoming, 2007. http://proquest.umi.com/pqdweb?did=1313914351&sid=1&Fmt=2&clientId=18949&RQT=309&VName=PQD.
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Rudén, Ludvig. "Neurobiology of opioid addiction." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-15735.
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Since the use of opioids started to emerge for analgesic reasons in the 19th century with the synthetization of morphine, opioids have been studied rigorously to better understand its effects on the brain. This thesis shows that both the analgesic effects and the reinforcing effects of opioids are mediated by the same receptor, the mu opioid receptor (MOR). MOR activity has been correlated to both primary and secondary reinforcers and should be considered to cause positive reinforcement together with increases in dopamine transmission for all drugs of abuse, and not only in relation to opioids. Opioid tolerance, dependence and even addiction are to some extent thought to relate to opioids’ acute effect of cyclic adenosine monophosphate (cAMP) superactivation. Based upon these findings, the allostasis theory of addiction is considered to be the most suitable in defining opioid addiction. The theory claims that the mesolimbic dopamine system becomes sensitized, increasing the attractiveness of opioids. This while counteradaptation increases the pleasurable tolerance of opioids, encouraging the user to increase its intake for the same initial reward. Furthermore the theory claims that cAMP superactivation is causing an unfolding effect of neurobiological and neurochemical expressions which leads to the disorder of addiction. cAMP superactivation is mediating the negatively reinforcing aspects of opioid addiction together with changes to corticotropin-releasing factor (CRF) in the brain stress system, such as the hypothalamic-pituitary-adrenal (HPA) axis and the extended amygdala.
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Oxberry, Stephen Grantley. "Opioids for breathlessness in heart failure." Thesis, University of York, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550494.
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Breathlessness is a common and problematic symptom in heart failure. Opioids have traditionally been considered as analgesics, but a potential role for their use in breathlessness is beginning to emerge. This thesis commences with a review of the existing literature in support of a possible role for opioids in the management of breathless in heart failure. A systematic review of existing human symptom control studies in this thesis suggests that opioid administration may have a small but significant benefit in chronic heart failure. However, only six studies were included in the review and most were either small or of poor methodological quality. This presents a relative gap in the knowledge on this topic. A randomised controlled trial was therefore performed to assess the effect of opioids on breathlessness in chronic heart failure. This crossover trial involved the comparison of two oral opioids with placebo. Thirty-five participants completed the trial, making it the largest trial of its type in this area. Opioid administration was shown to be safe in this patient cohort. No statistically significant differences were demonstrated for breathlessness severity between treatments. Participants were subsequently invited to participate in a three month open label extension. Thirty three participants in total were followed up with thirteen remaining on active therapy. This is the first trial of its type in breathlessness in heart failure and represents the longest participant follow-up in this area. Whilst not as robust as the initial trial, this extension period revealed that opioid continuers rated a statistically significant improvement in breathlessness severity from baseline compared to non-continuers. Finally, a semi-structured interview study in ten participants with heart failure revealed for the first time that opioids are acceptable in this population and they describe troublesome symptoms that might respond to opioid treatment.
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Bastami, Salumeh. "Practical and clinical use of opioids." Doctoral thesis, Linköpings universitet, Avdelningen för läkemedelsforskning, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-96795.
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Pain is a common symptom of a number of conditions including cancer and one of the most frequent reasons for seeking healthcare. Acute and chronic pain result in considerable discomfort with a detrimental impact on the quality of life. Opioids are the mainstay of pain management for many patients with severe pain. Opioids are, unfortunately, also commonly abused drugs, and are well-represented in forensic toxicology investigations. Side effects related to the central nervous system are the major reasons fordiscontinuation of opioid treatment. In this thesis, we tested the hypothesis that local analgesic treatment by opioids, without the usual opioid-related side effects, could be a potential alternative to systemic opioid treatment. We examined the analgesic effect of topically applied morphine in a randomized, double blind, cross over study in patients with painful leg ulcers. Significant reduction of pain was obtained after application of both morphine and placebo gel. Morphine reduced pain more than placebo but the difference was not statistically significant. However, morphine could reduce pain considerably more than placebo in those cases where VAS (Visual analog scale) was higher initially. Another issue with opioid therapy is the substantial individual variability in response to opioids including morphine and tramadol. We investigated the significance of UGT2B7, CYP2D6, OPRM1 and ABCB1 polymorphisms for pharmacokinetic and pharmacodynamic properties of morphine and tramadol. We showed that genetic variants in CYP2D6 and UGT2B7 have an important role in the metabolism of tramadol and morphine respectively. While the role of SNPs in ABCB1 remained unclear, genetic variants in OPRM1 gene were correlated with the required dose of morphine. Taken together, these findings suggest that genotypes should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results. Opioids, besides their analgesic properties, have other pharmacological effects including effects on immune system. We evaluated potential differences between commonly used opiates with regard to their effect on the immune system. We found an inhibition of cytokine release, in the order of potency as follows: tramadol > ketobemidone >morphine >fentanyl. All opioids with the exception of fentanyl were capable of inhibiting production of mRNAs for TNF-alpha and IL-8. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of opioids and to improve opioid treatment strategies in patients with cancer. Here, we have found that individual genotype matters and affects the individual response. Further research is warranted to tailor individualized treatment. Personalized medicine has increased in importance and will hopefully in the near future become standard procedure to improve and predict the outcome of treatment by opioids.<br><p>The series name in the title page is incorret. The correct title should be <em>Linköping University Medical Dissertations.</em></p>
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Ancona, Rachel M. "Prescribed Opioids as an Initial Exposure in Emergency Department Patients Reporting Nonmedical Opioid or Heroin Use." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1459244023.
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Baldacchino, Alexander. "Neuropsychological function as a result of chronic exposure to methadone and other opioids." Thesis, University of Dundee, 2012. https://discovery.dundee.ac.uk/en/studentTheses/9093e904-a5fe-4b81-923f-0c3309154b25.
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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.
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Lui, Wan Thomas. "Biochemical events induced by the specific kappa-opioid receptor agonist, U50488H /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38284157.
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Smith, Caroline Jackson. "Development of oxytocin, vasopressin V1a, and mu-opioid receptor expression in the rat brain: Implications for the regulation of juvenile social novelty-seeking behavior." Thesis, Boston College, 2017. http://hdl.handle.net/2345/bc-ir:107311.
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Thesis advisor: Alexa H. Veemena<br>Across species, the juvenile period is characterized by increased social interaction with peers and heightened novelty-seeking behavior, as compared to any other life stage. These behaviors are likely to be highly adaptive during this developmental phase. Still, an excessive novelty-seeking phenotype may predispose individuals to risk-taking and substance abuse, while too little social engagement and low novelty-seeking are characteristics of neuropsychiatry disorders such as autism. The over-arching aim of this dissertation research has been to elucidate the neural mechanisms underlying juvenile social novelty-seeking behavior. Central activation of oxytocin, vasopressin V1a, and µ-opioid receptors (OTR, V1aR, and MOR, respectively) have been implicated in the regulation of adult social behavior, but our understanding of the expression and function of OTR, V1aR, and MORs in the juvenile brain is incomplete. Therefore, in Studies 1 and 2, age differences in binding density of OTR, V1aR, and MOR throughout the rat brain were identified using receptor autoradiography. Next, in Study 3, I established the social novelty preference test, a new paradigm designed to assess the preference of juvenile rats to interact with either a novel or a familiar (cage mate) conspecific. Using this social novelty preference test, in Studies 3, 4, and 5, the functional involvement of OTR, V1aR, and MOR in the regulation of juvenile social novelty preference was characterized using both intracerebroventricular and local in-vivo pharmacological manipulations. The results of these experiments demonstrate that both OTR and MOR activation in the brain are involved in the regulation of juvenile social novelty preference, particularly acting within the nucleus accumbens. Finally, in Study 5, I investigated the impact of social isolation on juvenile social novelty preference. My findings show that social isolation potently reduces social novelty preference, which, in turn, can be restored by MOR activation in the nucleus accumbens. Taken together, this body of work significantly advances our understanding of the neural systems underlying juvenile social novelty preference, and suggests that both oxytocin and opioid systems in the brain may be potential clinical targets for restoring social novelty-seeking behavior in neurodevelopmental disorders, such as autism
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Electricwala, Batul. "Prevalence, Incremental Cost and Resource Utilization Associated with Opioid Overdoses." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4590.
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Background –
An increase in opioid prescribing has led to an increase in opioid overdoses.1,2 No study has estimated the incremental costs subsequent to an opioid overdose event in prescription opioid users, or the prevalence and costs of overdose events in family members of prescription opioid users and in overdose victims with no identifiable source of prescription opioid. The latter group will be referred to as “others”.
Objectives –
The first objective of this study was to estimate the prevalence of opioid overdoses in aforementioned groups. The second objective was to estimate the incremental costs and resource utilization associated with opioid overdoses in these groups.
Methods –
This study is a retrospective analysis using claims data from SelectHealth, a not-for-profit health insurance organization in Utah and southern Idaho. We estimated the prevalence of opioid overdoses in the sample population, as well as in each group, by year. For the cost estimation we collapsed family members and others into one category – “non-medical users”. To estimate costs we used an incremental cost approach whereby we used propensity scores to match cases (patients who suffered from an opioid overdose) to appropriate controls (patients who did not suffer from an opioid overdose) and estimated the direct medical costs incurred in each group in the year following an overdose. Generalized Linear Models were used to estimate incremental costs and resource utilization. Sensitivity analyses were conducted to measure the robustness of the estimates.
Results –
The prevalence of opioid overdoses increased by 84.8% in prescription opioid users (from 55.6 per 100,000 in 2011 to 102.8 per 100,000 in 2014), increased by 37.9% in family members of prescription opioid users (from 5.9 per 100,000 in 2011 to 8.2 per 100,000 in 2014) and increased by 179.9% in others (from 8.2 per 100,000 in 2011 to 23.1 per 100,000 in 2014).
The prevalence of opioid overdoses in acute users increased by 14.7% (from 43.8 per 100,000 in 2011 to 50.3 per 100,000 in 2014) as compared to 165.9% in chronic users (from 187.0 per 100,000 in 2011 to 497.3 per 100,000 in 2014).
The incremental direct medical costs per patient per year were estimated to be $65,277 (p-value<0.05) in prescription opioid users who suffered from an overdose and $41,102 (p-value<0.05) in non-medical users who suffered from an overdose. Overdose-specific costs were estimated to be $12,111 for prescription opioid users and $11,070 in non-users.
Conclusions –
Our study found that the prevalence of opioid overdoses increased steadily from 2011 to 2014 in the sample population. The prevalence of overdoses was much higher in chronic opioid users as compared to acute users. Differences between overdose-specific costs and total incremental costs may suggest that overdoses are associated with substantial costs in addition to costs for the initial treatment of the overdose. While the cost to payers due to overdoses in prescription opioid users is substantial, payers also incur costs from diversion of opioids.
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Williams, John Parry. "Opioids and a neuro-vascular-immune axis." Thesis, University of Leicester, 2009. http://hdl.handle.net/2381/4160.
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Opioid-based agents represent the cornerstone of analgesia in modern clinical practice. Additionally however opioids produce a range of unwelcome side-effects including immunomodulation. It has been suggested that this immunomodulation may result either as a direct effect of opioids on circulating immune cells or via a central action. Meanwhile studies show that classical opioid receptors are up-regulated in peripheral inflammation, while endogenous opioids are released from circulating immune cells producing local analgesia. Expression of opioid receptors on immune cells however remains contentious. This thesis has made a significant contribution to understanding the interaction between opioids and a neurovascularimmune axis by employing radioligand binding, flow cytometry and polymerase chain reaction techniques to make a systematic and detailed examination of the expression of the classical opioid receptors (MOP, DOP and KOP) and the non-classical opioid receptor (NOP) and the precursor for its endogenous ligand N/OFQ (ppN/OFQ) in the peripheral blood mononuclear cells (PBMCs) of healthy volunteers. Using these techniques we have shown (1) that naïve human PBMCs do not express classical opioid receptors, (2) that PCR techniques support the view that PBMCs do express gene transcripts for NOP and ppN/OFQ. In an additional clinical study during a profound vascular insult we have used quantitative PCR and radioimmunoassay techniques to follow the expression of the opioid receptors and native N/OFQ throughout a septic episode in patients admitted to the intensive care unit (ICU). Here we report for the first time an elevation in plasma N/OFQ concentration in non-survivors of sepsis requiring ICU admission, 3.0 [2.5 – 5.0]pg ml-1 in non-survivors vs. 1.0 [1.0 – 2.5]pg ml-1 in survivors (p=0.028). Similarly we are first in reporting an elevation in plasma N/OFQ following major abdominal surgery in septic patients. These findings lead us to suggest an amendment to the previously proposed neuroimmune axis to include the N/OFQ-NOP system.
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Li, Lin. "Safety of opioids for non-cancer pain." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12476.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.<br>While the use of opioids for chronic non-cancer pain has increased dramatically in the past 20 years, concern exists for safety of opioid analgesics, particularly for longterm use. Using a matched, nested case-control study design, this dissertation evaluates the safety of opioid treatment among non-cancer adults aged 18-80 years in the United Kingdom-based General Practice Research Database.
The first study examined the association between opioid treatment and risk of MI. Current opioid users and those with more than 10 opioid prescriptions had small increased adjusted ORs of around 1.30 compared with nonusers. There was no clear dose-response pattern in the associations between opioid duration of use and risk of MI. Morphine, meperidine, and polytherapy users each had an elevated risk of MI. However, these results could be partially or completely due to bias or confounding given the small increased ORs observed in this study.
The second study evaluated the association between opioid treatment and risk of type 2 diabetes mellitus (T2DM). After adjusting for confounders there was no increased risk for T2DM among those exposed to any opioid compared to nonusers (adjusted OR=1.03, 95% CI: 1.00-1.06). Nor was there an effect when we evaluated timing of opioid exposure, duration of use, and individual opioid types. These findings provide reassurance that there is no increased risk of T2DM associated with opioid treatment.
The third study examined the association between opioid treatment and risk of fracture. Current short-term opioid users had an increased fracture risk compared to nonusers. However, the risk decreased to the null for current long-term users and for recent or past users. Among current short-term users, there was a 2.75-fold fracture risk for those with one prescription (95% CI: 2.38-3.18), which decreased with increasing number of prescriptions. The findings were consistent for all fracture types including hip, humerus, and wrist sites, and the risk was observed for most opioid analgesics.
Since it is likely that use of opioids for chronic non-cancer pain will continue, this dissertation adds valuable safety information on this class of drugs, particularly for longterm use where there is a paucity of data.
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FAZZI, Debora. "CANNABINOID CB2 AND μ-OPIOID RECEPTORS SIGNALLING IN MICROGLIAL CELLS: POTENTIAL TARGETS TO INCREASE CLINICAL EFFICACY OF OPIOIDS". Doctoral thesis, Università degli studi di Ferrara, 2015. http://hdl.handle.net/11392/2388989.
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Among several pharmacological properties, analgesia is the most common feature shared by either
opioid or cannabinoid systems. In the nervous system, neurotransmission and neuroinflammation
are mediated by the endocannabinoid signalling system. Two subtypes of the mammalian
cannabinoid receptors, CB1 and CB2, have been identified. Opioids produce their pharmacological
effects by acting mainly through three types of receptors, namely μ, δ and κ. Anti-nociceptive
tolerance to opioids severely limits their clinical efficacy for the treatment of chronic pain
syndromes. It has been demonstrated that glia has a central role in the development of morphine
tolerance. Microglia, a specialized population of macrophages found in the CNS, are quiescent in
normal brain. However, after CNS injury these cells can be activated by cytokines produced by
infiltrating immune effector cells. Interestingly, receptors for opioids and cannabinoids are coupled
to similar intracellular signalling mechanisms leading to a decrease in cAMP production through
the activation of Gi proteins. Therefore, following the discovery that opioids and cannabinoids
produce not only similar biochemical effects but also similar pharmacological effects, the
interaction between these two classes of drugs has been extensively studied.
In the present study, at first we characterized the signal transduction pathways affected by CB2
receptors in quiescent and activated murine microglia. Our results demonstrated that CB2 receptors
stimulation, through MAPK pathway modulation, may promote anti-inflammatory responses in
activated microglia. Next, we investigated whether and how CB2 receptor stimulation affected
opioid actions on activated microglia. The results indicate that morphine increases PKCε expression
and activation and stimulates Akt pathway upstream of ERK1/2 and iNOS in activated microglia.
Furthermore, we found that morphine enhanced the release of IL-1β, TNF-α, IL-6 and of NO via μ-
opioid receptor-PKCε signalling pathway in activated microglial cells, mediating a
proinflammatory phenotype in mouse microglial cells. Interestingly, CB2 receptor stimulation
attenuated morphine-induced microglial proinflammatory mediator increases, interfering with
morphine action by acting on the Akt-ERK1/2 signalling pathway. Because glial activation opposes
opioid analgesia and enhances opioid tolerance and dependence, we suggest that CB2 receptors, by
inhibiting microglial activity, may be potential targets to increase clinical efficacy of opioids.
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Marques, Jenifer de Santana. "Efeitos da nalbufina e do tramadol após infusão contínua com fentanil em cães submetidos a osteotomia de nivelamento de platô tibial (TPLO)." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/10/10137/tde-16112015-151300/.
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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 µg/kg, seguido por 0,3 µg/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 ≥ 4, Glasgow ≥ 5 e/ ou Colorado ≥ 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 ±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±50 minutos no grupo NAL0,1, 220±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<br>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±1.2 years old and 34.7±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 µg/kg, following 0,3 µg/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 ≥ 4, Glasgow ≥ 5 and/or Colorado ≥ 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'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 ±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±50 minutes in NAL0.1 group, 220±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
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Walldén, Jakob. "The influence of opioids on gastric function : experimental and clinical studies." Doctoral thesis, Örebro universitet, Hälsoakademin, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-1762.
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Efter operation och anestesi får patienter ofta en negativ påverkan på magsäck och tarmar. Illamående och kräkningar är ett stort problem och många har svårt att komma igång med intag av föda och normal tarmfunktion då magsäcken och tarmarna ”står stilla”. Flera faktorer bidrar- bl.a. smärtan, det kirurgiska traumat och de läkemedel vi ger i samband med anestesin. Av de senare är opioider, d.v.s morfin och morfinliknande läkemedel, starkt bidragande. I detta avhandlings- arbete har opioiders effekter på magsäckens motilitet studerats. Med ett absorptionstest (paracetamolmetoden) studerades hos frivilliga hur opioiden remifentanil påverkar magsäckstömning och om kroppspositionen har betydelse för tömningshastigheten ut i tarmen. Remifentanil fördröjde magsäcks-tömningen och under pågående opioid behandling hade kroppspositionen ingen större betydelse, vilket det däremot hade under kontrollförsöken. Med samma metod jämförde vi hos patienter två anestesimetoder och studerade magsäcks-tömning direkt efter en operation. Ingen skillnad kunde påvisas mellan en opioidbaserad och en opioidfri anestesi, men inom respektive grupp var det en stor variation i magsäckstömning mellan individerna. Med en barostat studerades tonus i övre delen av magsäcken. Hos hälften av de frivilliga orsakade remifentanil en ökning av tonus och hos den andra hälften en minskning av tonus. Vidare undersöktes hos en grupp patienter opioiden fentanyls påverkan på den elektriska aktiviteten i magsäcken. Med en elekroga-strograf (EGG) registrerades de långsamma elektriska vågor som koordinerar muskelrörelserna i magsäcken. Hos hälften av de undersökta påverkades aktiviteten av fentanyl med en sänkt vågfrekvens eller upphörande av vågor, medan aktiviteten var opåverkad hos den övriga hälften. För att finna en förklaring till variationen gjordes genetiska analyser av genen för opioidreceptorn hos de undersökta i barostat och EGG studierna. Variationer i genomet, s.k. polymorfism, var inte associerad till utfallen i studierna. Studierna har visat på att opioider har en uttalad effekt på magsäckens motilitet och att den varierar kraftigt mellan individer. Polymorfism i genen för opioid- receptorn förklarade inte skillnaden mellan individer. Direkt efter operation bidrar sannolikt andra faktorer än anestesimetod till det variabla utfallet i magsäckstömning.<br>After anesthesia and/or surgical procedures, gastrointestinal motility is commonly impaired. The causes are multifactorial, with surgical trauma, pain and perioperative drugs playing a major role. This thesis explores opioid effects on gastric motility in healthy volunteers and patients undergoing surgery. Gastric emptying was studied by an absorption test (paracetamol method), and in healthy volunteers a remifentanil infusion delayed gastric emptying. Body position altered emptying during the control situations, but not during the remifentanil infusion. Further, two anesthetic methods were compared and no differences were found in immediate postoperative gastric emptying between a remifentanil/propofol based intravenous anesthesia and an opioid free inhalational anesthesia, although the interindividual variability was high. Proximal gastric tone was studied using a gastric barostat. An infusion of remifentanil caused two patterns of reaction regarding gastric tone, with half of the subjects increasing and half decreasing in gastric tone. Gastric myoelectrical activity was evaluated with electrogastrography (EGG), and a bolus dose of fentanyl caused a decrease in frequency of the gastric slow waves or disrupted this activity. However, the activity was unaffected in half of the investigated subjects. Analysis of polymorphisms (A118G and G691C) in the µ-opioid receptor gene was performed to find an explanation for the great interindividual variations seen in the barostat and EGG studies, but no association could be found. These studies have shown that opioids have pronounced effects on gastric motility with variable individual responses that are difficult to predict. Polymorphisms in the µ-opioid receptor gene could not explain the variations. Postoperatively, other factors might contribute more than opioids to the impairment in gastric motility.<br>ISSN 1652-4063
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Mazahery, Claire. "CD8+ T Cell Mediated Immunity is Disrupted by Ex Vivo and In Vivo Opioid Use." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1587376234022407.
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Louderback, Hunter. "AN ANALYSIS OF A MULTIVALENT HEROIN AND PRESCRIPTION OPIOID VACCINE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1458909859.
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Kompella, Sindura, Sylvester Olubolu Orimaye, Nigel Dsouza, et al. "Behavioral Correlates for Quitting Opioids among Opioid-Dependent Pregnant and Non-Pregnant Women of Childbearing Age in Rural Appalachia." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/31.
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Background: The opioid epidemic is particularly worrisome in the pregnant population, wherein concerns are raised about the health of a mother and her child, resulting in an alarming incidence and prevalence of Neonatal Abstinence Syndrome (NAS). The 2016 National Survey on Drug Use and Health (NSDUH) show the rate of illicit psychoactive substance use among the females aged 12 or older was 15.5% in the past year. Among pregnant women aged 15 to 44, 6.3% were illicit psychoactive substance users. In Tennessee, the number of hospital discharged NAS cases from 2002 to 2013 increased from 1.50 to 16.6 cases per 1,000 live births. This number is triple the national incidence of NAS cases over the same time period. Between 2013 and 2016, at least 52.5% of children diagnosed with NAS in Tennessee have had exposure to one prescription drug, while 27.2% were exposed to a combination of prescribed medications and illicit substances. We examined the behavioral correlates that determine the wish to quit opioids or not to quit opioids among opioid-dependent pregnant and non-pregnant women in rural Appalachia.
Methods: Ten women of childbearing age, whether pregnant or not, who were receiving prescribed opioids, were recruited to join the study. All the participating women were also receiving physician-managed Medication Assisted Treatment (MAT) therapy for the treatment of severe opioid use disorder, or are currently being prescribed an opioid medication. Study variables included age, Hamilton Depression Rating Scale (HAM-D), Visual Analogue Scale – Pain (VAS-P), the Modified Opiate Craving Scale (MOCS), the Visual Analog Commitment to Quit Opiates, the McGill Pain Index (MPI), prescriptions, tobacco and nicotine use, illicit substance use, the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES), and the Adverse Childhood Experience (ACE) questionnaire. The HAM-D, MOCS, MPI, and SOCRATES scores were log-transformed to approximate a normal distribution. Descriptive statistics and the Spearman’s rank correlation (with a 95% Confidence Interval) were conducted to examine significant behavioral correlates for quitting opioids.
Results: Descriptive statistics show that women with higher HAM-D and MOCS scores are not likely to express willingness to quit opioids. There is a statistically significant strong positive correlation of 0.679 (pppp
Conclusion: Women who recognize the need to quit opioids or are “taking steps” to quit are more likely to quit opioids. Women with high depression and pain scores are not likely to quit opioids. Non-opioid medications may reduce the number of opioid-dependent pregnant and non-pregnant women of childbearing age, and, in turn, lower the currently high incidence and prevalence rates of NAS.
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Lui, Wan Thomas, and 雷雲. "Biochemical events induced by the specific kappa-opioid receptor agonist, U50488H." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011345.
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McKeown, Stephen Carl. "A synthetic approach to novel morphine analogues." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283553.
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Arends, Rosalinda Helena Gerardus Petronella. "Pharmacokinetics and pharmacodynamics of opioid analgesics /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/7955.
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Sheng, Jianzhong. "Phosphoinositol/Ca2+ pathway in the cardiac k-opioid receptor : physiological role and alternations upon tolerance /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19616193.
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Heyman, Julius Scott. "Antinociceptive actions of central opioid delta receptors." Diss., The University of Arizona, 1989. http://hdl.handle.net/10150/184918.
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Opioids produce myriad effects, perhaps the most clinically relevant of which is the relief of pain. The understanding of the functions mediated by opioid systems is complicated greatly by the presence of several opioid receptor types. Understanding the functions associated with specific opioid receptors may lead to the development of receptor selective drugs which elicit only desirable effects. This dissertation addresses the possibility that supraspinal and spinal opioid δ receptors mediate and/or modulate thermal antinociceptive processes in the mouse. A number of approaches were utilized in parallel in this investigation which included: (1) the determination of the naloxone pA₂ in vivo against the opioid agonists morphine (μ), (D-Ala², NMePhe⁴, Gly-ol]enkephalin (DAMGO)(μ) and [D-Pen², D-Pen⁵]enkephalin (DPDPE)(δ); (2) the investigation of possible cross-tolerance between morphine and DPDPE; and (3) antagonism studies using N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-Oh, (ICI 174,864)(δ), β-funaltrexamine(β-FNA)(μ) and naloxonazine (μ₁). No differences were found in the apparent pA₂ values for naloxone against morphine, DAMGO and DPDPE at either supraspinal or spinal sites, but was demonstrated in the spinal cord. The antinociceptive effects of i.c.v. morphine and DAMGO were antagonized by β-FNA and naloxonazine, but not ICI 174,864. I.c.v. DPDPE antinociception was blocked by ICI 174,864, but not β-FNA or naloxonazine. Neither ICI 174,864 nor naloxonazine blocked the antinociceptive effects of i.th. morphine or DAMGO. ICI 174,864, but not naloxonazine, antagonized i.th. DPDPE antinociception. I.th. morphine, but not i.th. DPDPE antinociception was blocked by β-FNA. Co-administration of sub-effective doses of DPDPE and DAMA were shown to potentiate and attenuate, respectively, i.c.v., morphine antinociception. This potentiation was evident in naive and morphine tolerant mice, and was blocked by ICI 174,864. The modulatory effects of DPDPE and DAMA were blocked by β-FNA, but not naloxonazine. In contrast the supraspinal sites, i.th. DPDPE had no effect upon i.th. morphine antinociception. Collectively, the data demonstrate that supraspinal and spinal opioid δ receptors can directly mediate antinociception in the mouse. Additionally, supraspinal, but not spinal, δ receptors are also capable of indirectly modulating antinociceptive.
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Kawahata, Noriyuki. "The design and syntheses of novel peptidomimetic opioids /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9820877.
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Perrin-Ninkovic, Sophie M. "Syntheses of sterically constrained and diacylated peptidomimetic opioids /." Diss., Connect to a 24 p. preview or request complete full text in PDF formate. Access restricted to UC campuses, 2002. http://wwwlib.umi.com/cr/ucsd/fullcit?p3071007.
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Bossaer, John B., and Sarah T. Melton. "Max Dose Opioids: How High Can You Go?" Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etsu-works/2333.
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Learning Objectives: Describe the rationale for the belief that opioids have no maximum dose Describe the data supporting the rationale that high doses of opioids increase toxicity Describe the data supporting the rationale that high doses of opioids do not improve outcomes Identify potential safety concerns with patients taking high doses of opioids
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Pack, Robert P., Angela Hagaman, and Nicholas Hagemeier. "Forum hosts: Tennessee State Task Force on Opioids." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/1340.
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Jouvenel, Antoine. "Tolérance et hyperalgésie induites par la morphine : caractérisation de l’interaction physiopathologique entre MOR et FLT3." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT014.
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Bien que les opioïdes représentent la classe d’analgésique la plus efficace, les traitements de la douleur par les opioïdes présentent différents effets indésirables limitant leur efficacité. Le récepteur opioïde (MOR) exprimé par les neurones des ganglions dorso-rachidiens (DRG) est impliqué dans une partie de l’analgésie induite par la morphine ainsi que dans la tolérance (MIT) et l’hyperalgésie (MIH) induites par la morphine. Toutefois, les mécanismes moléculaires impliqués dans la MIT et la MIH sont sans cesse redéfinis. Les facteurs moléculaires essentiels impliqués dans la transduction du signal du MOR sont encore méconnus, empêchant le développement de thérapies permettant d’améliorer l’efficacité analgésique des opioïdes en évitant leurs effets secondaires. Récemment, notre équipe a démontré le rôle de FLT3 dans le développement et la maintenance des douleurs neuropathiques (NP) après lésion nerveuse. Au vu des mécanismes moléculaires communs entre NP et MIH, nous supposons que FLT3 exprimé par les neurones du DRG module l’analgésie morphinique en interagissant avec MOR. Nous avons découvert que MOR et FLT3 sont colocalisés au niveau du DRG et l’activation de FLT3 induit une MIT et une MIH au travers d’une interaction physique avec le MOR. Des approches in vitro ont révélé l’implication de voies signalétiques FLT3-dépendantes dans la régulation de l’effet inhibiteur de la morphine sur des cellules HEK293T co-exprimant MOR et FLT3. La délétion de FLT3 empêche l’apparition de MIT, de MIH et de potentiation à long terme au niveau spinal chez les murins sans altérer l’effet antinociceptif de la morphine. Le blocage extracellulaire de FLT3 par le BDT001 a permis de mettre en évidence une potentiation de l’effet analgésique morphinique tandis que le test du CPP a révélé un blocage des effets récompensants de la morphine. Sur un modèle de douleur chronique inflammatoire (CFA), le BDT001 peut prévenir la MIT et la MIH induits par le traitement chronique morphinique et est en mesure d’améliorer l’efficacité analgésique morphinique. Ensemble, ces résultats suggèrent une fonction essentielle de l’activité de FLT3 dans la modulation de l’activation du MOR et de ses fonctions<br>Despite opioids are the most effective class of analgesics, opioid pain medications have detrimental side effects limiting their analgesic efficacy. Morphine Opioid Receptors (MOR) expressed in Dorsal Root Ganglion (DRG) sensory neurons drive part of morphine analgesia and are involved in morphine-induced tolerance (MIT) and hyperalgesia (MIH). Although knowledge of the neural mechanisms underlying MIT and MIH has gradually advanced, the essential molecular factors involved in opioid receptor signal transduction are still unknown, which has prevented the development of efficient therapies to maximize and sustain opioid analgesic efficacy. Our team has previously shown that the Fms-Like Tyrosine kinase 3 receptor (FLT3) in DRG sensory neurons is critical for the development and the maintenance of neuronal hyperexcitability after nerve injury-induced Neuropathic Pain (NP). Since NP shares common mechanisms with MIH, we hypothesize that peripheral neuronal FLT3 modulates morphine analgesia by interacting with peripheral MOR. We found that MOR and FLT3 are colocalized and FLT3 activation induces MIT and MIH through a physical interaction with MOR in DRG neurons. Therefore, in vitro approaches revealed an involvement of FLT3-dependent signaling pathways in the regulation of morphine analgesia in HEK293T cells co-expressing MOR and FLT3. Deletion of FLT3 reduced MIT, MIH and long-term potentiation without altering morphine antinociception. In fact, extracellular blockade of FLT3 with BDT001 potentiated morphine analgesia while CPP paradigm revealed a blockade of morphine reward effects. On a pain model of chronic inflammatory pain (CFA), BDT001 prevented MIT and MIH development with chronic morphine administration and improved morphine efficacy during treatment. Altogether, these data suggest a trigger function of FLT3 activity on MOR peripheral activation and functions
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Gardner, Kevyn Danielle. "Synthesis of potential opioids based on the natural Pawhuskins." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/6106.
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Living organisms are capable of producing novel terpenoids with both remarkable ease and great selectivity. Many of these natural products exhibit significant biological activity useful for treatment of human diseases, but isolation of highly sought chemicals often results in only minute quantities. Consequently, extraction of these potential therapeutics from natural sources becomes an unrealistic method for obtaining enough material for a thorough biological evaluation, and so synthesizing these compounds becomes essential. Synthesis of terpenoids as potential therapeutics requires exceptional selectivity, especially when corresponding isomers elicit a contrasting biological response. The necessity for such selective syntheses along with the inherent structural complexities of terpenoids, often presents a number of significant challenges for the synthetic chemist.
Isolation of the terpenoids pawhuskins A–C and petalostemumol from Dalea purpurea was reported by Belofsky in 2004, and of the collected compounds pawhuskin A was found to exhibit the most significant activity in an opioid receptor assay in vitro. Natural pawhuskin A was extracted from “Purple Prairie Clover” in only a 39 mg quantity and therefore syntheses of the natural product along with several analogues were pursued. Two of the synthesized analogues demonstrated greater potency than pawhuskin A, and interestingly these two isomeric derivatives were found to be selective for two different opioid receptors. However, the synthetic route utilized to form these two derivatives was not very selective for either isomer, and thorough purification proved challenging. Ergo, an alternative approach was sought to ensure the purity of these potential therapeutics.
Parallel syntheses affording high selectivity for the key isomeric intermediates as well as a third regioisomer have been developed. The new isomeric intermediate also allowed the synthesis of two new analogues. This work is described in this report along with the formation of additional pawhuskin derivatives. The activity of these analogues as opioid receptor modulators also will be discussed.
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Nidey, Nichole Lynn. "Depression during the perinatal period: rurality, opioids and neurodevelopment." Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/7001.
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Depression during the perinatal time period is the most common medical condition related to pregnancy and childbirth. Based on previous research, this condition can have negative sequelae for mothers, their offspring, families and the community. Therefore, studies are needed to better understand risk factors and health outcomes among women with depression and the health outcomes among children born to mothers with depression.
We examined rurality as a risk factor for depression during the perinatal time period using data from the 2016 Pregnancy Risk Assessment Monitoring Survey (aim one). We found women who resided in rural communities, as defined by their individual states, had an increase in the odds of depression during the perinatal period by 21% (OR: 1.21; 95% CI 1.05,1.41) when compared to women who resided in urban communities. Based on the results from this study, future studies are warranted to examine mediators of this relationship to develop effective public health and clinical interventions.
Next, we examined the association between perinatal mental health conditions and postpartum prescription opioid use using private insurance claims data of women who delivered a baby in the state of Iowa 2005 to 2016 (aim two). Overall 38.63% of the women in our study filled at least one opioid prescription and 5.88% filled at least two prescriptions in the first 90 days postpartum. A significant interaction of having a perinatal mental health condition and delivery mode was observed for at least one (p=.04) and at least two opioid fills (<.0001). The presence of a mental health condition among women who delivered vaginally increased their odds of filling at least one opioid fill by nearly 50% (OR: 1.48 95% CI 1.35, 1.63) and by almost 20% (OR: 1.19 95% CI: 1.00, 1.43) among women with a cesarean delivery. A mental health condition significantly increased the odds of filling at least two opioid prescriptions among women with a vaginal or cesarean delivery by 2.78 (95% CI: 2.32-3.33) and 1.66 (95% CI: 1.40,1.98). Based on findings from this study, more research is needed to improve our understanding of the relationship between perinatal mental health and prescription opioid use.
Finally, the association between perinatal depression and attention deficit hyperactivity disorder (ADHD) use was examined using private insurance claims data from mother-child pairs from the state of Iowa (aim three). Children were born during years 2004 through 2015. In our study children born to mothers with perinatal depression were at an increased odds of ADHD diagnosis by 170% (OR: 2.70; 95% CI 2.06, 3.55). We also evaluated how timing of depression (during pregnancy vs. postpartum) influenced the odds of ADHD diagnosis. While we found children born to mothers with depression during pregnancy and postpartum had an increased risk of ADHD diagnosis, we observed children exposed to depression during fetal development had the greatest risk overall. Research is needed to better understand the mechanisms of risk between perinatal depression and ADHD risk in offspring. Additionally, due to low power we were not able to evaluate how treatment of depression during pregnancy or postpartum may influence childhood outcomes, therefore more studies are needed in this area.
Overall, findings from each study illustrate the importance of maternal mental health and how a mental health condition during the perinatal period can influence maternal and child health outcomes. Future prospective population-based studies are needed to better understand the etiologies of perinatal mental health conditions and how such conditions can influence outcomes for maternal and child health. Results from future studies have the potential to shift clinical practice to improve prevention and intervention in turn improving overall maternal and child health outcomes.
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Yu, Che-kwan. "Remifentanil induces delayed cardioprotection in the rat against ischaemic and reperfusion injury via Kappa, delta, mu opioid receptors and inducible heat shock protein 70." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39634395.
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Washburn, Stephanie Nicole. "Role of the opioid system in the behavioral deficit observed after uncontrollable shock." Texas A&M University, 2003. http://hdl.handle.net/1969.1/3993.
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Spinal cord neurons can support a simple form of instrumental learning that can
be used to assess behavioral potential (plasticity) within this system. In this paradigm,
subjects completely transected at the second thoracic vertebra learn to minimize shock
exposure by maintaining a hindlimb in a flexed position. Preexposure to uncontrollable
shock (shock independent of leg position) disrupts this learning.
Activation of opioid receptors seems to contribute to the expression of the
behavioral deficit observed after uncontrollable shock. Intrathecal application of
naltrexone, a nonselective opioid receptor antagonist, blocked the expression, but not the
induction, of the deficit. Treatment with nor-BNI, a kappa receptor antagonist, prior to
testing had a similar effect, whereas mu (CTOP) and delta (naltrindole) receptor
antagonists did not block the deficit. These findings suggest that prior exposure to
uncontrollable shock induces a kappa opioid mediated event that inhibits learning. The
current study examined the role of the kappa receptor in the behavioral deficit. Only
GR89696, a selective kappa-2 receptor agonist, inhibited learning. This impairment was
dose-dependent and, at the highest dose (30 nmol), inhibited learning for 96 hours.
However, GR89696 and uncontrollable shock did not interact in an additive fashion.
Instead, an intermediate dose attenuated the induction of the deficit. These findings
suggest that activation of kappa receptors, specifically the kappa-2 subtype, inhibit
instrumental learning and block the induction of the learning deficit. Both effects may
be linked to the inhibition of NMDA-mediated plasticity.
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Lu, Yu. "Ligands for the sigma receptor and the mu-opioid receptor." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/4961.
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Thesis (M.S.)--University of Missouri-Columbia, 2007.<br>The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on January 4, 2008) Includes bibliographical references.
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Yamamoto, Rinah T. "Glucose alters pain-response and other opiate-related behaviors /." Thesis, Connect to Dissertations & Theses @ Tufts University, 2005.
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Thesis (Ph.D.)--Tufts University, 2005.<br>Adviser: Robin B. Kanarek. Submitted to the Dept. of Psychology. Includes bibliographical references (leaves 79-91). Access restricted to members of the Tufts University community. Also available via the World Wide Web;
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Munro, Thomas Anthony. "The chemistry of Salvia divinorum /." Connect to thesis, 2006. http://eprints.unimelb.edu.au/archive/0002327.
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Wong, Tin-chun Gordon, and 黃田鎮. "Opioid cardioprotection in the perioperative period." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47657388.
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Many factors present during the perioperative period render patients susceptible in developing myocardial ischaemia reperfusion injury. Various mode of conditioning the heart against this type of injury has been discovered in animal models and involve powerful innate pathways that enhance cellular survival. These may be harnessed by applying a trigger either immediately before (preconditioning) or after (postconditioning) the lethal ischaemic injury, by physical or pharmacological means. Morphine was the first clinically used opioid shown to be cardioprotective but the intravenous dose required limited its use clinically. Remifentanil, an ultra-short acting opioid, was later also shown to be cardioprotective. A better understanding of how these opioids can protect the heart may enable the rational design of clinical regimens that best protect patients. The purpose of this thesis is to demonstrate and elucidate how these two agents provide cardiac protection.
I first demonstrated the clinical efficacy of remifentanil preconditioning in reducing the release CKMB, cardiac troponin I, heart type fatty acid binding protein and ischaemia modified albumin following cardiopulmonary bypass. As opioids cannot be omitted completely from patients undergoing cardiac surgery due to ethical considerations, I then used a well-established animal model of ischaemia reperfusion injury to complete the remainder of the studies. I demonstrated that remifentanil postconditioning was also effective in reducing myocardial infarct size, an effect mediated through the activation of kappa and delta opioid receptor subtypes, and in part triggered at the level of the myocardium. I then confirmed previous findings showing the efficacy of intrathecal morphine preconditioning using clinically relevant doses. In addition, I demonstrated that all three opioid receptor subtypes were involved. This effect was comparable to that achievable by classical ischaemic or intravenous morphine preconditioning and is mediated by central but not peripheral opioid receptor activation. Intrathecal morphine reduces the degree of myocardial apoptosis, alters the phosphorylation of Akt and the expression of endothelial nitric oxide synthatase and opens the potassium ATP channels. It also involves spinal adenosine receptors, similar to spinal morphine mediated analgesia. Intrathecal morphine preconditioning can be abolished by the interruption of autonomic nervous system function and blockade of calcitonin gene related peptide (CGRP) and bradykinin receptors. Intrathecal morphine postconditioning also has an infarct sparing effect. It also involves the activation of central opioid receptors and peripheral adenosine and CGRP receptors. Finally I demonstrated a pivotal role of central opioid receptor in remote preconditioning by showing that selective blockade of these receptors abolished the protective effects of remote but not classical ischaemic preconditioning.
Cumulatively, these results demonstrated the versatility of opioid mediated cardioprotection using morphine or remifentanil and the pivotal role of central opioid receptors in cardioprotection and revealed some of the mechanisms underlying these benefits. Not only does intrathecal morphine provide analgesia, it also generates signals that are transmitted through the autonomic nervous system resulting in changes in cellular function in the heart. This point to the possibility of a relationship between an organism’s intrinsic response to pain and the triggering of an innate organ protective response to ischaemia.<br>published_or_final_version<br>Anaesthesiology<br>Master<br>Doctor of Medicine
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Thorn, Simon Alexander. "Investigations into the peripheral and central actions of analgesics." Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238850.
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Nichols, Deborah Sue. "The periaqueductal gray : an examination of the distribution of opioid and non-opioid sites, their interaction, and the role of serotonin /." The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487332636476694.
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Pritchett, Kelley Carolyn Elisabeth. "Intra-nacc adenosine and its role in mediating palatable food intake interactions with striatal opioids /." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6103.
Full textAbstract:
Thesis (M.A.)--University of Missouri-Columbia, 2008.<br>The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed Aug. 21, 2009). Includes bibliographical references.
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Kam, Yuet Fong. "Regulation of c-jun n-terminal kinases by opioid receptors /." View Abstract or Full-Text, 2002. http://library.ust.hk/cgi/db/thesis.pl?BICH%202002%20KAM.
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Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2002.<br>Includes bibliographical references (leaves 83-103). Also available in electronic version. Access restricted to campus users.
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Zhang, Weimin. "Cardiac k-opioid receptor : multiplicity, regulation, signal transduction and function /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19588999.
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Xiaochun, Yu. "Negative modulation of B-adrenoceptor by K-opioid receptor in the heart : signaling mechanisms and clinical significance /." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21415377.
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