The type of cancer pain management used may have an effect on the quality of life (QOL) of cancer patients. Researchers have determined that cancer patients are inadequately treated for pain and pain management is an essential determinant of patient survivability and QOL. Numerous clinical studies have been accomplished concerning opioid administration and noncancer and cancer pain management exist. Previous studies have examined the relationship between cannabinoid products, noncancer pain, cancer pain, and related QOL for patients but have not focused on the QOL of cancer patients while also moderating for gender. These relationships were investigated using the health belief model. The cancer pain management treatments (opioids and/or marijuana [cannabis]) and QOL, measured with World Health Organization Quality of Life Survey (WHOQOL-BREF), of 236 cancer patients were analyzed using analysis of variance (ANOVA), planned contrasts, post hoc tests, and moderated ANOVA (PROCESS tool) in the causal-comparative research. Research findings indicated significant benefit in cancer patient physical and psychological QOL in participants using marijuana when compared to participants using opioids and physical QOL for participants using marijuana over participants using both opioids and marijuana combined. Enhanced pain management options for cancer patients in order to reduce opioid side effects, increase pain treatment effectiveness, and improve patient QOL could yield positive social change. Growing rates of opiate addiction, abuse, and mortality are public health concerns and cannabis may be an effective pain treatment to reduce these social costs. This research may be of use to legislators considering rescheduling marijuana to less than Schedule I.

Women in Central Appalachia represent a significant proportion of those engaging in problematic patterns of opioid use, which is concerning given the limited available services in the region and gender specific treatment barriers. This investigation seeks to understand the role of mental health and substance use symptoms among incarcerated Central Appalachian women and build on the conceptual model of substance use treatment utilization purposed by Leukefeld and colleagues (1998). Data for this study was drawn from a larger longitudinal investigation (NIDA 1R01-DA033866) and baseline data collected during initial interviews was analyzed. The sample included 400 women incarcerated at one of three central Appalachian jails. Bivariate analyses determined significant relationships between symptoms of depression, anxiety, trauma and substance use. Binary logistic regression was used to assess the factors influencing treatment utilization. The overall multivariate model of treatment utilization with eight factors (income, overdose history, injection drug use, entered detox, attended self-help groups, substance use problems, number of children, and no way to get to their provider) significantly improved the prediction of treatment utilization. Implications of this study highlight the importance of continued interventions at the individual, community, and policy level.

Background: The UK has a high prevalence of opioid use; although this population is ageing. The use of opioids is associated with excess mortality and offending and so remains a priority for public health and criminal justice policy. Aims: There are two broad aims for this thesis: firstly, to quantify excess mortality and offending associated with opioid use, and secondly, to assess the effectiveness of drug treatment at reducing these harms. Methods: Cohorts were extracted from the Drug Data Warehouse (DDW); a collection of case-linked drug treatment and criminal justice datasets, linked to mortality and offending records. Excess mortality was quantified by comparing deaths observed in a cohort of opioid users to that expected from the general population, matched on age and gender. The association between opioid use and offending was quantified using a cohort of drug-tested offenders, comparing those who tested positive for opiates and/or cocaine with those who tested negative. The effectiveness of treatment was calculated using two separate measures: the effect of being in treatment, using a time-dependent treatment exposure, and the effect of initiation to treatment. In the latter analysis, the approach was to use observational data to emulate randomised controlled trials, in an attempt to better establish the causal effect of treatment initiation. Confounding bias, when treatment exposure is time-dependent, was discussed, using path diagrams and simulations. Results: The opioid-user cohort extracted from the DDW is the largest assembled to-date (N = 198,247). Controlling for age and gender, opioid use was associated with considerably higher mortality and offending than non-users. Older age was a risk factor for drug related poisoning (DRP) death. The association with offending was considerably higher for females. Compared to periods out of treatment, the risk of a fatal DRP was lower during pharmacological treatment but not during periods where the user received psychological support only. Simulations illustrated that when treatment exposure is time-dependent, analyses may be biased in the presence of confounding by a time-dependent variable. Among opioid-using offenders, there was little support for the hypothesis that initiation to drug treatment was effective at reducing the risk of future acquisitive offending. Conclusion: In England and Wales, there remain considerable excess mortality and offending associated with opioid use. Age and gender have an important influence on these relationships. Treatment (as delivered in England and Wales) appears effective at reducing the risk of a drug-related death, provided there is a pharmacological component, but not at reducing the risk of future offending.

There is a large gap between contemporary evidence-based remedies for pain control and what is offered to Ukrainian patients with pain. Having thousands of people needlessly suffer from avoidable pain forces a consideration of 1) what prevents from their access to pain relief, 2) are their human rights being violated and 3) how can the situation be improved. In order to identify the obstacles to adequate pain management in Ukraine I collected evidence using two methods. First, I designed a questionnaire for the Ukrainian doctors, received approval from the University of Ottawa Ethics Board, distributed the questionnaire among potential responders and then organized the obtained results. Second, I did an extensive literature review to provide evidence from the patients. Then I analysed the provisions of Ukrainian domestic and international legislation as well as the available case law to find out if the human rights of Ukrainian patients and doctors are being violated by denial of adequate pain relief. According to my findings, the barriers to pain control in Ukraine are multidimensional and interdependent. They cause violations of human rights, which are not being effectively defended through the courts of Ukraine. These findings call for a more constructive approach to the development of the Ukrainian health law and policy, which I offer in this thesis.

Chronic pain is a significant healthcare problem. It is disabling and diminishes quality of life. Opioids, such as morphine, remain a primary pharmacologic management for chronic pain. Opioids act at mu opioid receptors (MOPr) in the rostroventral medial medulla (RVM) to produce their analgesic effect. The RVM is a critical relay in pain inhibitory and facilitatory pathways of pain modulation. Furthermore, chronic inflammatory pain, produced by CFA hindpaw injection, leads to adaptive changes in the RVM that change the balance of these pathways and increase the potency of opioids. MOPr are known to produce their effects via Gi/o proteins. Pretreatment of several pain modulatory regions with pertussis toxin (PTX) effectively attenuates the antinociceptive effects of MOPr agonists, such as DAMGO. In the RVM, PTX effectively reduced DAMGO stimulated GTPãS binding in uninjured rats. However, despite their effective inactivation of Gi/o proteins, PTX did not diminish the antinociceptive effects of DAMGO in the RVM of uninjured rats. In contrast, in rats with a chronic inflammatory injury, PTX completely abolished the antinociceptive effects of DAMGO. These results suggest a transition from Gi/o independent to Gi/o dependent mechanisms following CFA treatment. In addition, the anti-hyperalgesic effects of DAMGO were not inhibited by PTX, suggesting that DAMGO produces anti-hyperalgesia and antinociception by different mechanisms. In the RVM, MOPr are present both postsynaptically and presynaptically. Postsynaptic MOPr are thought to produce antinociception by activating GIRK channels, resulting in hyperpolarization and inhibition of pain facilitatory neurons. Indeed, inhibition of GIRK channels in the RVM, via microinjection of tertiapin-Q, attenuated the antinociceptive effects of DAMGO in uninjured rats, providing the first behavioral evidence that MOPr agonists produce analgesia via this proposed mechanism. Interestingly, however, tertiapin-Q did not block the anti-hyperalgesic effects of DAMGO, nor did it diminish the antinociceptive effects of DAMGO in the contralateral hindpaw of CFA treated rats. Furthermore, these differential effects of tertiapin-Q in the uninjured and injured rats are not the result of transcriptional down regulation of GIRK channels in the RVM. Finally, tertiapin-Q alone in the RVM produced a modest antinociception in uninjured rats, providing the first evidence of constitutive GIRK channel activity in the RVM and demonstrating a role for these in pain modulation. Presynaptic MOPr are thought to produce antinociception by decreasing GABA release onto pain inhibitory neurons. Indeed, microdialysis studies demonstrated that levels of GABA release were decreased in response to DAMGO perfused into the RVM, as well as to high potassium after perfusion of DAMGO. However, they were not decreased in rats after CFA treatment. This suggests that chronic inflammatory injury alters the presynaptic actions of MOPr agonists in the RVM. Interestingly, levels of GLU release where not altered by DAMGO in uninjured or injured rats. Moreover, basal levels of GLU and GABA were also unaltered by CFA treatment. In conclusion, although MOPr mediate their antinociceptive effects in other pain modulatory regions via Gi/o proteins, this is not the case in the RVM during an uninjured state. However, MOPr-induced antinociception transitions from Gi/o independent to Gi/o dependent mechanisms after CFA treatment. Additionally, these results support both the presynaptic and the postsynaptic postulates by which MOPr agonists are thought to produce their analgesic effects. However, although CFA treatment alters the activity of neurons in the RVM and promotes changes that result in an enhanced anti-hyperalgesic and antinociceptive response to DAMGO in the RVM, neither the postsynaptic nor the presynaptic mechanism, in isolation, seem to account for this enhancement.

Introduction: The prevalence of opioid abuse has increased throughout Northeast Tennessee. Subsequently, more infants are born drug-exposed or with Neonatal Abstinence Syndrome (NAS). According to the Tennessee Department of Health, hospitalizations for deliveries with maternal substance abuse tripled in Tennessee between 1999 and 2011. During this period, the inpatient hospitalization rate for NAS increased 11-fold. In 2017, there were 163 NAS cases reported in Northeast Tennessee. Depending on intrauterine and environmental exposures, there may be differences in health, growth, behavior, and development in infants. Our goal was to assess and explore those differences to help update education and care recommendations for pediatric primary care clinics. Methods: This cross-sectional study was set in a Northeast Tennessee pediatric clinic. 120 patients seen for a newborn visit between June 30, 2013 and July 1, 2014 were randomly selected. An additional sample of all infants with suspected drug exposure was identified for this period based on diagnosis codes. In total, 99 infants had no drug exposure and 62 were drug-exposed. An 83-item chart abstraction template was developed. Data was analyzed by SPSS. The chi-squared test and Mann-Whitney U test were used, with a critical value of p<0.05 to determine significance. The Bonferroni correction was applied to account for multiple comparisons. The research protocol was reviewed and approved by the Institutional Review Board of East Tennessee State University. Results: Of the 120 charts initially selected, 3.33% of infants were exposed to buprenorphine, 1.67% to methadone, 0.83% to marijuana, 0.83% to cocaine, and 1.67% to tobacco, 8.33% to benzodiazepine, and 1.67% to barbiturates during gestation. In total, 18.33% of infants had any drug exposure, 10.00% to any opiate, and 3.33% had a documented diagnosis of NAS in their chart. Prenatal drug exposure was significantly associated with multiple demographic factors as well as pediatric respiratory, behavioral, gastrointestinal, infectious disease, and cardiac conditions. Conclusions: Prenatal drug exposure was significantly associated with multiple pediatric complications. This illustrates the significance of addressing the increased incidence of prenatal drug exposure in Northeast Tennessee. Future multivariate analyses will attempt to control for potential confounders. This analysis is retrospective and exploratory, and any associations should be confirmed with a prospective study. A weakness of this study includes potential under-diagnosis of drug exposure and NAS due to lack of documentation in the EHR. Additional research will include further comparison of maternal and infant complications in drug-exposed and non-exposed infants. This will allow for a better understanding of the risks associated with maternal drug exposure. Findings from these research projects will be used to inform clinical initiatives for NAS in Northeast Tennessee.

1 ABSTRACT In this Thesis, we studied properties of μ-, δ-, and κ-opioid receptors in lymphocytes isolated from rat spleen. This splenocytes were exposed to mitogen concanavalin A or opiate morphine and cultivated for 48 hours. Under physiological conditions, level of opioid receptors in immune cells is very low. Due to various factors such as presence of opioids, mitogens, long-term exposition to stress, expression of these receptors can be amplified. In this study we demonstrated, that concanavalin A causes up-regulation of μ-, δ- and κ-opioid receptors in lymphocytes isolated from rat spleen. In control cells no significant signal of μ- or δ-receptors was observed. In contrast, κ-opioid receptors were detected already in control cells. Concanavalin A stimulation caused a 2.4 - fold increase of these receptors. In lymphocytes treated with morphine only μ-opioid receptors were up-regulated, whereas in control cells, there was no signal for these receptor type. δ-opioid receptors were not detected in control or morphine treated cells. κ-opioid receptors were determined in control and also in morphine affected lymphocytes but the amount of these receptors wasn't changed by morphine. Detection of μ-, δ- and κ-opioid receptors using Western blot technique in lymphocytes isolated from rat spleen, that were...

Opioid addiction is a serious national crisis impacting public health. Naloxone is a potent opioid antagonist administered to reverse the effects of opioid overdose. It is currently administered as an intravenous, intramuscular, subcutaneous injection and intranasal spray. The short duration of action of naloxone results in requirement of frequent re-dosing, especially in cases of larger overdoses, which may impact successful outcomes, especially when drug administration is provided by non-medical personnel as in case of intranasal sprays. These weaknesses necessitate the development of a non-injectable dosage form that has a rapid onset and extended duration of action. Delivery of drugs via skin is an attractive alternative that provides these benefits. Our study aimed to assess the effect of microneedles on the amount and lag time of permeation of naloxone across skin. In vitro permeation studies were performed to assess the delivery of naloxone through dermatomed porcine ear skin using Franz Diffusion cells. The donor and receptor chamber of the cells contained the drug solution and phosphate buffered saline, respectively. The receptor was sampled until 6 h and analyzed using HPLC. The permeation of naloxone across intact (passive) and microneedle-treated (Dr. Pen™ Ultima A6) skin was evaluated. Two microporation conditions with donor concentration of 10 mg/mL were investigated: needle lengths (500 µm and 250 µm) for 1 minute and 500 µm needle length for different durations (1 and 2 minutes). Further, the effect of application of different naloxone concentrations (10 and 20 mg/mL) on skin treated with 500 µm microneedles for 2 minutes was also tested. One-way ANOVA was applied to ascertain statistical difference between the different test groups. The amount of passive permeation after 6 h and lag time for naloxone was observed to be 8.251.06 µg/cm2 and88.58 ± 3.05 min, respectively. One minute treatment with 500 µm needles significantly enhanced the permeation to 463.24 ± 30.21 µg/cm2 and reduced the lag time to 15.90 ± 1.63 min (p0.05). Microneedles were found to enhance the permeation of naloxone across skin. The observation of quick onset of drug permeation in the in vitro settings is very encouraging and future studies would focus on developing a microneedle patch for quick onset and extended drug release.

Drug-associated stimuli trigger craving and relapse in addiction. Murine morphine conditioned place preference (CPP) was used to model learning of opioid associations. We examined how morphine and learning interact to alter neuron morphology in the nucleus accumbens (NAc) core and shell after acquisition and extinction of CPP. Conditioning with morphine dose-dependently increased place preference compared to saline. In comparison to those from saline conditioned and morphine non-conditioned controls, neurons from the NAc core of morphine conditioned mice had increased dendritic complexity, as defined by increased dendritic length, number, and Sholl intersections. This effect is due to the combination of morphine and learning, which is different from effects of morphine or conditioning alone. Morphine administration without conditioning was associated with increased spine density in the core, which was reversed by CPP acquisition. Control conditioning with saline produced no morphology changes. Morphine CPP extinction was associated with decreased dendritic complexity, reversing the increased complexity seen after acquisition. Mice that extinguished CPP had similar dendritic complexity to saline conditioned mice, in terms of dendritic count and intersections, but less dendritic complexity than non-extinguished mice that retained CPP. Since dopamine release imbues salience to stimuli that coincide with drug use, and the dopamine D1 receptor mediates CPP acquisition, we tested the effect of SKF81297 D1 receptor agonist on CPP extinction and associated accumbal neuron morphology. SKF81297 (0.8 mg/kg) injected after each extinction training session impeded extinction, and produced increased dendritic complexity compared to controls. SKF81297 may have sustained conditioned associations, disrupted consolidation of extinction, and/or disrupted the decline in dopamine levels that may occur throughout extinction sessions. We hypothesize that changes occurred in the NAc core because this region mediates how stimuli and drug effects direct motor action. Since D1 receptors oppose extinction of drug-cue-induced behavior, they play a role in reinforcing opioid addiction. Acquisition and extinction may be opposite processes in the brain, as in behavior. Extinction may include some reversal of acquisition learning as well as being new learning with its own pathway. Interventions that target D1 receptors or that selectively reduce NAc core dendritic complexity may contribute to opioid addiction treatment.

No description available.