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Thesis advisor: Marius Stan / This thesis explores America's Opioid addiction crisis through a philosophical lens, arguing for a need to adopt a national mandatory rehabilitative approach for the sake of maintaining our country's cultural ethos grounded in freedom and the subsequent capacity to flourish as a human being. It proceeds in four chapters: the development of our cultural ethos through an analysis of John Locke and J.S. Mill, the history of the opioid addiction crisis and development of the two dominant addiction theories, America's current measures to tackling the crisis, and the proposal of a new approach that recovers addicts' freedom and ability to flourish. The work concludes by arguing for the importance of using philosophical principles and interpretations to guide problem solving and tackling current crises. / Thesis (BA) — Boston College, 2023. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Philosophy.

Opioid Use Disorder is known to have a heritable component, but the genetics underlying this heritability are not well understood. Inbred laboratory mice provide a stable genetic platform useful for interrogating the genetic component of specific opioid related behaviors, with the goal of identifying novel biology underlying opioid phenotypes. In this work we used inbred mice, leveraging both the near isogenic nature of substrains and the strain-specific inheritance of ancestral haplotypes, to explore the genetics of opioid phenotypes. Through these studies we found 1) Robust, female-specific increases in oxycodone state-dependent reward learning and whole brain concentrations of the oxycodone metabolite oxymorphone in BALB/cJ vs BALB/cByJ substrains. Oxymorphone is a full agonist at the mu opioid receptor, with a higher potency and efficacy than oxycodone, and thus, increased brain oxymorphone could enhance state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. Cis-expression QTL analysis (eQTL), exon-level eQTL analysis, liver and brain proteomics identified Zhx2 as candidate underlying these differences. 2) In a study of ancillary phenotypes, BALB/cByJ mice showed enhanced sensitivity to thermal nociception and mechanical stimulation and decreased brain weight versus BALB/cJ. We identified a QTL on chromosome 13 for hot plate sensitivity and a QTL on chromosome 5 for brain weight. Cis-eQTL mapping identified H2afy and spliceome analysis revealed differential H2afy exon usage. Whole brain proteomics further supported H2afy as a candidate gene for thermal nociception and identified Acads as a candidate for reduced brain weight. 3) Using a panel of 29 inbred mice we assessed behavioral variation and associations within opioid sensitivity, reward, antinociception, and dependence. We identified very little correlation between measures, suggesting distinct genetic components regulating theses facets of OUD. This study is preliminary to GWAS analysis and identification of loci underlying phenotypic variation. In summary, inbred mice, combined with a multi-omic approach, provide a powerful tool to identify genetic loci and candidate genes underlying complex behaviors. Future studies will validate Zhx2 and H2afy through reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains and involve GWAS analysis using oxycodone strain survey data.

Thesis advisor: Lisa Wood Magee / Background: Chronic cancer-related pain is a considerable problem in cancer survivors. The incidence of chronic pain in cancer survivors is nearly double the rate in the general population. Chronic cancer-related pain reduces quality of life and results in higher healthcare utilization. Due to a lack of alternative treatments, the management of chronic cancer-related pain relies on a biomedical model, with opioids being the cornerstone of cancer-related pain management. As concerns about the risks of long-term opioid therapy rise, there is a need to understand the factors that influence chronic cancer-related pain experience. This manuscript dissertation aims to answer the overarching question, “What are the unique factors that inform the chronic cancer-related pain experience in cancer survivors?” Methods: First, an integrative review aimed to examine the evidence of long-term opioid use in cancer-survivors. Next, a qualitative study using descriptive phenomenology was conducted to develop a deeper understanding of the daily lived experience of chronic cancer-related pain. And finally, a prospective cross-section quantitative study was completed to quantify the contribution of unique cancer-specific factors to the chronic cancer-related pain experience in cancer survivors. Results: The integrative review shed light on the biopsychosocial factors associated with the transition to long-term opioid therapy (LTOT), including the role of cancer type, medical comorbidities, mental health diagnoses, and socioeconomic factors. No studies examined pain severity, pain interference, or cancer-specific psychosocial factors in cancer survivors prescribed LTOT. Second, cancer survivors describe living with chronic cancer-related pain as the cost of survival. Yet, their suffering was often invisible to others. The role of opioids in chronic cancer-related pain leads to strained communication with clinicians and the need to self-navigate a treatment plan characterized by ‘trying everything’. And finally, select cancer-specific psychosocial factors explained relatively little variance in the pain experience compared to non-cancer specific factors of multisite pain and pain catastrophizing. Conclusions: The constellation of the finding from this body of work demonstrates unique factors that inform the chronic cancer-related pain experience in cancer survivors, and several areas of overlap with other chronic pain syndromes. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

BACKGROUND: Many patients face chronic pain, which can be debilitating and dramatically impair patient's quality of life. These patients often seek treatment from their primary care physicians, who may utilize a wide range of options to manage their chronic pain, including opioids. Opioids provide analgesia while potentially leading to other adverse effects, including misuse, addiction and overdose. Therefore there is a need for clinicians to develop safe opioid prescribing practices. This has been recognized by the development of national guidelines and recommendations to improve the training and education of physicians in this domain. However, a gap in medical education and training for safe opioid prescribing skill exists, creating physicians who may feel ill prepared to treat this patient population. To remedy this problem, an educational intervention was designed that utilized a didactic session with or without an immediate or delayed observed structured clinical exam (OSCE) to improve safe opioid prescribing skills among internal medicine residents at an academic medical center. The specific aims of this thesis are to understand both quantitative and qualitative impacts of this educational intervention, specifically to describe participant characteristics, quantitatively evaluate within and between group changes at 8-months in safe opioid prescribing knowledge, confidence and self-reported practices and qualitatively describe participants' experience of the OSCE as a learning tool. METHODS: Using a quasi-experimental design, 39 internal medicine residents were assigned to either a control or intervention groups. The intervention groups received a didactic session alone, a didactic session and immediate OSCE or a didactic session and a delayed OSCE. Participants were surveyed at baseline, 4- and 8-month follow-up to assess their safe opioid prescribing knowledge, confidence, and self-reported practices. RESULTS: Participants in the didactic followed by immediate OSCE group significantly improved both within group confidence and practices at 8-month follow-up. Additionally, participants in this group improved their confidence at 8-month follow-up significantly compared to the control group. Participants from the other educational intervention groups (didactic followed by delayed OSCE and didactic only) also saw improvements in confidence and practice, but the effect was not as robust. OSCE participants found the OSCE to be a useful learning tool and both participants in the immediate and delayed OSCE groups highlighted the need to receive the didactic session immediately prior to the OSCE session. DISCUSSION: Despite many barriers in safe opioid prescribing facing internal medicine residents including limited faculty mentorship and difficult inherited patients, this educational intervention still improved their safe opioid prescribing knowledge, confidence and practice. The use of OSCEs as an education tool is an innovative approach to develop clinical skills and can be adapted in a variety of ways to accommodate institutional and learners' needs. / 2017-05-01T00:00:00Z

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Background: Opioid use disorder (OUD) has been an increasing concern in Canada as mortality rates continue to rise. Though OUD treatments, such as methadone maintenance treatment (MMT), reduce its burden, they could potentially cause harm due to OUD’s variance in severity and presentation across individuals. It is hypothesized that genetic variants such as single nucleotide polymorphisms (SNPs) could predispose patients to respond differently to MMT. In addition, sex differences have been observed in opioid use patterns, treatment outcomes, and genetic make-up. As such, this thesis aims to identify significant SNPs associated with treatment outcomes in genome-wide association studies, and test biologically relevant SNPs with MMT outcomes of interest, while highlighting sex differences. This is achieved through a systematic review protocol, a systematic review, and a candidate gene study. Methods: A protocol was prepared for the planning of the first ever systematic review of genome-wide significant findings of medication-assisted treatment outcomes for OUD patients. The systematic review assessed the literature findings and study qualities, narratively summarizing significant associations. Next, a candidate gene study analyzed the association between SNPs in OPRM1 and CYP2B6 genes, and continued opioid use, relapse, and methadone dose within an ancestrally European sample (n=1226). Sex-stratified and sex-interaction analyses were also conducted. Results: The systematic review included 5 studies and qualitatively assessed 43 unique genetic variants. The candidate gene study showed no significant associations between the selected OPRM1 and CYP2B6 SNPs and outcomes of interest. While no significant differences between the sexes were observed, rs73568641 and rs3745274 showed near significance associations in only one sex, females, and males, respectively. Discussion: Through the study of genetic variants associated with treatment outcomes in the literature and our sample of ancestrally European individuals on MMT, we were able to highlight gaps in pharmacogenetics research and identify areas of focus for future studies. / Thesis / Master of Science (MSc) / Recently, opioid use disorder (OUD) has been declared a national crisis in Canada. OUD treatments are helpful in reducing opioid use and adverse events. However, their dosing and metabolism in patients can impact continued opioid use, relapse, or treatment dose changes. Due to the variability in response between individuals, there might be a genetic basis to treatment outcomes. This thesis explores which genetic variants reported in previous studies are involved in OUD treatment outcomes. Then, it tests select genetic variants in OPRM1 and CYP2B6 genes to see if they are linked to specific outcomes in an Ontario population and tries to identify if these associations differ by sex. No significant associations were found, though associations in males and females had near-significant results in one sex but not the other. Despite suggesting sex’s possible involvement in treatment outcomes, more research is necessary to confirm these findings.