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<p>The opioid epidemic is an ongoing public health crisis in the United States (US). Although many treatment options exist for opioid use disorder (OUD), including evidence-based counseling, medications, rehabilitation programs, and support groups, access to care is a significant barrier. Pharmacists can play an important role in increasing patient access to OUD care; however, insufficient training is a well-documented barrier. Integrating comprehensive training into Doctor of Pharmacy coursework is a practical approach to preparing pharmacists to provide appropriate OUD care in a variety of practice settings. A shared OUD curriculum is one strategy to facilitate the integration of comprehensive training into Doctor of Pharmacy coursework.</p> <p><br></p> <p>My current research aimed to collect data from four key stakeholder groups – Doctor of Pharmacy program faculty, community pharmacists, multidisciplinary professionals, and patients experiencing OUD – to inform a shared OUD curriculum through a convergent, parallel, mixed methods study design. Specifically comprising this thesis are the quantitative findings from telephone surveys with Doctor of Pharmacy program faculty (“Study One”) and community pharmacists (“Study Two”); qualitative findings from multidisciplinary professional focus groups and patient interviews, as well as synthesized findings across quantitative and qualitative data sources, will be reported in future publications. Collectively, the results presented in this thesis provide a “snapshot” of the current pharmacy landscape with respect to the OUD education delivered to student pharmacists and opioid-related practices in community pharmacies.</p> <p><br></p> <p>The findings from Study One and Study Two indicate that OUD education in Doctor of Pharmacy programs and pharmacist-provided opioid interventions are inconsistent at best. The three main areas identified as needing future emphasis were: (1) the disease model of addiction and accompanying stigma of OUD; (2) harm reduction-, prescription-, screening-, and resource referral-related opioid interventions; and (3) skills-based, experiential education (vs. didactic education) for opioid intervention delivery and communication techniques. A shared OUD curriculum was of interest to faculty and is a viable solution to addressing OUD education gaps in Doctor of Pharmacy programs. Once qualitative data analyses are completed and findings from all four stakeholder groups are synthesized, development of the proposed shared OUD curriculum will commence.</p>

Kappa opioid receptor (KOPR) is involved in many physiological functions and pharmacological responses such as analgesia, anti-pruritic effect, sedation, motor incoordination and aversion (Simonin et al., 1998; Liu-Chen, 2004). The cellular mechanisms following activation of KOPR involve in part Gi/o protein-dependent pathways (Law et al., 2000). Following KOPR activation, the receptor is phosphorylated and arrestins are recruited. Arrestins mediate agonist-dependent KOPR desensitization, internalization and down-regulation (Liu-Chen, 2004). In recent years, arrestins were found to initiate arrestin-dependent downstream signaling. Thus, agonist-promoted KOPR phosphorylation plays a pivotal role in KOPR regulation and signaling. Previous studies from our lab showed that in Chinese hamster ovary (CHO) cells stably transfected with the human KOPR (hKOPR), U50,488H induced phosphorylation (Li et al., 2002a); however, sites of phosphorylation were not determined. Using LC-MS/MS, our lab recently identified four residues (S356, T357, T363 and S369) to be the sites of U50,488H-promoted phosphorylation in the mouse KOPR (mKOPR) stably expressed in N2A cells (Chen et al., 2016). Antibodies were generated against phosphopeptides and purified and three antibodies were found to have high specificity for the mKOPR phosphorylated at S356/T357, T363 and S369, respectively (Chen et al., 2016). Our lab previously showed that while U50,488H promoted robust hKOPR phosphorylation and internalization, etorphine induced little phosphorylation and internalization, although both were potent full agonists in enhancing [35S]GTPγS (Li et al., 2002a; Zhang et al., 2002; Li et al., 2003). Etorphine caused lower levels of KOPR phosphorylation at all the four residues than U50,488H by immunoblotting with the phospho-specific antibodies (Chen et al., 2016). Using the SILAC (stable isotope labeling by amino acids in cell culture) approach, we have found that compared to etorphine, U50,488H promoted higher levels of single phosphorylation at T363 and S369 and double phosphorylation at T363+S369 and T357+S369 as well as triple phosphorylation at S356+T357+S369 (Chen et al., 2016). These results indicate that an above-threshold phosphorylation is required for KOPR internalization. It has been reported that KOPR is involved in neuronal differentiation and neurogenesis. In the first chapter, I focused on whether there are differences in the mechanisms underlying neurite outgrowth induced by U50,488H and etorphine. In the chapter 2, mechanisms of KOPR phosphorylation were characterized in detail using phospho-specific KOPR antibodies. Protein kinase C was found, for the first time, to be involved in agonist-promoted KOPR phosphorylation. The roles of PKC in behavioral effects induced by KOPR agonists in mice were examined. For the chapter 1, in Neuro2a mouse neuroblastoma cells stably transfected with the hKOPR (N2A-3HA-hKOPR), U50,488H robustly induced neurite outgrowth, but etorphine caused outgrowth to a much lower extent. G protein-dependent pathway was found to be involved in the actions of both agonists, but β-arrestin-dependent pathway was not. Inhibition of ERK1/2 phosphorylation decreased neurite outgrowth promoted by both agonists, indicating the roles of MAP kinase cascades in KOPR agonist-induced neuritogenesis. In contrast, β-arrestin2, 14-3-3ζ, GEC1 and Rap1 are not involved in U50,488H- or etorphine-promoted neurite outgrowth. Thus, the two agonists appear to share the same signaling pathways and the difference between two agonists is likely due to the lower efficacy of etorphine. For the chapter 2, U50,488H caused phosphorylation of the mKOPR at S356, T357, T363 and S369 in N2A cells stably transfected with FmK6H (FmK6H-N2A cells). NorBNI abolished U50,488H-induced KOPR phosphorylation at all four residues. GRKs (GRKs2, 3, 5 and 6) and PKCs were involved in U50,488H-mediated KOPR phosphorylation. In addition, PKC also participated in agonist-independent KOPR phosphorylation. This is the first time that PKC was shown to be involved in agonist-induced KOPR phosphorylation. We found that U50,488H caused KOPR phosphorylation at T363 and S369 in the mouse brain and PKC participated in phosphorylation of S369, but not T363, by using the PKC inhibitor chelerythrine (CHL). Thus, we further characterized effects of PKC inhibition on KOPR-mediated behaviors in CD1 mice. PKC was involved in KOPR-mediated sedation, motor incoordination and conditioned place aversion, but not analgesia and anti-scratching effect in mice. Studies in this thesis revealed the mechanisms of KOPR-mediated neurite outgrowth and KOPR-mediated phosphorylation and the involvement of PKC in KOPR-mediated pharmacological effects in vivo. These studies push the frontier of molecular pharmacology of the KOPR, which may be useful for development of KOPR agonists for therapeutic use. / Pharmacology

Activation of the dynorphin-kappa opioid receptor (KOR) system produces a negative emotional state during drug withdrawal, thereby motivating continued cocaine-seeking behaviors. However, it is not clear whether dynorphin plays a functional role in the onset of compulsive cocaine-taking. Here, escalation of cocaine self-administration was significantly attenuated by pretreatment of a long-acting KOR antagonist, norbinaltorphimine (NBI), in long access (LgA; 6-hours) male rats, whereas there was no effect of NBI on short access (ShA; 1-hour) rats on a fixed or progressive ratio schedule of reinforcement. Additionally, optical density of prodynorphin was increased in the nucleus accumbens (NAc) core and shell, bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and basolateral amygdala (BLA) of LgA rats compared to both ShA and drug-naïve rats. These results suggest dynorphin in the stress-sensitive extended amygdala (NAc shell, BNST, CeA), and BLA-NAc core circuitry mediating cue-controlled cocaine-taking may be associated with the onset of compulsive drug-taking.

It is well known that people who use drugs (PWUD) leave the hospital via patient directed discharge (“PDD”; also known as against medical advice “AMA”) more often than people who do not use drugs. The introduction of xylazine – a veterinary tranquilizer – into the United States (US) synthetic opioid supply has only exacerbated this situation. The following paper reviews the literature on xylazine, hospitalization with opioid use disorder (OUD), and how xylazine has changed the experience of hospitalization with OUD. The research revealed that xylazine causes respiratory depression, sedation, and the formation of necrotic wounds. There is currently no treatment for xylazine dependence, overdose, or withdrawal. The literature further revealed that inadequate management of withdrawal and pain, along with stigma from health professionals, are major reasons why PWUD leave the hospital PDD before completing treatment. The difficulty the health system faces with the management of xylazine withdrawal and the necrotic wounds it produces only exacerbates this problem and necessitates increased attention to this topic. Using opioid agonists to treat withdrawal decreases rates of PDD for PWUD in the hospital. This paper will argue that the treatment of PWUD in the hospital with opioid agonists in order to address withdrawal and pain is ethically necessary; and that the introduction of xylazine into the synthetic opioid supply in the US only further necessitates the collective adoption of this viewpoint. / Urban Bioethics

Opioid abuse and opioid related deaths continue to affect families and communities across the United States. Medication-assisted treatment shows advantages over other types of interventions for opioid use disorder (OUD) (Bart, 2012). While buprenorphine, an approved medication for the treatment of OUD, has a wide research base to support its efficacy, there is little research or guidance on behavioral interventions to use in conjunction with the medication. Investigating clients' experiences in treatment can provide helpful and necessary information for improving treatment efforts. The following qualitative study used a phenomenological approach to explore the client experience of group therapy with buprenorphine for OUD. Results showed the importance of supportive, genuine relationships in recovery, as well as the need for accountability and a safe space for self-disclosure. This research highlights the importance of the therapeutic alliance, the 11 therapeutic factors of groups, and the necessity of building authentic relationships in treatment. / Doctor of Philosophy / As opioid overdoses continue to rise in the United States, it is essential that we improve addiction treatment. Medication-assisted treatment (MAT) combines the use of medications and counseling to treat the whole person. This type of approach shows advantages over counseling only interventions for opioid use disorder (OUD) (Bart, 2012). While MAT shows promise over counseling only approaches, there is little research or guidance on how to implement counseling with the medication. Investigating clients’ experiences in treatment can provide helpful and necessary information for improving counseling in MAT. The following qualitative study used in-depth interviews with participants who are currently in a MAT program to better understand their experiences in treatment. Results showed the importance of supportive, genuine relationships in recovery, as well as the need for accountability and a safe space for sharing. This research helps further knowledge of treatment for OUD to better serve those affected by addiction, as well as adding to the gaps in group therapy and addiction’s literature.

The region of Appalachia in the United States is a diverse region that is full of beauty, mountains, art, and culture. Due to a history of abuse from large corporations, the impact of the decline in coal mining and generational poverty, the region is currently on a road toward recovery. Substance misuse rates are disproportionality high, and there are limited resources available to address the issue. Literature suggests that church leaders may be a potential resource. The goal of the study was to provide a better understanding of the substance misuse epidemic through the eyes of church leaders. Interpretative Phenomenological Analysis guided this qualitative study. Church leaders (n = 10) were interviewed and four significant themes emerged: narratives used to describe their experiences with substance misuse, the stigma associated with substance misuse, the community impact that substance misuse has on Appalachia, and the lack of understanding and need for training on substance misuse for church leaders and healthcare practitioners. The results of the study are discussed and connected to discussions of the implications for clinical practice, recommendations for further research, and limitations of the study. / Doctor of Philosophy / Appalachia is a mountain range located in the eastern portion of the United States. It is a diverse region that is full of beauty, mountains, art, and culture. Due to a history of abuse from large corporations, the impact of the decline in coal mining and generational poverty, the region is currently on a road toward recovery. Substance misuse rates are disproportionality high, and there are limited healthcare resources available to address the issue. The goal of the presented study was to provide a better understanding of the substance misuse epidemic through the experiences of church leaders, which are abundant in the region. Church leaders, a sample of 10, were interviewed and four significant topics emerged from their stories shared: narratives used to describe their experiences with substance misuse, the stigma associated with substance misuse, the community impact that substance misuse has on Appalachia, and the lack of understanding and need for training on substance misuse for church leaders and healthcare practitioners. The results of this study suggest that church leaders may be used as a resource to help lower the impact of substance misuse. The experiences of the church leaders gained from this study can help provide training to church leaders and healthcare providers on ways to work together and lower substance misuse in Appalachia.

In recent years, the opioid epidemic in the United States has garnered attention on a federal and local level due to the increasing number of fatal overdoses. This study aimed to explore the experiences of parents who have an adult child who has passed away from an opioid overdose. This study used the Double ABC-X model of family stress theory. Bonadaptation versus maladaptation of each parent was discussed across a multitude dimensions. Qualitative semi-structured interviews were conducted with six parents living in the state of Maryland who each had an adult child, age 18+, die from an opioid overdose 2 or more years prior to the study. Data was analyzed using thematic analysis. Themes that emerged were as follows: the grieving process, support vs. stigma, experiences with state and local services, parental guilt, shame, and unanswered questions, coping mechanisms, and post-mortem life changes. While overall adaptation levels varied among participants, all participants reported positive and negative outcomes related to their experience of grief and loss. Implications for clinical practice and intervention are discussed. Researchers also make recommendations for future research. / Master of Science / This study aimed to explore the experiences of parents who have had an adult child pass away from an opioid overdose. The study utilized Family Stress theory, a theory which focuses on how families respond and adapt after a crisis occurs, for this research. The following themes emerged from interviews with parents: the grieving process itself, support vs. stigma, experiences with state and local services, parental guilt, shame, and unanswered questions, coping mechanisms, and post-mortem life changes. While adaptation varied among participants, participants reported both positive and negative outcomes related to their experiences of grief and loss.

Yes / Background: The place of opioids in the management of chronic, non-cancer pain is limited. Even so their use is escalating, leading to concerns that patients are prescribed strong opioids inappropriately and alternatives to medication are under-used. We aimed to understand the processes which bring about and perpetuate long-term prescribing of opioids for chronic, non-cancer pain. Methods: We held semi-structured interviews with patients and focus groups with general practitioners (GPs). Participants included 23 patients currently prescribed long-term opioids and 15 GPs from Leeds and Bradford, United Kingdom (UK). We used a grounded approach to the analysis of transcripts. Results: Patients are driven by the needs for pain relief, explanation, and improvement or maintenance of quality of life. GPs’ responses are shaped by how UK general practice is organised, available therapeutic choices and their expertise in managing chronic pain, especially when facing diagnostic uncertainty or when their own approach is at odds with the patient’s wishes. Four features of the resulting transaction between patients and doctors influence prescribing: lack of clarity of strategy, including the risk of any plans being subverted by urgent demands; lack of certainty about locus of control in decision-making, especially in relation to prescribing; continuity in the doctor-patient relationship; and mutuality and trust. Conclusions: Problematic prescribing occurs when patients experience repeated consultations that do not meet their needs and GPs feel unable to negotiate alternative approaches to treatment. Therapeutic short-termism is perpetuated by inconsistent clinical encounters and the absence of mutually-agreed formulations of underlying problems and plans of action. Apart from commissioning improved access to appropriate specialist services, general practices should also consider how they manage problematic opioid prescribing and be prepared to set boundaries with patients. / National Institute for Health Research (NIHR) under its Research for Patient Benefit Programme (Grant Reference Number PB-PG- 1010–23041).