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.

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Chronic opioid exposure in utero places the infant at risk of Neonatal Abstinence Syndrome (NAS), a clinical diagnosis of neurological, autonomic, and/or gastrointestinal withdrawal symptoms from opioid abstinence at birth. The prevalence of NAS is rising concurrently with the recent epidemic of opioid misuse among the general population in the United States, including pregnant women. Opioid misusing women typically receive methadone or buprenorphine as a treatment throughout pregnancy. However, the opioid misuse during pregnancy is associated with higher obstetric complications and a higher incidence of NAS in infants, at times requiring pharmacological intervention. The exact consequences to the human development from opioid exposure in utero remain unclear. Animal studies suggest that the fetal impacts of opioid exposure may differ from the consequences for an adult who uses opioids. Furthermore, there may be neurodevelopmental alterations in myelin physiology, dendritic length in the brain, and neurotransmitter systems when a child is exposed to opioids in utero. Clinical studies highlight associations between perinatal opioid exposure and gene mutation variants, cranial abnormalities on imaging, and a high prevalence of ocular and visual comorbidities. Ocular and visual comorbidities are of particular interest, because they may be treatable when detected early. The current literature about NAS infants and ocular and visual comorbidities is limited by the retrospective and small case-control study designs employed by the majority of the research groups. The proposed study design is a prospective study comparing groups of opioid exposed and non-opioid exposed infants born at Boston Medical Center in Boston, Massachusetts. The ocular and visual comorbidities detected in each group will be quantified, while analyzing the relationship and the relative risk attributable to the infant’s and mother’s demographics. The social context of opioid misuse may complicate the interpretation of the data; however, the design anticipates sufficient recruitment and generalizability as it is conducted at a safety net hospital. Ultimately, the goal of this proposal is to reduce the risk to the fetus with perinatal opioid exposure and build the knowledge base about ocular comorbidities in NAS infants so that optimal and comprehensive care can be provided in the future.

Opioid use disorder is a chronic, relapsing disease, with more than 85% of individuals experiencing a relapse episode within one year. One common reason patients relapse is due to intense cravings, which are defined as the compulsive urge to use the drug. In fact, craving was recently added to the DSM criteria for substance use disorder diagnosis. Counterintuitively, cravings intensify over the course of extended abstinence, especially in response to drug-paired cues, a phenomenon known as “incubation of craving”. This contributes to difficulty in maintaining long-term sobriety. The mesocorticolimbic reward pathway facilitates self-administration and cue-induced incubation of craving for drugs of abuse and natural rewards, such as sucrose. In particular, the shell sub-region of the nucleus accumbens is a critical brain region involved in context/cue-mediated reward seeking. In the experiments described here, we utilized an incubation of craving model, in which male and female rats self-administered opioids (morphine or heroin) or sucrose for 10 days. Sucrose served as an important control for delineating drug-induced changes from those caused in response to natural rewards, which are not the intended target of potential treatments. Reward delivery was paired with a cue light that was later used to elicit craving. After self-administration, rats underwent brief (one day) or extended (30 days) forced abstinence. One or 30 days later, they were returned to the chambers for a “cue test”, in which responses on the previously reward-associated lever triggered cue presentation, but no contingent reward. We used this model to further delineate behavioral and affective changes that accompany increased opioid craving in late abstinence, as well as molecular alterations underlying craving in rats that did not undergo a cue test. We found an opioid-specific behavioral signature in which peak opioid craving is accompanied by decreased grooming and hyperactivity in both sexes. We tracked the female estrous cycle throughout, as these fluctuations in reproductive hormones (akin to the menstrual cycle) are shown to affect cocaine- and nicotine-related behaviors. We found no differences between females in different phases of the estrous cycle in terms of self-administration, nor craving. RNA sequencing of the nucleus accumbens shell revealed robust changes in gene expression that occurred across extended abstinence, though the genes themselves were altered in a sex- and reinforcer-specific manner. In general, we found many behavioral and molecular changes that were unique to sex and reinforcer (sucrose versus opioids). This is promising in terms of identifying opioid-specific targets that are unlikely to affect the natural reward system in both sexes. Changes in gene expression in the brain are mediated in part by epigenetic processes that influence access of transcriptional machinery to DNA. Acetylation of histone tails, the proteins around which DNA is wrapped and packaged in the nucleus, have been identified as permissive marks that facilitate long-lasting changes in transcriptomics in response to environmental insults. Opioids promote increased acetylation, which may contribute to some of the reported changes here. We tested the efficacy of JQ1, a treatment that interferes with the read-out of opioid-induced acetylated marks, at attenuating heroin self-administration. When administered as an intracerebroventricular microinjection on self-administration day 11, JQ1 had no effect on subsequent heroin taking in either sex, suggesting that it may not be suitable as a systemic treatment at the dose given. These studies lay the groundwork for future studies to administer other treatments throughout abstinence, based on the opioid-specific genes and pathways identified here, to reduce cue-induced heroin craving and the accompanying suite of behaviors in males and females. / Psychology

Opioid misuse and addiction constitute a significant public health challenge in the 21st century, with opioids involved in the majority of drug overdose deaths since 1999. A vigorously researched area that contributes substantially to the opioid misuse and addiction challenge is pain. The impact of pain, however, on important health outcomes for individuals in recovery from opioid use is less well understood. The effects of pain on substance use and mental health outcomes was investigated among individuals in recovery from opioid use disorder. Two studies are reported. First, the relationships between pain status and severity on substance use, treatment utilization, and mental health outcomes (e.g., depressive symptoms) was characterized cross-sectionally. Second, subgroups of OUD recovery defined by depression, opioid withdrawal, and pain were identified. Relationships between recovery subgroups, OUD symptoms, remission, opioid use, and quality of life were assessed. Finally, transitions among subgroups across 4 years of recovery were characterized. The present findings support pain as a key dimension of opioid use disorder recovery, highlighting the distinction between acute and chronic pain, the dynamic nature of opioid use disorder recovery, and emphasizing the necessity of integrating pain into opioid use disorder treatment. / Doctor of Philosophy / Misuse of and addiction to opioids is a significant health challenge. Pain has played a central role in facilitating the opioid epidemic in the United States, but the impact of pain on substance use and mental health outcomes for individuals in recovery from opioid use is less well understood. The following two studies investigated how pain affects substance use and mental health outcomes among individuals in recovery from opioid use disorder. Study 1 examined how different types of pain (chronic pain, acute pain, no pain) affect substance use, treatment use, and mental health measures (e.g., depression, quality of life). Study 2 investigated the role that depression, opioid withdrawal, and pain have in defining different groups in opioid recovery. Together these studies support pain as an important factor in OUD recovery, highlight the distinction between acute and chronic pain, emphasize the importance of integrating treatment for opioid use disorder and pain, and demonstrate that opioid use disorder recovery is a dynamic process with individuals transitioning among different recovery groups over time.

Background: Social adversities are prevalent among those with psychiatric disorders and may be involved in poor outcomes among patients receiving treatment. Identification of social risk factors influencing outcomes will help provide targeted interventions for at-risk patients. This thesis explored the role of social and behavioural factors in relation to adverse psychiatric outcomes, specifically relapse to substance use and attempted suicide. Methods: We used scoping study methodology to perform a comprehensive review to identify the gaps in the literature examining social functioning and MMT outcomes. This review informed our primary cohort study examining the association between social factors and continued opioid use in MMT. Lastly, we conducted a case-control study to identify risk factors for suicide attempts by comparing psychiatric patients with and without suicide attempt history (cases and controls, respectively). Multivariable logistic regression analyses were conducted in both primary studies to examine the association between predictors and outcomes. Results: The review included 101 observational studies and determined the need for further research on social factors and MMT outcomes among a current sample of Canadian patients. Our cohort study included 1043 participants (mean age=38.4 years, standard deviation [SD]=11.06); 45.8% women) to investigate this and found that unemployment, criminal activity and interpersonal conflict with friends significantly increased odds of illicit opioid use. In examining risk factors for suicide attempts, we recruited 146 cases (mean age=45.18 years, SD=14.70 years; 55% female) and 104 control participants (mean age=45.01 years, SD=14.23 years; 50% female). No sociodemographic differences existed between groups, however higher impulsivity and borderline personality symptoms significantly increased odds of attempted suicide. Conclusions: Findings from these studies may indicate the need for structured monitoring of at-risk psychiatric patients. It may be important to develop tools to measure social and behavioural factors in clinical settings and promote further integration of social services in treatment settings. / Thesis / Master of Science (MSc)

<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>

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.

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 use disorder (OUD) and opioid overdose are pervasive public health problems in the U.S. Medications for opioid use disorder (MOUD) have been shown effective to reduce OUD morbidity and mortality. Two distinct approaches to MOUD are currently used: agonist therapy (methadone or buprenorphine) or antagonist therapy (naltrexone). Limited information is available about the patterns of use, adherence to therapy, and characteristics of those who use agonist vs. antagonist therapy. The objective of this study is to assess recent trends in MOUD, adherence in use of MOUD, and the characteristics of those who use agonist vs. antagonist therapy in a nationally representative population of commercially insured patients in the U.S. This retrospective descriptive study utilized data from Truven Marketscan Commercial Claims and Encounters database from years 2011 to 2016. All individuals aged 18 years and older who have a diagnosis of OUD and utilize MOUD at any point during the study period were included. Demographic characteristics of interest included age, gender, geographic region, and type of insurance coverage. Clinical characteristics of interest included diagnosis of OUD and type of MOUD used, including extended – release naltrexone for injection, oral naltrexone, buprenorphine in combination with naloxone, and buprenorphine alone. Descriptive analyses were employed to understand utilization patterns and trends over time and proportion of days covered was used to measure adherence. Frequency and percentage are presented for categorical variables. Adherence of MOUD will be estimated by measuring proportion of days covered. As this study uses de-identified commercial health claims data, it has been determined as not human subjects research by the University of Kentucky’s Office of Research Integrity. Agonist therapy with buprenorphine or buprenorphine/naloxone was the most common treatment, representing 75.7% of those receiving treatment. Between 2011 and 2016, the percentage of individuals receiving treatment with partial agonist therapy decreased 16.5% to 9.2%, respectively. Meanwhile, the percentage of individuals receiving treatment with antagonist treatment increased from 0.1% in 2011 to 0.3% in 2016. In the analysis of proportion of days covered, all MOUD reported a decrease at both 180 and 365 days. In the commercial population, younger female patients were more likely to be treated with injectable naltrexone. Specifically, in the North Central geographic region, commercial adult patients were more likely to be treated with buprenorphine monotherapy. Overall, this study found a decrease in use of agonist therapy from 2011 through 2016, with an increase in use of antagonist therapy in the same time period. However, the increase in use of antagonist therapy does not fully account for the decrease in use of agonist therapy, suggesting that since 2011 many patients with OUD still remain untreated. All MOUD types were analyzed and saw a decrease in proportion of days covered, as a measure of adherence, from 2011 to 2016 putting patients at an increased risk for relapse, further complications, emergency visits, and hospitalizations. More information is needed about characteristics of patients who not only seek out treatment for OUD, but also maintain their treatment overtime.