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The purpose of this project was to investigate the mechanism of action of acupuncture on a critical neural substrate involved in alcoholism. Specifically, this study evaluated the effects of stimulation of the acupuncture Shenmen (HT7) point on inhibitory GABA neurons in the ventral tegmental area (VTA), a midbrain structure implicated in drug and alcohol abuse, and ethanol self-administration. In addition, the role of opioid receptors (ORs) in ethanol and acupuncture effects was explored. Using electrophysiological methods in mature rats, we evaluated the effects of HT7 stimulation and opioid antagonists on the VTA GABA neuron firing rate. With behavioral paradigms, we also assessed those effects on ethanol self-administration, using a modification of the sucrose fading procedure. We found that HT7 stimulation produced a biphasic modulation of VTA GABA neuron firing rate characterized by transient enhancement at the onset of stimulation followed by a prolonged inhibition and subsequent recovery in 5 min. HT7 stimulation blocked the typical suppression of VTA GABA neuron firing rate produced by a moderately intoxicating dose of ethanol. The late inhibition produced by HT7 stimulation as well as HT7 reversal of ethanol's effects on GABA neuron firing rate was blocked by the non-selective opioid receptor antagonist, naloxoneIn addition, HT7 acupuncture reduced ethanol self-administration without affecting sucrose consumption. More important, systemic administration of the δ-opioid receptor (DOR) antagonist, naltrindole blocked ethanol suppression of VTA GABA neuron firing rate and significantly reduced ethanol self-administration without affecting sucrose consumption. These findings suggest that DOR-mediated opioid modulation of VTA GABA neurons may be related to the role of acupuncture in modulating mesolimbic DA release and suppressing the reinforcing effects of ethanol. We confirmed that acupuncture stimulation may have a significant impact on the inhibitory neuron activity in the VTA and that acupuncture may serve as an effective adjunct to OR antagonist therapy for alcoholism.

BACKGROUND AND OBJECTIVES: Research on in utero opioid exposure impacts has focused on Neonatal Opioid Withdrawal Syndrome (NOWS). However, possible impacts on fetal growth and newborn wellbeing have emerged, with inconsistencies likely driven by methodological issues. Our goal was to compare birth outcomes between newborns with prenatal opioid exposure and a matched control group. METHODS: Participants were identified manual review of electronic medical records of all deliveries over five years within a regional health system (6 delivery hospitals across 2 states). From over 18,000 births, 300 with prenatal opioid exposure and 300 control newborns matched on exposure, medical, and background factors were included. Additional factors were statistically controlled. Outcomes included pregnancy/delivery complications, newborn size, and newborn health complications. RESULTS: Compared to biochemically verified controls, exposed newborns had higher rates of fetal growth restriction, weighed less, had decreased length and head circumference, and had higher rates of respiratory distress, sepsis, and jaundice. No significant differences in gestational length, Apgar scores, or neonatal hypoglycemia were found. Adjusted regression analyses revealed that compared to controls, those exposed had an average 150 g decrease in birth weight, a two-fold increased risk for IUGR (OR = 2.09), a nearly three-fold (OR = 2.80) increased risk for jaundice, a more than seven-fold (OR = 7.40) increased risk for respiratory distress, and a thirty-fold (OR = 30.47) increased risk for sepsis. CONCLUSIONS: Results suggest significant pregnancy and newborn outcomes beyond NOWS following pregnancy opioid use, informing clinical screening and treatment decisions to enhance health and wellbeing in pregnancy, during the neonatal period, and beyond.

Introduction: Race/ethnicity and sex disparities in substance use and substance use treatment completion are well documented in the literature. Previous literature has shown that participation in self-help groups is associated with higher rates of substance use treatment completion. While most of this research has focused on the completion of treatment for alcohol and stimulant use, research examining this relationship using an intersectional approach for individuals in treatment for opioid use is limited. Methods: Thus, the current study utilized responses from the Treatment Episodes Data Set–Discharges, 2015–2017 to examine disparities in the relationship between participation in self-help groups and substance use treatment completion for individuals undergoing treatment for opioid use based on sex, race, and ethnicity. Results: Results revealed a positive association between participation in self-help groups and treatment completion among those in treatment for opioid use across race, ethnicity, and sex. Further, the study found several differences in this association based on one's race, ethnicity, and sex. When compared to men of other races/ethnicities, the association between self-help group participation and treatment completion was highest among Black men. Conclusions: The results of the current study extend the knowledge-base about self-help participation's role in promoting successful substance use treatment completion to individuals in treatment for opioid use. Results also highlight the need to examine treatment outcomes with an intersectional lens.

Background and objectives: Research on in utero opioid exposure impacts has focused on Neonatal Opioid Withdrawal Syndrome (NOWS). However, possible impacts on fetal growth and newborn wellbeing have emerged, with inconsistencies likely driven by methodological issues. Our goal was to compare birth outcomes between newborns with prenatal opioid exposure and a matched control group. Methods: Participants were identified via manual review of electronic medical records of all deliveries over five years within a regional health system (6 delivery hospitals across 2 states). From over 18,000 births, 300 with prenatal opioid exposure and 300 control newborns matched on exposure, medical, and background factors were included. Additional factors were statistically controlled. Outcomes included pregnancy/delivery complications, newborn size, and newborn health complications. Results: Compared to biochemically verified controls, exposed newborns had higher rates of fetal growth restriction, weighed less, had decreased length and head circumference, and had higher rates of respiratory distress, sepsis, and jaundice. No significant differences in gestational length, Apgar scores, or neonatal hypoglycemia were found. Adjusted regression analyses revealed that compared to controls, those exposed had an average 150 g decrease in birth weight, a two-fold increased risk for IUGR (OR = 2.09), a nearly three-fold (OR = 2.80) increased risk for jaundice, a more than seven-fold (OR = 7.40) increased risk for respiratory distress, and a thirty-fold (OR = 30.47) increased risk for sepsis. Conclusions: Results suggest significant pregnancy and newborn outcomes beyond NOWS following pregnancy opioid use, informing clinical screening and treatment decisions to enhance health and wellbeing in pregnancy, during the neonatal period, and beyond.

Background: The consequences of continued opioid abuse among patients treated with opioid substitution therapy (OST) are serious and can result in abnormal cardiovascular function, overdose, and mortality. Conflicting evidence exists that both implicates and refutes the role of chronic non-cancer pain (CNCP) as a major risk factor for continued opioid abuse within the addiction treatment setting. This thesis aims to 1) evaluate the impact of chronic pain on the treatment outcomes of patients with opioid addiction receiving OST, 2) determine whether a clinical or inflammatory profile exists to distinguish pain in this population, 3) explore the sources of heterogeneity in previous studies examining this question, 4) determine the best therapy for patients with chronic pain, and 5) evaluate the most effective treatment for opioid addiction. We anticipate chronic pain to be an important predictor of continued opioid abuse such that patients with comorbid pain will require careful consideration when managed on OST. Methods: We systematically reviewed the literature to determine the impact of pain in opioid addiction patients receiving methadone maintenance treatment (MMT). We determined the clinical and inflammatory profile of MMT patients using data from the Genetics of Opioid Addiction (GENOA) research collaborative between the Canadian Addiction Treatment Centres (CATC) and the Population Genomic Program. GENOA is a prospective cohort study aimed to determine the genetic, biological, and psychosocial determinants of treatment prognosis for opioid addiction patients receiving MMT. GENOA recruits patients ≥ 18 years of age meeting the DSM-IV criteria for opioid dependence. All GENOA participants are receiving MMT for the management of opioid addiction. Baseline data from the GENOA pilot study (n=235) were used to evaluate the impact of pain on illict opioid use behaviour and determine the clinical and inflammatory profile of patients with comorbid pain. We explored sources of heterogeneity in previous studies using data from the full-phase GENOA study (n=444), examining the prognostic value of different pain measures for predicting illicit opioid use. We then performed a multiple treatment comparison of all opioid substitution and antagonist therapies in efforts to determine the best intervention for improving treatment outcomes for patients with comorbid pain. We lastly determined the most effective treatment for opioid addiction by performing a network meta-analysis using data from a systematic review of opioid maintenance therapy trials. Results: Our initial systematic review confirmed a lack of consensus in the literature, whereby some studies suggest pain increases risk for illicit opioid use and other studies suggest pain has no effect on substance use behaviour. Findings from the analysis of GENOA pilot data confirmed chronic pain to be an important predictor of sustained opioid abuse and also showed patients with pain to have elevated Interferon-Gamma. Using data from the GENOA prospective cohort study we determined the Brief Pain Inventory (a commonly used pain measurement in pervious studies) to be highly sensitive with poor prognostic value. Our final reviews propose 1) there is limited evidence to suggest any OST is superior for managing patients with comorbid pain, and 2) heroin and high-dose methadone are the most effective treatments for improving treatment retention. The final systematic review and network meta-analysis in this thesis also highlights a major problem in the treatment of opioid use disorders, primarily the lack of consensus as to what outcomes matter for determining success in patients with addiction. Conclusion: Patients with comorbid pain and addiction are at high-risk for continued opioid abuse and should be managed closely by clinicians administering OST. Contention in the previous literature likely resulted from the use of pain measurements with poor prognostic value. No OST demonstrated superiority for managing patients with chronic pain. While our findings indicate heroin is the most effective treatment across multiple endpoints, we use this thesis to provide readers with 1) a sense of the feasibility issues associated with heroin administration, 2) a summary of the limitations of this evidence base, and 3) recommendations for how to improve the addiction trials’ design for future research. / Thesis / Doctor of Philosophy (PhD)

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)

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