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Objectives: Women with substance use disorders often experience unique challenges to obtaining contraception and adhering to user-dependent methods. As a result, this at-risk population of women tends to have higher than average rates of unintended pregnancy. The objective of this study was to describe contraceptive use, pregnancy intentions, and adequacy of access to reproductive healthcare among women receiving opioid agonist therapy in northeast Tennessee. Methods: A cross-sectional survey was piloted among female patients aged 18 to 55 years from two opioid agonist therapy clinics. Descriptive analyses were conducted using logistic regression to evaluate the statistical significance of bivariate associations. Results: Of 91 participants, 84% reported having health insurance, with 70% perceiving having adequate access to health care. More than half had a history of unwanted pregnancy (53%), among whom few (23.1%) reported the consistent use of contraception at time of conception. Although most desired to avoid pregnancy (90%), only 59% of women reported the current use of regular contraception. Most of those not using regular contraception believed that they were not at risk for pregnancy (54.3%). Conclusions: Although most participants reported adequate access to health care and a desire to avoid pregnancy, few reported the consistent use of regular contraception. Furthermore, misperceptions regarding pregnancy risk were common among participants. Research is needed to identify barriers to contraceptive acceptance and causes of pregnancy risk misperceptions in this population of women at increased risk of unintended pregnancy.

Aims: Opioid use disorder (OUD) is associated with significant morbidity and mortality, and opioid agonist treatment (OAT) with methadone or buprenorphine represents the most efficacious treatment. However, data suggest that chronic administration of opioids may be associated with significant weight gain, possibly by altering an organism’s perception of and preference for sweet foods. The primary aim of this laboratory study was to rigorously examine sucrose subjective response among adults receiving OAT and a comparison sample without OUD. As secondary outcomes, we also sought to compare the groups on additional baseline characteristics that may influence subjective sucrose response and weight gain during treatment. Methods: Participants were 40 adults receiving treatment for OUD (OUD+) and a comparison sample of 40 adults without OUD (OUD-). All participants completed an initial screening visit that included questionnaires on eating behaviors, diet and nutrition, recent substance use, and measurement of body mass index. Eligible participants completed two, same-day outpatient laboratory sessions during which they sampled six experimenter-administered concentrations of sucrose solution (0, 0.1, 0.25, 0.5, 0.75, and 1.0M in distilled water) each three times under double-blind counterbalanced conditions. Following each exposure, participants rated the pleasantness and intensity of each sample using 100-point visual analog scales. Results: OUD+ participants rated sucrose solutions as less pleasant than OUD- participants (p<0.001). However, this effect was limited to the three lowest sucrose concentrations (0, 0.1, 0.25M), and at higher concentrations there were no group differences. There were no between-group differences on ratings of intensity (p=0.35). Given these baseline group differences in placebo (0M) responding, sucrose response was also examined in terms of change from baseline. In this analysis, there was a significant group effect, with a higher magnitude of change in pleasantness ratings and a lower magnitude of change in intensity ratings from 0M in OUD+ vs. OUD- participants (p’s<0.05). With regard to baseline characteristics that may influence sucrose response and eating behavior more generally, the OUD+ group had a higher prevalence of obesity, food insecurity, unhealthy eating behaviors, high sugar consumption, and nutrition knowledge deficits compared to the OUD- group (p’s<0.05). Conclusion: Data from preclinical and clinical research have suggested that opioid agonist medications may enhance subjective response to sweet flavors. In the present study, OUD+ participants exhibited a higher magnitude of change in pleasantness ratings from placebo compared to OUD- participants. However, this effect was largely driven by pronounced group differences in perceived pleasantness of essentially unsweet solutions. On the outcome of sucrose intensity, findings were more mixed with no consistent differences between OUD+ and OUD- participants. In contrast, group differences were far more pronounced in participants’ daily eating behaviors and nutrition knowledge, with OUD+ participants presenting with a consistently more severe profile. These data highlight the significant risk factors experienced by OUD+ individuals that extend beyond drug-related risks and may inform future scientific and clinical efforts to improve health outcomes in this vulnerable population.

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)

Contexte: La crise des surdoses d’opioïdes qui sévit actuellement est un problème majeur de santé publique. Les personnes faisant usage de drogues par injection (PUDI) avec un trouble d’usage d’opioïdes (TUO) sont particulièrement vulnérables aux méfaits des opioïdes. Le traitement par agonistes opioïdes (TAO) est une intervention clé pour contrer l’épidémie de surdoses. L’engagement à long terme en traitement est un facteur important dans l’atteinte d’issues favorables. Nous avons examiné les facteurs individuels, contextuels et programmatiques qui sous-tendent la rétention en TAO dans une population de PUDI à Montréal, Canada. Méthodes: Nous avons mené une étude transversale basée sur les données provenant du questionnaire initial d’une cohorte longitudinale de PUDI à Montréal (HEPCO). Les participants recrutés avaient ≥ 18 ans et s’étaient injectés des drogues dans les derniers 6 mois. L’éligibilité au TAO était définie par l’utilisation d’opioïdes dans les 6 derniers mois et/ou l’engagement récent ou actuel en TAO. La rétention en TAO a été définie par la mesure auto-rapportée du temps passé en traitement au moment de l’entrevue, catégorisée en 4 groupes (non-engagé en TAO, <1 an, 1-3 ans, ≥3 ans). Des analyses par régression logistique multinomiale ont été menées pour identifier les facteurs associés à la rétention en traitement. Résultats: Parmi les 805 participants recrutés entre mars 2011 et janvier 2020, 546 (68%) étaient éligibles au TAO (78% hommes, âge moyen 37 ans), desquels 255 (47%) étaient engagés en TAO. Parmi ceux-ci, 29% l’étaient depuis <1 an, 21% entre 1-3 ans et 50% ≥3 ans. Dans les analyses multivariées, être une femme, l’âge, la stabilité de logement et l’infection chronique par le virus de l’hépatite C (VHC) étaient positivement associés avec une plus longue durée d’engagement en TAO (comparé aux non-engagés), alors que des associations négatives étaient observées pour la consommation régulière d’opioïdes, de cocaïne et de cannabis. Parmi les participants engagés en TAO, ceux recevant davantage de doses non-supervisées et ceux non soumis à des dépistages urinaires réguliers étaient davantage retenus en traitement. Une dose de méthadone ≥ 60 mg/jour était associée à une cote 3 fois plus élevée d’être engagé en traitement pour ≥1 an (vs <1 an), mais cette association n’était pas statistiquement significative pour la rétention ≥ 3 ans. Conclusion: La moitié des participants éligibles au TAO étaient engagés en traitement. Parmi les PUDI en TAO, une grande proportion était engagée en traitement pour ≥ 3 ans. En plus des facteurs sociodémographiques, nous avons identifié des facteurs programmatiques associés à une plus longue durée d’engagement en traitement. Des approches plus flexibles dans les programmes de TAO pourraient contribuer à une plus longue rétention en traitement. En raison du devis transversal employé, la causalité inverse ne peut être exclue; des analyses longitudinales sont nécessaires. / Background: The ongoing opioid overdose crisis is a major public health issue. People who inject drugs (PWID) with opioid use disorder (OUD) are the most vulnerable to opioid-related harms. Opioid agonist therapy (OAT) is a safe and efficient treatment for OUD and is a key intervention to curb the epidemic. Longer-term engagement in OAT has been associated with better health and social outcomes. Retention in treatment is paramount. We sought to identify individual, contextual and treatment factors associated with retention in OAT in Montréal, Canada. Methods: We conducted a cross-sectional analysis of baseline data collected within a longitudinal cohort study of PWID in Montreal (HEPCO). Eligible participants were aged ≥18 years and had injected drugs in the previous 6 months. We restricted the analysis to those eligible for OAT, inferred from self-reported illicit opioid use or OAT receipt in the past-six months. The outcome variable, retention in OAT, was defined as self-reported time spent in treatment at baseline, categorized as not on OAT, < 1 year, 1-3 years, ≥3 years. Multinomial logistic regression analyses were conducted to identify factors associated with retention. Results: Of 805 cohort participants enrolled between March 2011 and January 2020, 546 (68%) were considered eligible for OAT (mean age: 37; 78% male) and included in analyses. Of those, 255 (47%) were currently enrolled in OAT (29% in treatment for <1 year, 21% for 1-3 years and 50% for ≥ 3 years). In multivariable analyses, female gender, older age, stable housing, and chronic hepatitis C infection were positively associated with longer stay in OAT (compared to not on OAT), whereas negative associations were noted for regular opioid, cocaine and cannabis use. Among PWID enrolled in OAT, those receiving take-home doses and those who did not have regular urine drug screening were more likely to have a longer stay in treatment. Methadone dose ≥ 60 mg/day was associated with over 3-fold odds of retention ≥ 1 year (vs < 1 year), but the association was not statistically significative for ≥ 3 years retention. Conclusion: Half of participants likely to be eligible for OAT were enrolled in treatment. Among active PWID receiving OAT, high prevalence of long-term engagement in treatment was observed. In addition to sociodemographic factors, we identified treatment-related factors associated with greater treatment duration, suggesting the need for flexible implementation approaches in OAT programmes. Due to our cross-sectional design, however, reverse causation cannot be excluded; findings should be confirmed in longitudinal samples.

L’infection par le virus de l’hépatite C (VHC) est l’un des principaux problèmes de santé publique chez les utilisateurs de drogues injectables (UDI). Actuellement, plusieurs outils sont disponibles pour réduire le fardeau du VHC dans cette population. Ceux-ci incluent des programmes de réduction des méfaits, tels que le traitement par un opioïde agoniste (TAO), pouvant réduire le risque d'infection par le VHC, ainsi que des traitements antiviraux extrêmement efficaces pour éradiquer le virus parmi les infectés. Plus récemment, il y a eu un intérêt national et international à éliminer le VHC en tant que menace pour la santé publique d'ici 2030, tout en priorisant les UDI dans les efforts de prévention et traitement. Parallèlement à ce mouvement, plus globalement, le fardeau des méfaits liés aux pratiques d’injection chez les UDI, tels que la surdose, soulignent la nécessité d’adopter une vision plus large sur leur santé. Dans l’ensemble, cette thèse vise à combler certaines lacunes dans les connaissances vis-à-vis de l’élimination du VHC chez les UDI. Premièrement, puisque le lien entre l’adéquation du dosage des TAO et le risque d’infection au VHC est peu connu, j’examine cette relation dans un échantillon d’UDI suivis dans la cohorte HEPCO à Montréal. Les résultats indiquent que le risque d'infection par le VHC ne serait pas systématiquement réduit chez toutes les personnes recevant des TAO, mais plutôt que ce risque varie en fonction de la dose prescrite et de l’adéquation du dosage telle que perçue par le patient. Ces résultats soulignent qu’un élargissement de l'accès aux TAO ne serait pas suffisant pour atteindre les objectifs de prévention et d'élimination du VHC, et que l’adéquation du dosage devrait être prise en compte dans le cadre de nos efforts de prévention. Deuxièmement, l’accès aux traitements antiviraux est faible chez les UDI, en partie à cause des préoccupations des prestataires et des décideurs politiques qui craignent une augmentation de la consommation de drogues et des comportements à risque après le traitement. En capitalisant sur deux études différentes - la cohorte IMPACT à Montréal et les essais SIMPLIFY / D3FEAT menés dans plusieurs pays - je montre que les comportements liés à la drogue diminuent ou restent stables après le traitement du VHC. Ensemble, ces deux études suggèrent que les préoccupations liées à une consommation élevée de drogue ou à une hausse des comportements à risque après le traitement ne seraient pas fondées. Ainsi, ces résultats appuient davantage une augmentation de l’accès au traitement chez les UDI. Troisièmement, allant au-delà du VHC en tant que problématique principale, en capitalisant une fois de plus sur les données collectées dans HEPCO, j’examine les associations entre trois facteurs - le TAO, le logement et le revenu - et la fréquence d’injection chez les UDI. Puisque la consommation de drogues est dynamique dans le temps, j'examine dans quelle mesure ces trois facteurs sont liés à la fréquence d’injection chez des UDI ayant des trajectoires d’injection variées. Nos résultats indiquent que la stabilité socioéconomique et le TAO seraient systématiquement liés à une fréquence d'injection inférieure chez les UDI, quelles que soit leurs trajectoires d’injection sous-jacentes. Globalement, ces résultats suggèrent qu’il y aurait des moyens de soutenir tous les UDI à atteindre de petits changements comportementaux qui pourraient réduire les risques liés aux pratiques d’injection, qu’ils soient ou non en mesure d’arrêter l’injection de drogues. En conclusion, alors que presque tous les pays ont lancé un effort mondial pour éliminer le VHC, des efforts sont nécessaires pour optimiser les programmes de réduction des méfaits bien établis afin de réduire la transmission du VHC, et d’accroître l’accès au traitement chez ceux qui sont infectés, tout en considérant les besoins et les préoccupations des communautés touchées. Cette thèse a fourni des données permettant d’éclairer (i) l’optimisation des TAO dans la prévention de la transmission du VHC, (ii) l’élargissement de l’accès au traitement du VHC et (iii) l’accès à des logements et revenus stables afin de réduire plus globalement les risques liés aux pratiques d’injection chez les UDI. Ainsi, ces résultats pourraient aider à réduire le fardeau du VHC chez les UDI et à soutenir le progrès vers l'élimination du VHC. / Infection with hepatitis C virus (HCV) is one of the main public health concerns affecting people who inject drugs (PWID). Although no effective prophylactic vaccine currently exists to prevent acquisition of HCV, a number of other tools are available to curb the HCV burden among PWID. These include harm-reduction programs, such as opioid agonist treatment (OAT), which can reduce the risk of HCV infection among those susceptible, and highly effective antiviral therapies to eradicate the virus among those who are infected. In recent years, there has been national and international interest in eliminating HCV as a public health threat by 2030, prioritising PWID in prevention and treatment efforts given that they are the population most affected. In parallel to this global effort, the high prevalence of injection-related harms among PWID that are unrelated to HCV, such as overdose, highlight a need to adopt a broader view on drug user health. Overall, this thesis is concerned with addressing some of the knowledge gaps and barriers that remain to achieving HCV elimination in PWID. First, because little is known about the importance of OAT dosage in influencing the risk of HCV acquisition, I examine this relationship in a sample of PWID followed in the Hepatitis Cohort (HEPCO) in Montreal. Findings indicate that the risk of HCV infection may not be systematically reduced for everyone receiving OAT and rather, that the risk of infection varies considerably according to the level of the prescribed OAT dosage and patient-perceived dosage adequacy. These findings suggest that simply scaling-up OAT access may not be sufficient to achieving the HCV elimination goals, and that the dosage of treatment should be considered as part of prevention efforts. Second, uptake of HCV treatment is low among PWID, partly due to concerns among providers and policymakers that drug use and injection risk behaviours may increase following treatment, thereby negating the benefits of therapy. Capitalising on two different studies - the IMPACT Cohort in Montreal and the SIMPLIFY/D3FEAT trials conducted in several countries - I illustrate that drug-related behaviours decrease or remain stable following HCV treatment. Together, these two studies suggest that concerns of escalating drug use or risk behaviours following HCV treatment are unfounded, further supporting the importance of expanding access to therapy among PWID. Third, moving beyond HCV as the primary focus of research, and capitalising once more on data collected in HEPCO, I examine the associations between three factors- OAT, housing and income, and patterns of injection frequency among PWID. Recognizing that injection patterns are dynamic over time, I examine the extent to which these three factors relate to injection frequencies among PWID with diverse trajectories of injection drug use, followed over a period of 7.5 years. Our findings indicate that socioeconomic stability and OAT are consistently associated with a lower injection frequency among all PWID, irrespective of their underlying injection trajectory and whether or not they are on a path to cessation. These findings suggest that there may be ways to support PWID in making small behavioral changes that could reduce their risks of injection-related harms, irrespective of whether or not they are in a position to stop injecting. In conclusion, at a time when many countries have embarked onto a global effort to eliminate HCV, efforts are needed to ensure that well-evidenced harm-reduction programs are optimised to reduce transmission of HCV, treatment for HCV infection is scaled-up among those who are infected ,and efforts do not overlook the basic needs and concerns of affected communities. This thesis provided data to help inform (i) optimisation of OAT provision for the prevention of HCV transmission, (ii) expanded access to HCV treatment, and (iii) access to stable housing and income to reduce the risk of injection-related harms among PWID. Ultimately, findings could contribute to reducing the HCV burden among PWID, helping move towards HCV elimination and, more broadly, improving the overall health of this marginalised group.

<p>The following thesis will focus on understanding the downstream behavioral effects of δORmediated β-arrestinsignaling. δORagonists have been implicated as effective targets for a variety of diseases, however detrimental side effects of opioid-targeting agonists limit their clinical use. δORagonists specifically can induce seizures, however the underlying mechanism contributing to this  behavior  is  unknown.  We  review  this  phenomenon  in  more  detail,  highlighting  current agonists known to induce seizures and potential circuits and pathways involved. Our work suggests β-arrestinsignaling  is  involved,  specifically β-arrestin2  mediated  signaling  may  be  largely contributing  to δORagonist-induced  seizure  behavior.  As  it  is  possible  the β-arrestinisoforms have unique roles in seizure behavior, we also analyzed methods in which to provoke β-arrestinisoform bias of δORtargeting compounds. Though the full mechanism relating δORagonists with seizures remains unknown, our work provides foundational detail of this behavior, implicating the importance of β-arrestinisoform signaling through δOR; allowing for future studies to full define this seizure pathway and develop δORsafer agonists.  </p>