La douleur chronique non-cancéreuse (DCNC) est un problème de santé qui touche environ une personne sur cinq au Canada. Elle est associée à une dégradation de la qualité de vie physique et mentale et occasionne des coûts économiques importants. Pour lutter contre la DCNC, les opioïdes ont été largement recommandés et prescrits malgré l’absence de preuves de leur efficacité à long terme, entraînant une augmentation des surdoses. Ces surdoses mais surtout celles causées par le fentanyl illicite ont fait naître une crise sanitaire, la crise des opioïdes. Pour juguler cette crise, des lignes directrices ont été émises pour encadrer de façon plus stricte la prescription d’opioïdes pour la DCNC. Cependant ces mesures peuvent constituer des barrières d’accès aux traitements pour les personnes vivant avec de la DCNC. Il est donc important de garantir un accès sécuritaire aux opioïdes à ceux qui en ont besoin pour fonctionner tout en limitant l’accès inapproprié qui alimente la crise des opioïdes. L’objectif de cette thèse était d’identifier les personnes susceptibles de bénéficier d’une utilisation efficace et sécuritaire des opioïdes à long terme et de mieux comprendre la douleur et les difficultés d’accès au traitement chez les personnes utilisatrices de drogues (PUD). Une première étude, visant à identifier les prédicteurs de l’efficacité des opioïdes à long terme, n’a pas permis de faire ressortir des caractéristiques des personnes susceptibles d’en bénéficier. Deux autres études ont permis d’étudier le nomadisme médical (doctor shopping), un indicateur d’utilisation problématique d’opioïdes, qui consiste à obtenir des ordonnances qui se chevauchent de plusieurs médecins et à les faire dispenser dans différentes pharmacies. Les résultats ont montré que cette pratique est rare chez les personnes vivant avec de la DCNC mais qu’elle peut être associée à la survenue de surdose. Les caractéristiques des personnes à risque de faire du nomadisme médical ont été identifiées permettant ainsi un meilleur suivi. Enfin, une dernière étude a montré que la DCNC est très fréquente chez les PUD et qu’une proportion importante de cette population a recours à des drogues illicites pour soulager leur douleur, courant ainsi le risque de faire une surdose. Ces études montrent la nécessité d’une médecine personnalisée tenant compte des caractéristiques et situations individuelles afin de prescrire le bon médicament à la bonne personne. En somme, ces résultats ont permis d’accroître les connaissances scientifiques sur l’utilisation des opioïdes pour la DCNC. / Chronic non-cancer pain (CNCP) is a health problem that affects about one in five people in Canada. CNCP is associated with a deterioration of physical and mental health-related quality of life and incurs significant economic costs. To better manage CNCP, opioids have been widely recommended and prescribed despite the lack of evidence on their long-term effectiveness, leading to an increase in opioid overdoses. These overdoses but mainly those caused by illicit fentanyl have led to the opioid crisis. To address this crisis, guidelines have been issued to tighten the prescribing of opioids for CNCP. However, these measures can exacerbate barriers of access to treatment for people living with CNCP. Therefore, it is important to ensure safe access to opioids for those who need this medication to improve function while reducing inappropriate access that contributes to the opioid crisis. The aim of this thesis was to identify the characteristics of patients who may benefit from effective and safe long-term opioid therapy and to better understand pain and treatment access difficulties among people who use drugs (PWUD). An initial study, which aimed at examining predictors of long-term opioid efficacy, failed to identify characteristics of those likely to benefit from opioid therapy. Two other studies investigated doctor shopping, an indicator of problematic opioid use, which consists of obtaining overlapping prescriptions from several doctors and pharmacies. The results showed that this practice is rare among people living with CNCP but may be associated with the occurrence of opioid overdose. The characteristics of people at high-risk to engage in opioid doctor shopping were identified, thus allowing better monitoring. Finally, a last study showed that CNCP is very frequent among PWUD and that a significant proportion of this population uses illicit drugs to relieve their pain, which can increase the risk of overdose. These studies show the need for personalized medicine considering individual characteristics and specific situations to prescribe the right drug to the right person. In summary, these results have increased the scientific knowledge about the long-term opioid use in CNCP.

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Opioid analgesics have been a major contribution to pain therapy with opioids being used as an effective treatment for various recalcitrant pain conditions. The drug class has come under increased scrutiny due to the raising concerns about the public health crisis of opioid misuse and addiction, thereby increasing the need for alternative and safer analgesics. The exploration of alternative pharmacotherapy for pain management has led to an increasing paradigm shift towards the development of a single-drug-multiple-target approach that takes inspiration from numerous naturally occurring drugs. The mu-opioid receptor has been the primary target for the management of pain; however, the voltage-gated sodium channel Nav1.7 is gaining attention as a putative antinociceptive target based on human genetic evidence. The proposed research aims to develop multi-target directed ligands (MTDL) that modulates two key targets for pain perception, the MOR, and Nav1.7 to generate analgesics with reduced side effects and enhanced analgesia. This will be achieved by exploiting polypharmacology to develop hybrid analgesia in two ways: (i) performing structure-activity relationship (SAR) studies to design a single drug with two pharmacophores that specifically interacts with both the targets (ii) exploiting in silico techniques by performing structure-based virtual ligand screening (VLS) of a chemical library. In our work, we report that through SAR studies and molecular docking studies that the designed compounds having in combination the pharmacophore of PZM21 and aryl sulfonamide demonstrate significant interactions between the active compounds and both the MOR and Nav1.7 proteins. This study also reports the first ever bifunctional virtual ligand screening where a library consisting of over a million compounds was screened for bifunctional activity at the MOR and the Nav1.7 ion channel. We also report the development of a novel mechanism-specific membrane potential assay to that can be used to screen for subtype selective Nav1.7 inhibitors. The research performed in this thesis will serve as a platform to explore the possibility of MTDL as potential therapeutic solutions to diseases of complex etiologies such as chronic pain. It will also serve as a starting point to exploring bifunctional VLS as a way to screen large chemical libraries for MTDLs.

During the early stages of any epidemic, simple interventions such as quarantine and isolation may be sufficient to halt the spread of a novel pathogen. However, should this opportunity be missed, substantially more resource-intensive, complex, and societally intrusive interventions may be required to achieve an acceptable outcome. These disparities place a differential on the value of a given unit of knowledge across the time-domains of an epidemic. Within this dissertation we explore these value-differentials via extension of the business concept of the time-value of knowledge and propose the C4 Response Model for organizing the research response to novel pathogenic outbreaks. First, we define the C4 Response Model as a progression from an initial data-hungry collect stage, iteration between open-science-centric connect stages and machine-learning centric calibrate stages, and a final visualization-centric convey stage. Secondly we analyze the trends in knowledge-building across the stages of epidemics with regard to open and closed access article publication, referencing, and citation. Thirdly, we demonstrate a Twitter message mapping application to assess the virality of tweets as a function of their source-profile category, message category, timing, urban context, tone, and use of bots. Finally, we apply an agent-based model of influenza transmission to explore the efficacy of combined antiviral, sequestration, and vaccination interventions in mitigating an outbreak of an influenza-like-illness (ILI) within a simulated military base population. We find that while closed access outbreak response articles use more recent citations and see higher mean citation counts, open access articles are published and referenced in significantly greater numbers and are growing in proportion. We observe that tweet viralities showed distinct heterogeneities across message and profile type pairing, that tweets dissipated rapidly across time and space, and that tweets published before high-tweet-volume time periods showed higher virality. Finally, we saw that while timely responses and strong pharmaceutical interventions showed the greatest impact in mitigating ILI transmission within a military base, even optimistic scenarios failed to prevent the majority of new cases. This body of work offers significant methodological contributions for the practice of computational epidemiology as well as a theoretical grounding for the further use of the C4 Response Model. / Doctor of Philosophy / During the early stages of an outbreak of disease, simple interventions such as isolating those infected may be sufficient to prevent further cases. However, should this opportunity be missed, substantially more complex interventions such as the development of novel pharmaceuticals may be required. This results in a differential value for specific knowledge across the early, middle, and late stages of epidemic. Within this dissertation we explore these differentials via extension of the business concept of the time-value of knowledge, whereby key findings may yield greater benefits during early epidemics. We propose the C4 Response Model for organizing research regarding this time-value. First, we define the C4 Response Model as a progression from an initial knowledge collection stage, iteration between knowledge connection stages and machine learning-centric calibration stages, and a final conveyance stage. Secondly we analyze the trends in knowledge-building across the stages of epidemics with regard to open and closed access scientific article publication, referencing, and citation. Thirdly, we demonstrate a Twitter application for improving public health messaging campaigns by identifying optimal combinations of source-profile categories, message categories, timing, urban origination, tone, and use of bots. Finally, we apply an agent-based model of influenza transmission to explore the efficacy of combined antiviral, isolation, and vaccination interventions in mitigating an outbreak of an influenza-like-illness (ILI) within a simulated military base population. We find that while closed access outbreak response articles use more recent citations and see higher mean citation counts, open access articles are growing in use and are published and referenced in significantly greater numbers. We observe that tweet viralities showed distinct benefits to certain message and profile type pairings, that tweets faded rapidly across time and space, and that tweets published before high-tweet-volume time periods are retweeted more. Finally, we saw that while early responses and strong pharmaceuticals showed the greatest impact in preventing influenza transmission within military base populations, even optimistic scenarios failed to prevent the majority to new cases. This body of work offers significant methodological contributions for the practice of computational epidemiology as well as a theoretical grounding for the C4 Response Model.

L’atteinte d’un soulagement adéquat de la douleur garantissant aussi une utilisation sécuritaire des opioïdes et répondant aux attentes des patients s’est beaucoup complexifiée dans le contexte d’une attention accrue à l’utilisation et aux effets néfastes des opioïdes. Cette attention a remis en question les pratiques de prescription et distribution de médicaments visant le soulagement de la douleur. En tant que dispensateurs de médicaments, les pharmaciens assument un rôle central pour en assurer leur utilisation sécuritaire et appropriée. L’objectif général de ce travail est de décrire les pratiques pharmaceutiques portant sur le soulagement de la douleur dans le contexte actuel en Amérique du Nord en général et au Québec en particulier, et mieux comprendre les facteurs facilitants et les barrières à l’amélioration de ces pratiques au Québec. Ce projet a été mené en deux parties. Tout d’abord, une revue de la littérature a été effectuée pour recenser les publications examinant les pratiques pharmaceutiques visant le soulagement de la douleur et la gestion des opioïdes en lien avec une préoccupation généralisée sur l’usage des opioïdes. Les objectifs étaient d'identifier ces pratiques et d'évaluer si elles avaient été amenées à évoluer suite à ces préoccupations. Pour la deuxième partie du projet, qui visait à approfondir les perceptions des pratiques pharmaceutiques portant sur la douleur au Québec, des entrevues semi-structurées ont été menées avec des pharmaciens (n = 8) oeuvrant dans divers milieux cliniques (pharmacie communautaire, pharmacie en établissement de santé et groupe de médecine de famille). Alors que les pharmaciens ont exprimé le désir de jouer un rôle central dans l'atteinte des objectifs de traitement de la douleur tout en assurant l’utilisation sécuritaire des opioïdes, ils ont rapporté plusieurs obstacles dans leur pratique. De plus, la prestation des soins pharmaceutiques visant le soulagement de la douleur pourrait être améliorée en tirant parti des facilitateurs de chaque milieu de pratique et en favorisant les partenariats intraprofessionnels à travers les différents milieux de pratique. / Providing adequate pain relief while ensuring safe opioid use and managing patient expectations has become an intricate endeavor in the context of increased attention to opioid use and its harms. This attention has put into question the practices of prescribing and dispensing medications for pain relief. As the dispensers of medications, pharmacists play a crucial role in ensuring their safe and proper use. The general objective of this work is to describe the pharmaceutical practices encompassing pain relief in the current context in North America in general, and in Quebec in particular, and to better understand the facilitating factors and the barriers to the improvement of these practices in Quebec.This project was conducted in two parts. First, a scoping review of the literature was conducted for publications examining pharmaceutical practices aimed towards pain relief and opioid management in the context of widespread concern about opioid use. The objectives were to identify these practices and assess whether they had been called on to evolve as a result of these concerns. For the second part of the project, which aimed to deepen the perceptions of pharmaceutical practices relating to pain in Quebec, semi-structured interviews were conducted with pharmacists (n = 8) working in various clinical settings (community pharmacy, health facility pharmacy and family medicine group). While pharmacists have expressed a desire to play a central role in achieving pain treatment goals while ensuring the safe use of opioids, they reported several barriers in their practice. Lack of time to perform adequate follow-ups, gaps in pain assessment and pharmacotherapy knowledge, and communication skills tailored to patients who suffer were the main barriers mentioned by pharmacists. Adjustments to teaching and practice curricula, standardized assessment and monitoring tools, and increased patient involvement in decision-making could prove beneficial. In addition, delivery of pharmaceutical care for pain relief could be improved by leveraging facilitators from each practice setting and fostering intraprofessional partnerships across different practice settings.

There is an identified problem with patients receiving suboptimal pain management at a hospice agency in the northwestern United States. At this agency, undertreatment of pain is prevalent. Evidence indicates that this may be a result of a lack of guidelines, education, and knowledge of appropriate prescribing. Known barriers to the correct prescription and administration of potent opioids in the hospice setting include prevailing beliefs, knowledge, skills, and attitudes, all of which can impact care negatively. Contextually, hospice principles mandate patient comfort and caregiver involvement in continuous quality improvement, which includes adequate and informed pain management. Moreover, hospice metrics demand requisite knowledge, skills, and attitudes for optimal care, including pain management at the end of life. The Academic Center for Evidence-Based Practice (ACE) star model was used to guide the development of an evidence-based, guideline-supported educational program that will improve pain management at the hospice agency when implemented. The purpose of this project was to use transdisciplinary expertise and team collaboration to develop the program and then to conduct a formative and summative evaluation utilizing experts to prepare the guidelines and process for implementation. Ten experts reviewed the guideline, the educational materials, the process, and the evaluation plan and conducted reviews using the AGREE II tool. The panel of experts agreed within the 6 AGREE domains. Future implementation of this guideline, translation process, and evaluation tool will impact social change through the empowerment of the clinical staff, patients, and caregivers to provide the best pain control and comfort at end of life, a vulnerable time for all patients.

La douleur chronique non cancéreuse (DCNC) est un phénomène complexe et des interventions multimodales qui abordent à la fois ses dimensions biologiques et psychosociales sont considérées comme l’approche optimale pour traiter ce type de désordre. La prescription d'opioïdes pour la DCNC a augmenté d’une façon fulgurante au cours des deux dernières décennies, mais les preuves supportant l'efficacité à long terme de ce type de médicament en termes de réduction de la sévérité de la douleur et d’amélioration de la qualité de vie des patients souffrant de DCNC sont manquantes. L'objectif de cette étude était d'investiguer dans un contexte de vraie vie l'efficacité à long terme des opioïdes pour réduire l’intensité et l’impact de la douleur et améliorer la qualité de vie reliée à la santé des patients souffrant de DCNC sur une période d’une année. Méthodes: Les participants à cette étude étaient 1490 patients (âge moyen = 52,37 (écart-type = 13,9); femmes = 60,9%) enrôlés dans le Registre Québec Douleur entre octobre 2008 et Avril 2011 et qui ont complété une série de questionnaires avant d'initier un traitement dans un centre multidisciplinaire tertiaire de gestion de la douleur ainsi qu’à 6 et 12 mois plus tard. Selon leur profil d'utilisation d'opioïdes (PUO), les patients ont été classés en 1) non-utilisateurs, 2) utilisateurs non persistants, et 3) utilisateurs persistants. Les données ont été analysées à l'aide du modèle d'équation d'estimation généralisée. Résultats: Chez les utilisateurs d’opioïdes, 52% en ont cessé la prise à un moment ou à un autre pendant la période de suivi. Après ajustement pour l'âge et le sexe, le PUO a prédit d’une manière significative l’intensité de la douleur ressentie en moyenne sur des périodes de 7 jours (p <0,001) ainsi que la qualité de vie physique (pQDV) dans le temps (p <0,001). Comparés aux non-utilisateurs, les utilisateurs persistants avaient des niveaux significativement plus élevés d'intensité de douleur et une moins bonne pQDV. Une interaction significative a été trouvée entre le PUO et le temps dans la prédiction de l’intensité de douleur ressentie à son maximum (p = 0,001), les utilisateurs persistants sont ceux rapportant les scores les plus élevés à travers le temps. Une interaction significative a aussi été observée entre le PUO et le type de douleur dans la prédiction de l'impact de la douleur dans diverses sphères de la vie quotidienne (p = 0,048) et de la mQDV (p = 0,042). Indépendamment du type de douleur, les utilisateurs persistants ont rapporté des scores plus élevés d'interférence de douleur ainsi qu’une moins bonne mQDV par rapport aux non-utilisateurs. Cependant, la magnitude de ces effets était de petite taille (d de Cohen <0,5), une observation qui remet en question la puissance et la signification clinique des différences observées entre ces groupes. Conclusion: Nos résultats contribuent à maintenir les doutes sur l'efficacité d’une thérapie à long terme à base d’opioïdes et remettent ainsi en question le rôle que peut jouer ce type de médicament dans l'arsenal thérapeutique pour la gestion de la DCNC. / Chronic non-cancer pain (CNCP) is a complex phenomenon and multimodal interventions that address both its biological and psychosocial dimensions are considered as the optimal approach for treating this type of disorder. Prescription of opioids for CNCP has dramatically increased over the past two decades but little is known about the long-term effectiveness of this type of medication for reducing pain severity and improving quality of life of CNCP patients. The objective of the present study was to investigate in a real life context the long-term effectiveness of opioids for reducing pain intensity and interference, and improving health-related quality of life in patients with CNCP over a one-year period. Methods: Participants were 1,490 patients (mean age = 52.37 (SD = 13.9); female = 60.9%) enrolled in the Quebec Pain Registry between October 2008 and April 2011 who completed a series of questionnaires before initiating treatment at a tertiary multidisciplinary pain management facility as well as 6 and 12 months thereafter. Based on their opioid use profile (OUP), patients were categorized into 1) non users, 2) non-persistent users, and 3) persistent users. Data were analyzed using generalized estimating equation models. Results: Among the users of opioids, 52% stopped taking them during the follow-up period. After adjusting for age and sex, patients’ OUP significantly predicted pain intensity felt during 7-day periods (p < 0.001) and physical quality of life (pQOL) over time p < 0.001). Compared to non-users, persistent users had significantly higher levels of pain intensity and poorer pQOL. A significant interaction was found between patients’ OUP and time in the prediction of worst pain intensity (p = 0.001) but the persistent users reported the highest pain scores across time. A significant interaction was also observed between patients’ OUP and type of pain in the prediction of pain interference (p = 0.048) and mental quality of life (mQOL) (p = 0.042). Irrespective of the type of pain they suffered, persistent users reported higher pain interference scores and lower mQOL compared to non users. However, all effect sizes were small (Cohen’s d < 0.5), thus questioning the power and clinical significance of these group differences. Conclusion: These results contribute to the debate by adding evidences on the effectiveness of long term opioid therapy and question the role this type of medication should play in the therapeutic arsenal for managing CNCP.

The thesis is devoted to the issue of addiction services with a focus on substitution treatment. Theoretical part focuses on presenting of susbstitution treatment, its history and description of the substitution substances and their effects on the human body. Describes the abuse of substitution treatment by problem drug users and tries to map out the various addiction treatment services with a focus on substitution treatment in Prague. The research section defines the attitude of society towards the establishment and functioning of Prague substitution centers. The thesis concludes with an overview of addiction services and substitution programs in the capital city of Prague. Powered by TCPDF (www.tcpdf.org)

The thesis investigates the theoretical knowledge about the issue of addictive substances and personal experience with their use for pupils 6. and 8. classes of primary school and for students 2. and 4. year of the grammar school. In the first part of my work, I focused on the definition of basic concepts, the outline of the characters and the possible causes that lead to addiction to drugs, I presented the most commonly used drugs and identified the possibilities of drug prevention. The second part is devoted to a survey in the form of a questionnaire, which directly examines the knowledge and experience with the drug specific age groups of pupils and students. This work could be material for teachers who want to participate in the drug prevention.

Bases: A antinocicepção induzida por substâncias doces tem sido largamente estudada. Contudo, a investigação dos neurotransmissores envolvidos nesse processo antinociceptivo ainda carece de mais estudos, pois é de extrema importância entender o envolvimento desses neurotransmissores no sistema neural que controla este tipo de antinocicepção. Objetivo: O objetivo deste estudo é clarificar o envolvimento dos sistemas opióide e serotoninérgico na antinocicepção induzida por substância doce. Método: O presente trabalho foi realizado em modelo animal (Rattus norvegicus, Rodentia, Muridae), objetivando investigar se a ingestão crônica de solução de sacarose é seguida de antinocicepção. A latência de retirada de cauda após a aplicação de estímulo nocivo térmico foi medida antes e após esse tratamento no teste de retirada de cauda (provavelmente um reflexo espinal). Não houve diferenças estatisticamente significantes entre os valores de linha basal dos diferentes grupos e foi calculado um índice de analgesia da latência de retirada de cauda antes e depois do tratamento. O envolvimento de opióides endógenos e de serotonina neste processo antinociceptivo foi pesquisado com fármacos antagonistas específicos e não-específicos dos receptores opióides e serotoninérgicos. Resultados: O efeito analgésico da ingestão de sacarose depende da concentração da solução de sacarose e do tempo de duração do consumo da mesma. Naltrexona e metisergida diminuíram a antinocicepção induzida por substâncias doce (após 14 dias de ingestão da sacarose). Estes efeitos foram corroborados pela administração periférica de naloxonazina e cetanserina. Conclusões: Os resultados sugerem o envolvimento de opióides endógenos e serotonina no processo antinociceptivo atualmente estudado. Tudo apontando para a participação de receptores opióides µ1 e serotoninérgicos 5-HT2 na regulação central da antinocicepção induzida por substâncias doces. / Rationale: Sweet substance-induced antinociception has been widely studied, and the investigation of the neurotransmitters involved in the antinociceptive process is an important way for understanding the involvement of neural system controlling this kind of antinociception. Objective: The aim of this study is to investigate the involvement of opioid and serotonergic system in the sweet substance-induces antinociception. Methods: the present work was made in animal model (Rattus norvegicus, Rodentia, Muridae); with the aim of investigating if the chronic intake of sweet substance, such as sucrose, is followed by antinociception. Their tail withdrawal latencies in the tail-flick test (probably a spinal reflex) were measured before and immediately after this treatment. As there was not statistic significant differences between baseline values of different groups, an analgesia index was calculated from the withdrawal latencies before and after treatment. The involvement of endogenous opioid and serotonin in the antinociceptive process was investigated with specific and non-specific pharmacological antagonism on opioid and serotonergic receptors. Results: The analgesic effect of sucrose intake depends on the concentration of sucrose solution and on the time during which the solution is consumed. Naltrexone and methysergide decreased the sweet substance-induced antinociception (post 14 days of sucrose intake). These effects were corroborated by peripheral administration of naloxonazina and ketanserin. Conclusions: The present results suggest the involvement of endogenous opioids and serotonin in the antinociceptive process presently studied. µ1-opioid and 5-HT2 serotonergic receptors may be involved in the central regulation of the sweet substance-produced antinociception.