Dysregulation of low-voltage-activated calcium channels (CaV3.1-CaV3.3) underlies diseases including chronic pain, autism, and hypertension. As a major determinant of protein half-life, the ubiquitin-proteasome system (UPS) may not only cause abnormal CaV3 expression but also be targeted to control channel levels for therapy. There are >600 E3 ubiquitin ligases that catalyse the final step in ubiquitination. A crucial aspect of harnessing the UPS is knowing which E3 ligases regulate a given substrate, and whether their actions are redundant. We report that CaV3.1 and CaV3.2 are distinctively regulated by two NEDD4 family E3 ligases – NEDD4L and Smurf1. Reconstituted CaV3.1 currents were robustly suppressed by Smurf1 but not NEDD4L, whereas CaV3.2 was inhibited by both NEDD4L and Smurf1, concomitant with diminished channel surface density and expression. FRET experiments revealed NEDD4L and Smurf1 interact with distinct loci in CaV3.1 and CaV3.2. Nanobody-mediated targeting of NEDD4L or Smurf1, but not WWP1, HECT domains to CaV3.1 and CaV3.2 strongly suppressed currents through both channels. shRNA knockdown of either NEDD4L or Smurf1 in dorsal root ganglion (DRG) neurons substantially increased both low-voltage and high-voltage-activated calcium channel currents. The results reveal non-redundant regulation of CaV3 channels by NEDD4L and Smurf1; introduce Smurf1 as a potent determinant of ion channel expression; suggest a new mechanism for CaV3.2 up-regulation in chronic pain; and advance leveraging the UPS to control CaV3 expression for therapy.

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.

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Chronic pain has an adverse impact on the quality of life in children and adolescents. It can impair a child’s physical, psychological, and social functioning, leading to lower satisfaction with life and poor self-image related to health status. Forty-five percent of children experience chronic pain related to either disease processes or idiopathic causes. Not all children who suffer from chronic pain respond to traditional therapies. The purpose of this literature review was evaluation of current research on the use of yoga as an integrative therapy for chronic pain management in the pediatric population. A database search of CINAHL, MEDLINE, and PsycINFO was conducted. Yoga has few side effects, is inexpensive, and can be practiced almost anywhere, regardless of physical ability or age. There is limited research on the use of yoga as an intervention within the pediatric population. Existing research supports the efficacy of yoga for chronic pain management.

While chronic pain is an increasingly prevalent condition in the United States, it is twice as common among the military veteran population. As many Vietnam War era veterans are aging and experiencing comorbid medical conditions, their chronic pain is becoming increasingly complex. Policies enacted in response to the ‘opioid epidemic’ have in some ways made treatment of pain safer, but have also left remaining questions regarding how to properly provide care. There are three fields of complexity that interact within this topic: patients with a clear need for care and pain management, providers committed to helping patients, and structural barriers that unintentionally interfere with the provision of care. The lived experience of chronic pain and receiving care through the VA healthcare system combined with a common military culture exemplifies a lifeworld centered on pain—which I call a ‘painworld.’ This painworld is seen in the illness narratives of older, white, male veterans with chronic pain. Examining the way a single VA site provides pain care shows the providers are dedicated to treating veteran patients and offer a large number of treatment options. While the need for pain management services is clear from both the patient and provider perspectives, translating the lived experience of these veterans and their medical needs into a hierarchical bureaucratic structure is difficult. Furthermore, the bureaucratic nature of a large federal organization creates gaps in the healthcare system. This leads to the creation of informal systems through systems-correcting praxis to fill the gaps and attempt to prevent siloing and slippage throughout. Together, these fields of complexity are organized into three chapters, building the argument that the convergence of veteran painworlds, pain care, and bureaucracy can contribute to miscommunication, leading to unintended slippage through the system and inadequate care, despite good intentions of staff. Furthermore, the VA system and structure of providing pain care both influences and is part of the painworld, as are the interactions that occur between veteran patients and staff.

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)

Bakgrund: Långvarig smärta är ett vanligt förekommande tillstånd, även bland unga vuxna. Smärtproblematik leder ofta till inskränkningar i det dagliga livet, till exempel genom minskad fysisk aktivitet vilket kan leda till försämrad funktionsförmåga. Vid komplex långvarig smärta rekommenderas ofta multimodala smärtrehabiliteringsprogram i syfte att förbättra funktionsförmågan. Det saknas dock i dagsläget kunskap om hur dessa program upplevs av unga vuxna patienter. Syfte: Att undersöka hur unga vuxna med långvarig smärta upplever ett multimodalt smärtrehabiliteringsprogram och hur de upplevt att deltagande i programmet påverkat deras fysiska funktionsförmåga och tankar om fysisk aktivitet Metod: En kvalitativ, semistrukturerad intervjustudie. Tio deltagare rekryterades utifrån ett bekvämlighetsurval. Databearbetning skedde med hjälp av kvalitativ innehållsanalys. Resultat: Deltagarna i studien upplevde att de under smärtrehabiliteringsprogrammet var i en trygg miljö där de blev förstådda. De hittade nya förhållningssätt med ökad acceptans och tilltro till den egna förmågan. Många beskrev ett nytt sätt att se på att vara fysiskt aktiv trots smärta, där viktiga faktorer var att lyssna på kroppen och anpassa aktiviteten efter dagsformen. Flera deltagare önskade att rehabiliteringsprogrammet hade haft ett större fokus på fysisk aktivitet. Slutsats: Studien visade att unga vuxna patienter med långvarig smärta som genomgick ett smärtrehabiliteringsprogram upplevde sig vara i ett sammanhang där de blev förstådda och bekräftade. Programmet resulterade i nya kunskaper som underlättade vardagen och nya förhållningssätt till ett liv med smärta och till att vara fysiskt aktiv. Fortsatt forskning inom området är av vikt för att säkerställa att patientgruppen erbjuds väl utformad rehabilitering / Background: Chronic pain is a common diagnosis, also among young adults. Pain conditions often have an impact on daily life by causing patients to be less physically active and hence affecting their functional capacity. In order to improve functional capacity, multimodal rehabilitation programmes are often recommended. However, there is a significant knowledge gap in how young adults with chronic pain experience such programmes. Objective: To examine young adults’ experience of participating in a multimodal pain rehabilitation programme, and how they consider the programme having affected their functional capacity and thoughts about being physically active. Method: A qualitative, semi structured interview study. Ten participants were recruited based on convenience sampling. The data analysis was performed using qualitative content analysis. Results: The participants described the rehabilitation programme as a safe and validating environment. They were helped to develop a new, more accepting, approach to life with pain. Many participants described a new attitude towards physical activity, which involved paying attention to signals from the body and adjusting activities accordingly. Several participants wished for the programme to have a greater focus on physical activity. Conclusion: The study shows that young adults with chronic pain experienced being understood and validated when attending a rehabilitation programme. The programme provided new skills that improved daily life, and gave rise to new attitudes towards a life with pain and the possibility of being physically active. More research on the subject is important in order to ensure that young adults with chronic pain are offered well suited rehabilitation programmes.

Background: Pediatric chronic pain is prevalent and comes with diagnostic uncertainty and biopsychosocial complexity. The literature significantly lacks evidence and clinical guidance to inform triage decisions to interdisciplinary pediatric chronic pain programs, which likely impacts timely and appropriate access to much needed interdisciplinary care. Purpose: To methodically conduct foundational investigation into triage within interdisciplinary pediatric chronic pain programs to develop a preliminary series of Clinical Decision Support (CDS) triage tools grounded in evidence to facilitate nurses' triage decision-making. Methods: A pragmatic, multi-method study was conducted and fundamentally guided by the Knowledge to Action Framework (KTA). Included studies involved: 1) A modified Delphi study to attain expert consensus on the diagnostic expectations of pediatric patients referred to interdisciplinary chronic pain programs; 2) A systematic review of multidimensional biopsychosocial tools used in the pediatric chronic pain population, guided by the Multidimensional Biobehavioral Model of Pediatric Pain; and 3) An explorative descriptive qualitative study guided by the Cognitive Continuum Theory (CCT) and the Theoretical Domains Framework (TDF) to explore and describe the decision-making practices of and contextual influences on nurses triaging patients to interdisciplinary pediatric chronic pain programs. Findings: Following two survey rounds, the Delphi study demonstrated consensus on 84% of diagnostic items and general agreement regarding the diagnostic expectations of referred patients. The systematic review revealed six valid and reliable multidimensional biopsychosocial tools and highlighted 84 significant relationships between pain and functional interference across 11 biopsychosocial variables. The qualitative study emphasized the leading and complex triage role nurses lead in interdisciplinary pediatric chronic pain programs, and comprehensively described the triage process and determinants of the triage decision. Conclusions: Findings from the three studies have been integrated into the preliminary development of a series of CDS triage tools to be used in interdisciplinary pediatric chronic pain programs. This series offers decision guidance to accept or redirect care based on diagnostic clarity and a strategy to prioritize access to interdisciplinary care based on biopsychosocial needs. To determine clinical utility and validity of the tool, future research will target end-users to finalize tool development.

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