Funded Projects

Opioid use disorder (OUD) is a significant public health problem in the United States. Particularly troubling is the rapid evolution of an opioid epidemic within the past decade, characterized by a surge in unintentional overdose deaths involving synthetic opioids, such as fentanyl. The current standard of care for opioid overdose is reversal with opioid antagonist naloxone. Naloxone is effective at reversing overdose from prescription opioids and heroin, but less effective when combating fentanyl, due to fentanyl?s high potency. Therapeutic monoclonal antibodies (mAbs) against fentanyl could overcome this problem by specifically preventing the drug from entering the central nervous system, averting overdose and attenuating opioid-induced respiratory depression. This study will develop and design of laboratory protocols needed to establish a Good Manufacturing Practice (GMP) process, quality assurance protocol, and stability profile for a new human mAb against fentanyl. Subsequent production of current GMP material will enable Good Laboratory Practice (GLP) toxicology studies in rats and dogs and eventually a Phase I/IIa clinical trial. This material will also be used in final opioid-induced respiratory depression studies in mice and non-human primates to confirm therapeutic efficacy of final drug product. If successful, these activities will enable filing for an investigational new drug application for this mAb candidate with the FDA.

Difficulty breathing is a hallmark symptom of an opioid-related overdose and can result in permanent brain injury or death within minutes. This project will develop a community-deployable Automated External Respiration System device that can restore and sustain breathing in people experiencing opioid-induced respiratory depression. The device stimulates the phrenic nerve in the chest that controls breathing until other medical interventions are available or the patient recovers. The research will develop and validate the automated external respiration system for testing in human research participants and ultimately aims to develop a system usable in a community setting.

Mismanagement of orofacial chronic pain, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, substantially contributes to opioid overuse; overdose-related deaths; and cardiovascular, renal, and neurological complications at epidemic proportions. The current paradigm implies that orofacial conditions could trigger maladaptation of the immune system and plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LT?), members of the tumor necrosis factor superfamily, provide a balance between protective immunity and immunopathology during chronic inflammatory diseases. This project will test the hypothesis that targeting LIGHT and LT? signaling could prevent the development and inhibit the maintenance of chronic pain produced by TMJD and oral cancer, via peripheral mechanisms involving plasticity of immune, stromal, and tumor cells, as well as sensory neurons. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain and offers new therapeutic targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer.

Abuse of opioids constitutes a national public health crisis. Data from the Lummi Nation show that for the 18 Tribal member deaths occurring in the first seven months of 2016, five were opioid related, with the average age of the deceased being 29 years. The proposed Native Transformations Opioid Project (NTOP) seeks to develop research capacity at Northwest Indian College and its surrounding tribal communities to develop effective and culturally congruent strategies to reduce the burden of death from opioid and other drug-related overdoses in tribal communities in the Pacific Northwest. The primary aim of the proposed project is to identify the strengths and behavioral strategies in successful recovery from OUD in three Coast Salish communities. The ultimate goal of the proposed research is to identify Coast Salish recovery factors from OUD to develop a data-driven, culturally congruent intervention to reduce OUD and OUD overdose deaths.

American Indian and Alaska Native (AI/AN) youth and young adults experience disproportionately high rates of suicide, mental health disorders, traumatic life events, and substance use disorder. More effective, culturally informed interventions are needed that are tailored to the specific needs of this population. This supplement will examine how a person?s social network contributes to their behavioral health (suicide risk, mental health, substance use) status and how this network can be leveraged to improve the uptake of prevention interventions. The long-term goal is to disseminate and translate the lessons learned into practical policy, organizational changes, and preventive innovations that optimize patient-centered health outcomes and ultimately reduce or eliminate the dramatic and tragic suicide-related health disparities among urban AI/AN YYAs.

Mortality and morbidity related to suicidal behavior and opioid use disorder (OUD) have increased significantly over the past decade. These two public health crises are intertwined at multiple levels. Medications for OUD, especially buprenorphine, have been shown to decrease opioid use and reduce the multiple negative consequences of OUD, including fatal and nonfatal overdose, criminal justice involvement, infectious complications, and misuse of other substances. In addition, small randomized trials of buprenorphine treatment in treatment-resistant depression (with or without co-occurring OUD) suggest that buprenorphine reduces depressive symptoms and suicidal ideation. This large study will evaluate the effects of starting buprenorphine treatment on self-harm and suicide attempt among people with opioid use disorder, including those with and without co-occurring mental health conditions or other known risk factors for suicidal behavior. Comprehensive health records data from four large health systems serving a combined member/patient population of approximately 11 million will be examined for the overall effect of buprenorphine treatment on subsequent self-harm or suicide attempt, including differences in effects between patient subgroups and specificity of effects to buprenorphine vs other medications.

This study will evaluate the implementation of the Zero Suicide framework across six health systems serving over nine million people in collaboration with the Mental Health Research Network. The project will incorporate the voice of the patient and provider stakeholders as part of the implementation of the Zero Suicide framework in three health settings from the NIMH-funded parent award as well as the Southcentral Foundation which is an Alaska Native-owned, nonprofit health care organization serving nearly 65,000 American Indian/Alaskan Native people living in and around Anchorage, Alaska. The team will first systematically engage patients, providers, national consumer advocacy groups, and MHRN scientists in formulating research questions to address the prevention of opioid-related overdoses in people with Opioid Use Disorders (OUD) or people without diagnosed OUD who are using opioids for pain management. Next, the team will utilize semi-structured interviews to determine how people with OUD or people without diagnosed OUD who are using opioids for pain management are experiencing the implementation of the Zero Suicide framework in four diverse health systems. Experiences will be recorded using 80 semi-structured phone interviews in a diverse sample of patients who have survived an opioid-related overdose (50% intentional; 50% unintentional), as well as 20 Addiction Medicine, Primary Care, and/or Specialty Pain Medicine providers.

The parent U19, “Southwest Hub for American Indian Youth Suicide Prevention,” builds capacity among local tribal governments, investigators, interventionists, and service providers across three Southwestern states to: 1) identify at-risk youth and gather robust local data through surveillance; 2) provide regular monitoring and brief interventions to close gaps in continuity of care; and 3) convene regularly for shared learning, policy development, and dissemination of best practices. The parent U19 includes an innovative SMART trial study design. The purpose of this supplement is to gather data on opioid use. Our supplement aims are to: 1) expand suicide surveillance in the Southwest Hub to include opioid use as a potential precipitant, facilitator, and risk factor for subsequent suicidal behavior; 2) explore community beliefs about correlates of risk, protective factors, and behavior functions of opioid abuse in Native American youth; and 3) examine opioid use among SMART trial participants.

The System of Safety (SOS) represents an opportunity to study the implementation of best practice suicide-related care processes that embody the Zero Suicide Essential Elements of Care across emergency departments, inpatient medical and behavioral health units, and primary care clinics associated with a large healthcare system. This effectiveness trial will use a stepped wedge design across a total of 39 clinical units. Aim 1 will measure suicide risk screening and screening's impact on risk identification. Aim 2 will measure the effective implementation of clinician-administered interventions, such as safety planning with means restriction counseling, on suicide, suicide attempts, and suicide-related acute healthcare. Exploratory aims will examine mechanisms of action, moderators, economics, and population effects of the intervention. This study's innovative approach positions it for a significant impact on the fields of suicide prevention, CQI, and effectiveness trial design and analysis.

Medication-assisted treatment (MAT) represents the gold-standard intervention for opioid use disorder (OUD). However, only 20% of Americans with OUD received any formal or informal addiction treatment in the past year. Lack of access and engagement in MAT is driving poor OUD outcomes, especially in rural areas lacking specialty addiction services. The Advancing Integrated Mental Health Solutions (AIMS) Center at the University of Washington has successfully helped over a thousand primary care clinics across the country implement collaborative care for mental health disorders. The study will determine whether collaborative care can be used to successfully treat mental health disorders and OUD concurrently in primary care settings. Clinics offering collaborative care will randomize sites to add OUD to their collaborative care program or remain unchanged. Clinics not offering collaborative care will randomize sites to implementing collaborative care for OUD and mental health disorders simultaneously or for mental health disorders only.

Some medications for opioid use disorder (MOUD) can be provided in primary care (PC). Systems of team-based PC show promise for improving access and retention in OUD treatment. One such model, collaborative care (CC), includes a care manager, supervised by experts, who help provide evidence-based high-quality OUD care. While CC improves outcomes of depression, other mental health and substance use (MH/SU) disorders and pain, it is unknown how to optimally integrate CC for OUD with other MH/SU disorders. This pragmatic trial tests whether our model of CC for OUD and comorbid conditions increases engagement in MOUD treatment and improves depression symptoms in PC patients with OUD and depression. Innovative pragmatic elements include inclusion of all eligible patients in participating PC clinics, random recruitment and consent, and measurement of main outcomes using only secondary data. These pragmatic elements avoid studying only motivated patients and avoid activating patients randomized to usual care.

American Native (AN) communities experience high rates of trauma that compromise the mental health of parents and caregivers that in turn increases their children?s risk for suicide and substance use during adolescence and young adulthood. Without intervention, this intergenerational cycle may repeat. The goal of this study is to understand opioid use, suicide, and the social network characteristics of Fort Peck Assiniboine and Sioux parents and caregivers to determine how the social network of parents/adult caregivers are related to both risk for and protection from suicide and opioid use. This supplement will examine the effectiveness of a community health worker delivered, culturally tailored prevention intervention called Wa?Kan Ye?Zah on caregiver and child behavioral and mental health outcomes and assess the benefits of culturally enhancing the intervention for caregivers? well-being.