Funded Projects

The opioid crisis continues its highly negative impact, with more than 49,000 opioid-related overdose deaths in 2017. In 2016, the Centers for Disease Control and Prevention (CDC) issued guidelines for opioid prescribing that included opioid dosing and risk mitigation strategies, and health systems implemented similar initiatives even earlier. This has resulted in a quickly changing and more conservative prescribing environment. National data indicate the number of prescriptions has fallen between 2013 and 2016. Registries and electronic health record (EHR) data are increasingly cited as valuable resources to address critical research questions on opioid use with high efficiency. To our knowledge, no investigators have established an EHR-based prescription opioid registry across several diverse health systems with common data algorithms with the flexibility to address multiple questions. The goal of the proposed research is to develop a prescription opioid registry across 10 diverse health systems with harmonized EHR data from years 2012-2018 and leverage it to answer several key “next-step” research questions in response to the opioid crisis. The registry will include medications prescribed for treatment of OUD, including buprenorphine products.

The Planning for the HEALthy Early Development Study will contribute to the design and recommended protocol for a future large-scale, multi-site research study to prospectively examine human brain, cognitive, behavioral, social, and emotional development of children beginning prenatally through ages 9–10 and to determine the impact of maternal pre- and postnatal substance use on short- and long-term development of children. The planning study will link investigators across 6 research sites who have complementary experience and expertise in the areas that are essential to designing the study. Planning activities will be accomplished using a coordinated set of 10 working groups. By the end of the planning phase, the 6 consortium sites will have produced and tested a recommended protocol for the future multi-site study and will have established feasibility of carrying out the study protocol at each of the 6 linked sites.

People who use opioids in rural areas suffer worse health and less insurance coverage. The opioid problem in rural areas is of particular concern, as rural areas have higher overdose rates despite equivalent rates of OUD. This is because rural areas have a scant number of clinics and clinicians who provide medication treatment for OUD. Thus, people living in rural areas must travel long distances to access clinics that may or may not have expertise in providing treatment to patients with OUD. Telemedicine (TM) could efficiently increase capacity for delivery of buprenorphine in rural areas and may increase the number of patients receiving medication treatment and improve treatment retention and outcomes. While the development of medication treatments for opioid use disorder (MOUD) capacity in primary care settings with optimal/comprehensive services is desirable, the current opioid crisis with escalating overdose death rates in rural areas suggests a need to implement an efficient, cost-effective system of MOUD services that can be scaled up quickly. The use of a centralized and Medicare-covered TM vendor utilizing a developed methodology and established organizational infrastructure offers the great potential for a rapid rollout to increase access to MOUD and improve treatment retention in rural areas. This cluster randomized clinical trial with two phases will test expanded treatment access to improve retention on MOUD in highly affected rural areas. Phase I will include implementing telemedicine in a limited number of rural sites with varying levels of office-based opioid treatment (OBOT) to inform implementation strategies for the main trial, and Phase II will include evaluate comparative effectiveness between OBOT alone and OBOT + TM at 30 sites.

Most opioid misuse begins during adolescence and young adulthood. Adolescence is the best time for prevention interventions in settings like school-based health centers (HCs), yet few programs focus on preventing initiation of opioid misuse. This study harnesses the power of video game interventions and incorporates components of effective substance use prevention programs to develop an evidence-informed intervention to prevent the initiation of opioid misuse in adolescents. In partnership with the national School-Based Health Alliance (SBHA), researchers will develop and test a new video game intervention, PlaySmart. It will build on our previous video game intervention that has demonstrated efficacy in improving attitudes and knowledge related to risk behaviors. The study will evaluate the game in a randomized controlled trial (RCT) in 10 school-based HCs and examine strategies for implementing PlaySmart in school-based HCs nationally. This research has considerable potential for wide implementation, reach, and impact on high-risk adolescents through school-based HCs.

A large number of probationers/parolees with opioid use disorder have limited access to effective treatment. This study is the first random clinical trial in the United States that will assess the effectiveness of buprenorphine treatment using MedicaSafe, a system composed of secure pre-packaged buprenorphine/naloxone cartridges, designed to be dispensed by a SmartKey device that enables clinicians to track patient adherence. The study will initiate treatment at a community corrections office compared to referral to a community program. The public health impact of the proposed study would be widespread, as this model of care could be implemented throughout many areas of the United States with high rates of opioid use disorder in their probation/parolee populations that lack access to methadone treatment.

Mortality rates in Appalachia have progressively increased over recent years, in contrast to decreasing mortality rates observed in the remainder of the U.S. The West Virginia Clinical and Translational Science Institute (WVCTSI) was created in 2012 through the initial Clinical and Translational Research (CTR) award and has subsequently formed a well-connected, statewide research network, creating the infrastructure to address the substantial health disparities that exist in West Virginia. WVCTSI is now well positioned to attain the goals of this renewal application that include: 1) building sustainable research infrastructure that substantively contributes to improving West Virginia health outcomes by 2022; 2) recruiting the next generation of clinician scientists and translational researchers that excel in team science and are positioned for long-term success; and 3) actively engaging with multiple stakeholders that include communities, medical providers, and policy makers to drive research that improves the health of West Virginians.

Extended-release naltrexone (XR-NTX) reduces overdose risk; however, transitioning to XR-NTX requires detoxification, which is a major hurdle. Non-opioid detoxification with an alpha-2 adrenergic receptor agonist, such as lofexidine, may shorten detoxification time, but it does not reduce the subjective effects of withdrawal. Pregabalin potentiates the activity of glutamic acid decarboxylase, inhibits calcium influx and release of excitatory neurotransmitters, raises GABA levels, and is approved for neuropathic pain, for fibromyalgia, and as an adjunctive therapy for adults with partial onset seizures. The study will test whether pregabalin can be combined with lofexidine to better reduce the subjective effects of opioid withdrawal than lofexidine alone and increase the proportion of patients that transition to XR-NTX. Such a dosing combination could lower the detoxification hurdle for patients who are interested in antagonist treatment or who are in settings where it is unavailable or difficult to access.

The Appalachian Node of NIDA Clinical Trials Network (CTN) will address clinical research questions that arise from Central Appalachia, an epicenter of the current opioid epidemic. Its rural geography, culture of independence, strained economy, and lack of access to substance use treatment have all contributed to the epidemic. The three aims of the node are to (1) conduct multi-site trials that address the current opioid crisis, with an emphasis on conducting studies among rural and other underserved populations; (2) propose studies to test innovative uses of existing resources to implement evidence-based practices that will extend state-of-the-art care into resource-poor regions, both rural and urban; and (3) disseminate CTN findings to regional payers and policymakers, practitioners, and the community. Proposed studies built on the work of node investigators include “Serious Bacterial Infections Related to Injection Drug Use: Quality Metrics and Intervention” and “Pharmacist-Assisted Buprenorphine Treatment,” among others.

Deaths from opioid overdose are highly preventable with early detection and administration of naloxone, but overdose victims often die because they are alone or among untrained or impaired bystanders and thus do not receive timely resuscitation. There is an urgent, unmet need for a low-barrier, easily scalable solution that can identify opioid overdoses in real time and rapidly connect victims to naloxone therapy. This proposal seeks to commercialize an innovative overdose detection software product that can be downloaded on any commodity smartphone and can detect opioid- induced respiratory failure (i.e., overdose) and summon help. The software-only product, SecondChance, converts a smartphone into a short-range active sonar system capable of monitoring breathing and detecting overdose.

This project will develop a human cell-based model of the afferent pain pathway in the dorsal horn of the spinal cord. The research team’s approach utilizes novel human pluripotent stem cell (hPSC)-derived phenotypes in a model that combines 3D organoid culture with microfabricated systems on an integrated, three-dimensional (3D) microelectrode array. Researchers will establish the feasibility of a physiologically relevant, human 3D model of the afferent pain pathway that will be useful for evaluation of candidate analgesic drugs. They will then improve the physiological relevance of the system by promoting neural network maturation before demonstrating the system’s utility in modeling adverse effects of opioids and screening compounds to validate the model. Completion of the study objective will establish novel protocols for deriving dorsal horn neurons from hPSCs and create the first human microphysiological model of the spinal cord dorsal horn afferent sensory pathway.

Addiction to opioids is related to the physiology of the brain’s dopamine-based reward system. As a modulator of dopaminergic systems, the neurotensin 1 receptor (NTR1) should be a molecular target for treating addictive disorders; however, few non-peptide brain penetrant neurotensin modulators have been identified, and orthosteric NTR1 ligands display side effects that have limited their clinical development. This group discovered a series of brain-penetrant NTR1 modulators, including a lead compound SBI-553, with a unique mechanism of action at NTR1. SBI-553 is an orally available, brain penetrant ?-arrestin biased allosteric modulator of NTR1, which shows efficacy in a range of addiction models and circumvents the clinically limiting side effects. While potentially high risk, the activity of SBI-553 has been validated in vitro and in vivo, and the initial safety profiling indicates no issues that would preclude further development. This study will develop SBI-553 as a treatment for opioid use disorder.

Current opioid overdose treatment requires administration of naloxone by first responders, which requires timely identification of the overdose, the need for a rescue injection, and immediate availability of the medication. The development of a fail-safe treatment that would provide a life-saving dose of naloxone without the need for intervention by another party could significantly reduce mortality. The researchers aim to develop a new medical device comprising an implantable, closed-loop system that senses the presence of an opioid overdose, automatically administers a life-saving bolus injection of naloxone, and simultaneously alerts first responders.