Funded Projects

Relapse is common in people with opioid use disorder, and recovery attempts often fail within 6 months. This research project will test a novel virtual reality intervention to improve recovery outcomes for people recovering from opioid use disorder. By increasing future orientation and delay-of-reward behavior with a precision medicine personalized experience, the intervention is designed to enhance advantageous decision-making and increase positive future outcomes. The results of this study will provide critical data for creating a commercially viable software product for facilitating relapse prevention and improving opioid use disorder recovery outcomes.

High rates of relapse and overdose deaths pose significant challenges to the treatment of Opioid Use Disorder (OUD). Anti-opioid immunotherapies (i.e., vaccines and monoclonal antibodies) have great potential to reduce long-term opioid use and overdose, with minimal risk of side effects, when used in conjunction with pharmacological treatments and/or behavioral therapies. The ability of an anti-opioid vaccine to induce antibodies that render an opioid less effective, or less rewarding, and protect from accidental overdose could provide an important therapeutic option for patients undergoing treatment for OUD. The goal of this collaborative study is to design, develop, and evaluate vaccines for use in the treatment of opioid use disorder

The first ten years of life are accompanied by rapid changes to the developing brain and cognitive abilities. Complex interacting factors including genetics, early-life exposure to substances, family and social interactions, and home and community environments can affect brain and cognitive development. Three linked projects aim to develop effective research protocols to lay a foundation for a future HEALthy Brain and Cognitive Development (HBCD) birth cohort study. Project 1 will develop protocols for recruitment and retention of a diverse sample of pregnant and postpartum women with oversampling of mothers with prenatal opioid use. Project 2 will identify ethical, legal, and regulatory challenges for investigations in this vulnerable population and define effective solutions to enable recruitment and study of these participants. Project 3 will develop and evaluate protocols for acquiring high-quality, quantitative neuroimaging measures with magnetic resonance imaging and functional near infrared spectroscopy and assess effective strategies for measuring cognitive performance in young children, including those exposed to opioids.

A more than 5-fold increase in the incidence of neonatal abstinence syndrome has been reported since 2000. Preliminary studies show that prenatal opioid exposure is associated with increased risk of impaired neurodevelopment. Five institutions (Duke University, Arkansas Children’s Research Institute, Cincinnati Children’s Hospital, University of Illinois at Urbana–Champaign, and University of North Carolina at Chapel Hill) have formed a consortium to develop strategies for the Phase II HEALthy Brain and Child Development Study. Research teams will develop instruments and strategies (recruitment/retention protocols, assessment batteries, and novel tools); conduct pilot studies (fetal and postnatal imaging, advanced imaging harmonization and quality control, assessment administration, biosampling) to evaluate instruments; and analyze available data, including imaging, behavioral, cognitive, and maternal data from studies on early brain development, to guide the Phase II study design. Upon completion, the consortium aims to conduct the Phase II study.

Central Appalachia has been devastated by opioid use disorder and overdose deaths for decades. Treatment access is improving across that region, yet few individuals successfully remain on treatment with medications for opioid use disorder (MOUD). Peer recovery support services can be highly effective in improving treatment outcomes and recovery, but there is limited evidence of how they can be implemented and used most effectively, particularly for individuals receiving MOUD. This project will create the Studies To Advance Recovery Supports (STARS) Network that aims to expand the infrastructure necessary to implement and evaluate peer recovery support services for these individuals. It will build research capacities at universities and health partners, enroll MOUD clinics and peer recovery support professionals, and promote data harmonization across network partners.

New Mexico (NM) is an epicenter of the opioid crisis in the United States. Many challenging social determinants, including poverty and unemployment, contribute to high rates of opioid use disorder (OUD) in NM. The aims of the NM node are to (1) develop and maintain a highly efficient platform to conduct clinical trials that will inform evidence-based prevention and treatment of OUD; (2) collaborate on and lead research that addresses and improves outcomes across the OUD Cascade of Care (CoC); and (3) promote uptake of best practices in OUD prevention and care in NM and nationwide through effective dissemination of evidence-based innovations. NM node research will ensure the development of robust and generalizable methods for prevention, identification, and treatment of OUD, including evaluation and modification of the CoC to expand the local and national knowledge base.

Rates of neonatal abstinence syndrome have reached a staggering 6.5 per 1,000 births nationwide, creating an urgent need to identify how in-utero exposure to opioids and associated risk factors influence the developing brain. A multidisciplinary team will address these challenges in Oregon, a state particularly hard hit by the opioid epidemic. Through linking sites, the impact of the Phase I project is enhanced and will provide critical information to support a national-level effort for Phase II of the HEALthy Brain and Child Development Study. Aim 1 will develop, implement, and evaluate innovative recruitment and retention strategies for high-risk populations. Aim 2 will address anticipated challenges of the planned Phase II study by implementing and evaluating a multi-site, standardized research protocol including multimodal MRI of placenta, fetus, neonate, and 24-month-old brain; biospecimen collection; and assessment of substance use and other key domains. Aim 3 will evaluate data acquisition, processing, and statistical considerations to maximize data quality, usability, and integration across sites.

The ongoing opioid crisis has led to renewed concerns about the clinical prescription of addictive opioid analgesics. However, there are currently no suitable alternatives for treating severe or malignant pain. Studies of opioid signaling mechanisms in mice deficient in ?-arrestin have suggested that biased agonists displaying preferential activation of G-protein signaling over ?-arrestin signaling could offer a promising avenue for the development of opioid analgesics with a reduced adverse effects profile. However, there is no concluding evidence showing that such biased signaling can indeed be associated with reduced opioid side effects and, consequently, an improved safety profile. This research will address the need for preclinical data to rigorously evaluate this hypothesis with a program of in vivo studies to compare the effects of “balanced” opioids (morphine, oxycodone, and fentanyl) with that of the “biased” agonists PZM21 and two novel ligands provided by colleagues at the NIDA IRP in nonhuman primates. The results of these studies will provide critical information regarding the dependence liability of “biased” agonists that, in clinical practice, might be given on a repeated, or chronic, basis, potentially adding a powerful new tool for the safer management of severe or malignant pain.

The HEALthy Brain and Child Development National Consortium (HBCD-NC) will establish a normative model of developmental trajectories over the first 10 years of life. All sites in the HBCD-NC will carry out a common research protocol and will assemble and distribute a comprehensive research dataset to the scientific community. The HBCD-NC will collect neural, behavioral, physiological, and psychological measures, as well as biospecimens, to characterize neurodevelopmental trajectories. Most participants will be recruited in the second trimester of pregnancy, with a smaller subset recruited at birth, and followed for the first 10 years of life. The Pennsylvania State University study site is in a region hard hit by opioid and methamphetamine use disorders and will recruit mother-infant pairs from largely rural communities.

Sober Grid™ has developed a smartphone-based mobile application currently in use by more than 120,000 individuals worldwide who are in, or seeking, recovery from drug and alcohol addiction. The “Grid,” as it is known, is a mobile-based, social recovery community providing rapid context-specific peer support, efficient help seeking, motivational enhancement exercises, and member ratings of support content—all aimed to prevent relapse. The overarching goal of this phase II project is to extend the current capabilities of the Sober Grid app to achieve a comprehensive social recovery support app featuring intelligent, context-appropriate resource matching and 24/7 rapid-response peer coaching that is effective in reducing disordered substance use and is cost-effective. This projects tests whether providing this functionality to high-risk members will be acceptable, feasible, increase access to and engagement with resources, and have a positive effect in increasing time to relapse and days of consecutive abstinence.

Due to the opioid misuse epidemic across the nation, more infants are being exposed to narcotics during fetal life and developing neonatal opioid withdrawal syndrome (NOWS) in the neonatal period. Critical gaps remain in our knowledge with respect to best practices for identifying and managing infants with NOWS and no large-scale studies have been published on treatments undertaken and later outcomes of infants with NOWS. To address these gaps in knowledge, the Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW) study will evaluate treatment options and improve clinical care of infants with NAS/NOWS. This collaborative effort will conduct two trials: 1) Eating, Sleeping, Consoling for Neonatal Withdrawal (ESC-NOW): a Function-Based Assessment and Management Approach (ESC Study); and 2) Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS) (Weaning Study).

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.