Funded Projects

This project aims to develop a new way to stimulate the delta opioid receptor to treat withdrawal and abstinence from chronic opioid use. Withdrawal can cause pain, depression, and anxiety, which contribute to relapse. The research will test promising drug candidates in animal models with the intention of bringing at least one effective and safe compound to the final stage of drug development before human clinical trials can begin.

Prescription opioids provide pain relief, but overdose can be fatal because opioids also depress breathing through opioid-induced persistent apnea, when breathing stops. This research will determine whether targeted activation of a specific, opioid-insensitive brain region that triggers exhalation can increase tolerance to fentanyl-induced apnea. The research also seeks to identify the receptors responsible for this exhalation, which could be targets for new medications that prevent the negative impact of opioids on breathing. This research lays the groundwork for more preclinical and translational studies to prevent opioid-induced persistent apnea. 

Rates of opioid use (OU), opioid use disorder (OUD), and overdose (OD) disproportionately affect those in the justice system. Yet, despite such high rates of misuse and associated negative outcomes of untreated OUD, screening and the availability or use of evidence-based treatments for OU and OUD—including medication to treat OUD—are substantially underused in justice populations. This project will leverage the unique, real-time scale-up of a new opioid court model (OCM) to address a critical public and correctional health problem by developing and evaluating an implementation intervention (OCM RISE), designed to build cross-system partnerships to permit the development of generalizable yet tailored strategies that allow the OCM to be scaled up across a variety of contexts.

The expansion of opioid prescribing in recent years to better treat pain has markedly increased their usage and availability and fueled an epidemic of abuse. Up to 80 percent of addicts reported initiating their habit through prescriptions drugs. Decreasing opioid prescriptions would lower opioid exposure, with fewer people receiving the drugs and less drug available for diversion. Study investigators have identified a novel target in the brain, distinct from any of the traditional opioid receptors capable of mediating potent analgesia without the reward behavior and side effects seen with traditional opioids. They targeted this site with a series of arylepoxamides and have identified a clinical candidate (MP1000) and backup compound. MP1000 is a potent analgesic in a range of thermal, inflammatory, and neuropathic analgesic assays. It fails to show reward behavior and does not produce respiratory depression at doses 5-fold greater than its analgesic ED50. Chronic administration does not produce physical dependence or withdrawal when challenged with an antagonist. It shows no cross tolerance to morphine and can be co-administered to subjects already on opioids for pain to lower their opioid usage (i.e., opioid sparing), facilitating the eventual discontinuation of the opioid. If successful, this project could lead to the development of a viable alternative to current opioid-based analgesics with reduced side effects (such as reward and respiratory depression) compared to opioids.

Over 2 million Americans have an Opioid Use Disorder (OUD) and the risks associated with misuse of opioids have prompted a public health crisis. There are three effective FDA-approved drugs for medication assisted treatment (MAT) of OUD. However, while MAT can reduce overall OUD related mortality by as much as fifty percent, relapse and treatment discontinuation are common within the first 5 to 12 weeks of MAT. As longer treatment retention is correlated with better long-term outcomes, the development of an adjunctive medication to alleviate key psychiatric symptoms associated with treatment failure would address an important unmet need. This study seeks to evaluate the safety and efficacy of brexpiprazole as adjunctive treatment to buprenorphine/naloxone in OUD. If successful, this study could enhance the effectiveness of OUD treatments by extending the duration of treatment, thereby reducing the likelihood for relapse and overdose.

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. This study will take place at Washington University in St. Louis, Missouri, and will recruit participants from an urban environment with a high African American population.

With the entwined crises of opioid use and chronic pain, there is a need for alternative, safe therapies to manage opioid use disorder, opioid withdrawal symptoms, chronic pain, and/or associated anxiety and depression. A proof-of-concept preclinical study has already been conducted of a cannabinoid-opioid combination that demonstrated opioid-sparing and synergistic analgesic effects, with the combination providing greater analgesia in a rodent model of chronic pain than a standard dose of the opioid alone. This proposal aims to develop a fixed-dose combination (FDC) of the cannabinoid-opioid that may have improved analgesia with lower opioid doses and thereby lower the risk of dependence, withdrawal, diversion, abuse, and overdose. Preclinical pharmacokinetic and ?in vivo ?safety studies will help determine if co-administration alters the pharmacokinetics and/or respiratory depression related to either compound in rodents.

The orbitofrontal cortex (OFC) plays an important role in regulation of addiction, and OFC impairment from cocaine and opioids use leads to repetitive drug use. Brief optogenetic activation of the OFC reduces self-administration of drugs in neurobiology studies. However, the OFC is less accessible for noninvasive stimulation using direct transcutaneous current stimulation or transcranial magnetic stimulation. The small business EvON Medics LLC and Howard University have created a home-based olfactory pulsing prototype, called computerized chemosensory-based orbitofrontal cortex training (CBOT), using a high-fidelity chemosensory and computerized olfactory training approach to enable home-based neuromodulation of the OFC for treatment of opioid use disorder (OUD). A pilot feasibility study in OUD samples suggests that CBOT can minimize withdrawal symptoms, reduce drug cravings, enhance positive affect, and reduce rate of positive urine drug tests. The project seeks to establish CBOT stimulation parameters needed to maximally improve outcome inference and emotion regulation in OUD.

There is a significant treatment gap between patients diagnosed with OUD and those who seek treatment, and only a small proportion of those seeking treatment receive MOUD. Primary care is the most common point of health care contact in the U.S. and is an important venue to address stigma, improve access to treatment and improve quality of care. Over the past decade, electronic health record (EHR)-linked Web-based point-of-care clinical decision support (CDS) systems designed to improve quality of chronic disease care have become increasingly sophisticated and successful. A Web-based and EHR-integrated OUD CDS system to offer expert guidance to primary care providers (PCPs) on the diagnosis and management of OUD was developed and piloted. This project will implement the OUD clinical decision support system in three large diverse health care systems and randomize a minimum of 30 clinics to receive the OUD-CDS intervention or usual care (UC). The project will evaluate the impact of OUD CDS on practice process measures and patient outcomes. The study will also prepare for scalability and dissemination by evaluating facilitators and barriers to implementation, determining the costs of implementation and maintenance and assessing the short-term cost impacts of the OUD-CDS.

Although medication-based treatment for opioid use disorder can effectively reduce overdose risk and improve health outcomes, most people discontinue treatment too soon. Quality measures that inform opioid treatment programs about how many patients remain in treatment relative to peer programs could motivate those programs to pursue quality improvement activities, such as helping patients navigate logistical barriers to receiving treatment. This project will test approaches to developing and disseminating retention and outcome measures for opioid treatment programs.

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.

Current agonist treatments for opioid use disorder (OUD) are not adequate to address the opioid crisis and have abuse liability concerns. Chemokines (hormones of the immune system that mediate innate immune inflammation) enhance pain, reduce opioid analgesia, and promote drug-seeking behavior and addiction—giving them a central role at the crossroads of chronic pain and the opioid crisis. So blocking chemokines (rather than opioid receptors) provides an exciting and untested treatment opportunity for pain and OUD. This proposal will assess, in animal self-administration models that mimic human drug-taking, whether a chemokine antagonist peptide R103 reduces morphine intake, as well as if R103 will prevent or blunt naloxone-precipitated withdrawal signs in morphine-dependent rats and stop relapse.

Health care services for patients with both chronic pain and opioid use disorder are fragmented in the United States. To develop effective and feasible interventions for chronic pain and opioid misuse/disorder that can be implemented in both general medical and addiction treatment settings, this research examines two different care-delivery strategies. The first project will compare the effectiveness of a pharmacist-led, collaborative care approach for patients prescribed long-term opioids who have chronic pain and  opioid misuse/disorder compared to a pharmacist program with a cognitive behavior therapy-based pain self-management program. The second project will examine the effectiveness of a multimodal, interdisciplinary chronic pain management program that includes cognitive behavioral therapy, exercise, and stress management. With input from stakeholders and individuals with lived experience, this research has the potential to generate novel, reproducible, and scalable findings that addresses fragmented care delivery for co-occurring chronic pain and opioid misuse/disorder.