Funded Projects

Data from 2015 show that American Indians/Alaska Natives (AI/AN) have the highest rates of diagnosis for opioid use disorder (OUD) and death from drug overdose. Of particular concern is the prevalence in emerging adults (ages 18-25), as this is a developmental period of heightened vulnerability and critical social, neurological, and psychological development. This study will develop and implement a culturally centered intervention to address opioid misuse among urban AI/AN emerging adults in California: POMANAYA (Preventing Opioid Misuse Among Native American Young Adults). POMANAYA will developed by adapting and enhancing our existing culturally sensitive prevention intervention program that uses motivational interviewing in AI/AN youth to address social network factors in emerging adults that amplify (or reduce) opioid and other drug use risk. Results from this study could significantly advance scientific knowledge and clinical practice for AI/AN emerging adults.

This study will conduct preclinical and clinical assessments of the NMDA modulator NYX-783 for treatment of opioid drug-seeking and relapse to opioid use disorder (OUD). NYX-783, a novel small molecule being developed by Aptinyx, has shown evidence of safety/tolerability in Phase 1 studies and is currently in Phase 2 trials for post-traumatic stress disorder. This project will test the safety, tolerability, and pharmacokinetics (PK) of NYX-718 in morphine-maintained patients in residential settings and then conduct a combined inpatient (safety/tolerability/PK) / outpatient (preliminary efficacy) study testing NYX-783’s effects on opioid use and relapse, stress/cue reactivity, craving, and quality of life in OUD subjects maintained on standard extended release naltrexone over a 10-week period. Successful completion of these studies will set the stage for larger scale Phase 2/3 studies of efficacy in OUD that will ultimately be required for FDA approval of NYX-783 for the treatment of drug-seeking and relapse in OUD.

Despite increased efforts to understand the neurodevelopmental sequelae of in utero opioid and other substance exposure on long-term behavioral, cognitive, and societal outcomes, important questions remain, specifically, 1) How is brain growth disrupted by fetal substance and related pre- and post-natal exposures? and 2) How are these disrupted growth patterns causally related to later cognitive and behavioral outcomes? This project seeks to formulate an approach to addressing these key questions and decipher the individual and cumulative effect of these intertwined pre- and post-natal exposures on child neurodevelopment. First, researchers will address the legal, ethical, and mother-child care and support concerns implicit in this study. Next, they will integrate across our areas of neuroimaging expertise to develop, implement, and harmonize a multi-modal MRI and EEG protocol to assess maturing brain structure, function, and connectivity. Finally, researchers will develop and test advanced statistical approaches to model and analyze this multidimensional and longitudinal data.

Analgesia for post-operative populations remains a significant health need that calls for innovative therapies which improve both safety and outcome measures. Recent FDA drug safety warnings and studies focusing on post-operative analgesia have highlighted the imperative need for new approaches that can be utilized for common clinical scenarios. Accordingly, novel treatment options that are safe and afford additional benefit in relief of pain are needed. In this proposal, the development of an innovative surgical sealant technology is proposed that functions at the level of the surgical wound bed and actively delivers local pharmacologic agents to therapeutically address post-operative pain. New formulations of several analgesic regimens will be assessed for their ability to seal wounds and provide appropriate pain management.

Expanding access to naloxone in the community through the pharmacy can be a critical mechanism for extending this lifesaving medication’s reach. This study will partner with two large retail pharmacy chains and integrate two interventions that provide knowledge and training for pharmacists to identify and effectively engage with patients who may be at high risk for an opioid overdose. The interventions will be combined into a cohesive educational program, implemented in 160 community pharmacies and tested for effectiveness. Study findings will create a generalizable, evidence-based training and toolkit for pharmacists caring for patients who use prescribed or illicit opioids, in more than 40 states adopting or expanding pharmacy naloxone.

Researchers will develop a novel transcranial focused ultrasound (tFUS) device for pain treatment and establish its effectiveness for treating sickle cell disease (SCD) pain in humanized mice. The tFUS will target the specific cortical regions involved in SCD pain using a novel non-invasive electrophysiological source imaging technique. The project’s goals have several aims. Aim 1: Develop tFUS devices for pain treatment. The mouse-scale system will be designed to validate the therapeutic effect of stimulating the anticipated cortical targets. This will inform development of the simpler human-scale system, which will use models of the skull to select cost-effective transducers to reach the targets. Aim 2: Evaluate tFUS effectiveness and optimize stimulation parameters in an SCD mice model. Researchers will determine effective tFUS parameters to chronically reduce SCD pain in mice and validate this using behavioral measures. Aim 3: Use electrophysiological source imaging to target and trigger closed-loop tFUS in animal models. This aim also includes performing safety studies to prepare for human trials. The project will develop a transformative, noninvasive tFUS device to effectively and safely treat pain in SCD. 

Responding to urgent calls for non-opioid treatment, this research group has been evaluating the therapeutic potential of cannabidiol (CBD), a non-intoxicating cannabinoid, for the treatment of some clinical aspects of opioid use disorder (OUD). Preclinical animal studies show that CBD decreases cue-induced heroin-seeking behavior during drug abstinence, associated with incubation of craving. Clinical work has also shown that CBD was safe in combination with a potent opioid agonist to address a potential relapse condition and decreased craving and anxiety associated with heroin cues in abstinent individuals with heroin use disorder. Building on this foundation, the researchers will investigate an oral CBD powered by a novel patented technology (leveraging the kinetics of long-chain fatty acid absorption) in a gelcap delivery system that improves bioavailability, reduces the incidence of gastrointestinal side effects, reduces first pass metabolism, and enhances onset time. This study could lead to the development of a non-opioid, non-intoxicating FDA-approved medication to reduce opioid craving and relapse and restore global functioning in individuals with OUD.

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.

Several abuse-deterrent opioid products (primarily formulations) are currently marketed or in clinical development, but they fall short of being resistant to abuse. Rather than abuse-deterrent formulations, this project, in partnership with Ensyce Biosciences, has created two complementary, novel technologies that control the release of known opioids. One technology delivers prodrugs — drugs that are not active until they have been exposed to the right conditions within the body, at which point they are gradually converted into active drugs, making them difficult to tamper with and reducing the potential for misuse. Another technology makes it so that taking increasing numbers of pills inhibits the process of converting prodrug into active drug, reducing the potential for overdose. This project aims to refine the development of these two technologies and work to combine them, and to translate promising animal results into human use.

The clinical utility of opioids for pain treatment is limited by its risk for developing opioid usage disorders (OUD). These untoward effects impose a severe burden on society and present difficult therapeutic challenges for clinicians. We propose to extend our cerebral organoid MPS to facilitate the investigation of neuronal response to opioids and identify cellular and molecular signatures in patients vulnerable to OUD. We have assembled a team with complementary expertise in clinical characterization of OUD, cerebral organoid MPS modeling, single cell RNA-seq technology, and functional characterization of neurons in a mesolimbic reward system to test the hypothesis that midbrain MPS is a clinically relevant pre-clinical model for study of opioid usage disorder.

While traditional epidural spinal cord stimulation (SCS) for intractable pain has been very efficacious for the patients responsive to it, the success rate has held at approximately 55%. Dorsal root ganglion (DRG) stimulation has shown promise in early trials to provide greater pain relief. Although the decrease in back pain at 3 months was significantly greater in the DRG arm vs. SCS, the adverse event rate related to the device or implant procedure was significantly higher in the DRG arm. Researchers will develop the “Injectrode” system to make the procedure simpler and safer by using an alternative to implantation: using an injectable pre-polymer liquid composite that cures quickly after injection adjacent to the DRG. They will compare an Injectrode-based system with traditional electrode stimulation at the DRG as an alternative to opioid administration. Researchers will perform benchtop characterization and refinement as a precursor to a clinical study, use modeling and animal testing to refine the efficiency of energy transfer from a transcutaneous electrical nerve stimulation unit to an Injectrode/Injectrode collector concept, and optimize the procedure for the complex anatomy of the human DRG.

As part of an ongoing teleECHO learning collaborative (LC),this study will expand clinical research training in evidence-based quality improvementmethods that were central to delivering and sustaining science-based medication-assisted treatment for opioid use disorder (MOUD) within the Vermont Hub-and-Spoke Model (HSM) with fidelity. Participating primary care practices will be trained in the (1) use of astudy-developedtoolkit of research and evaluationquality improvementmethodsintended to expand provider knowledge and performance in the delivery of evidence-based MOUD, (2) systematic tracking of standardized outcome metrics, and (3) sharing of these standardized data with other LC membersso that practices can use this empirical information to refine their care model over time. The study will measure changes in providers’ knowledge about best practices for MOUD, their comfort in caring for OUD patients with MOUD and their performance on all the standardized outcome metrics.