Funded Projects

Opioid agonist therapy (OAT), such as buprenorphine/naloxone (BUP/NAL), is proven effective against opioid use disorder (OUD), but poor medication adherence is a major barrier. This project aims to substantially increase adherence to oral BUP/NAL with Pillsy, a smart technology platform, which acts like a digital medication coach, providing education and reminders using a mobile app, text messages, and automated phone calls. The platform is built around a Bluetooth-based smart pill bottle cap that automatically tracks doses and timing, and sends intelligent reminders to create a unique feedback loop, which allows constant optimization of the incentive/reminder messages to meet user needs to increase adherence. A dashboard enables providers to easily track medication use and patient engagement. The Pillsy platform only nominally increases the cost of oral BUP/NAL treatment, and physicians can bill for monitoring time (CPT code 99091). The project team will adapt the current Pillsy platform and perform a randomized efficacy trial of BUP/NAL adherence.

Pain is one of the most common and debilitating symptoms of a wide range of injuries and diseases. Safe and effective alternatives for treating pain that reduce dependence on opioids are, therefore, a primary goal of the NIH. This project proposes a non-invasive, non-pharmacological alternative to treat pain by combining an innovative electroencephalography (EEG)-based Neurofeedback (NF) solution in an immersive virtual reality (VR) environment. NF and VR have been shown to independently produce ameliorative effects on pain, and it is hypothesized that an NF training in VR would have synergistic effects, as VR would distract from pain perception to improve patient compliance in more engaging NF protocols that improve their ability to control pain perception. In the scope of this project, we will initially focus our work on chronic low back pain (cLBP), as this is a growing segment of chronic pain sufferers with a 39 percent worldwide lifetime prevalence, and whose sufferers have historically been heavy users of opiates; later stages of this project will expand this application to address other forms of pain.

 Chronic persistent post-operative pain (CPOP) is a devastating outcome from any type of surgical procedure. Its incidence is anywhere between 20-85% depending on the type of surgery, with thoracotomies showing one of the highest annual incidences of 30-60%. Given that millions of patients (approximately 23 million yearly based on incidence) are affected by CPOP, the results are increased direct medical costs, increased indirect medical costs due to decreased productivity, and associated negative effects on an individual’s physical functioning, psychological state, and quality of life. Given these extensive public health and economic consequences there is a resurgence of research in the area of preventative analgesia.  The goal of this project is to evaluate a novel small molecule antagonist of MD2-TLR4, DT-001 in preclinical models of surgical pain representative of persistent post-operative pain. In collaboration with University of California, San Diego, DT-001 will be evaluated for its ability to block the development of neuropathic pain states. These studies will evaluate dose escalating efficacy of DT001 in rats in formalin and spinal nerve injury (SNI) models using both intrathecal and intravenous routes of administration. Tissues will be preserved to assess functional effects on relevant pain centers for analysis by Raft. With demonstration of efficacy, these studies will determine the optimal dose and route of administration of DT001 and guide a development path to IND and eventually clinical trials.

Noninvasive brain stimulation (NIBS) may be effective in treating some forms of addiction, but the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), have not been found to be effective in treating opioid use disorder (OUD). This project seeks to test the efficacy in OUD patients of Electrosonic Stimulation (ESStim™), an improved NIBS modality that combines independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue.

Chemotherapy-induced peripheral neuropathy (CIPN) is detected in 64% of cancer patients during all phases of cancer. CIPN can result in chemotherapy dose reduction or discontinuation, and can also have long-term effects on the quality of life. Taxanes (like Paclitaxel) may cause structural damage to peripheral nerves, resulting in aberrant somatosensory processing in the peripheral and/or central nervous system. Dorsal root ganglia (DRG) sensory neurons as well as neuronal cells in the spinal cord are key sites in which chemotherapy induced neurotoxicity occurs. T-type Ca2+ channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Though Cav3.2 has been targeted clinically with small molecule antagonists, no drugs targeting these channels have advanced to phase II human clinical trials. This proposal aims to explore multicomponent reaction products, for the rapid identification of potent and selective T-type Ca2+ channel antagonists. The work proposed here is the first step in developing non-opioid pain treatments for CIPN. The team anticipates success against paclitaxel-induced chronic pain will translate into other chronic pain types as well, but CIPN provides focus for early stage proof-of-concept.

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.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a first line pharmacologic pain therapy for chronic musculoskeletal pain, and rheumatoid arthritis (RA) and moderate to severe osteoarthritis (OA) specifically. However, insufficient pain relief by NSAID monotherapy has encouraged the use of combination therapy. Combinations of NSAIDs plus weak opioids are widely used although objective evidence for efficacy is limited and they have many adverse events.  A growing body of evidence suggests that ?2/?3 subtype-selective positive allosteric modulators (PAM) of the ?- aminobutyric acid A receptor (GABAAR) may effectively restore central pain regulatory mechanisms thus providing effective relief of chronic pain with reduced prevalence and severity of side-effects.  Based on these promising preliminary studies and considerable supporting literature data, the research team will test the hypothesis that combination dosing of TPA-023B with an NSAID will work synergistically to suppress the acute and chronic pain components of chronic musculoskeletal pain. 

 Investigating the broader efficacy of sEH inhibition and specifically our IND candidate, EC5026, has indicated that it is efficacious against chemotherapy induced peripheral neuropathy (CIPN). This painful neuropathy develops from chemotherapy treatment, is notoriously difficult to treat, and can lead to discontinuation of life-prolonging cancer treatments. Thus, new therapeutic approaches are urgently needed. The research team will investigate if EC5026 has potential drug-drug interaction with approved chemotherapeutics or alters immune cells function, and assess the effects of sEHI on the lipid metabolome and probe for changes in endoplasmic reticulum stress and axonal outgrowth in neurons. The team proposes to more fully characterize the analgesic potential of our compound and investigate on and off target actions in CIPN models and model systems relevant to cancer therapy.

One of the current critical needs in addressing the opioid crisis is the development of new overdose-reversal interventions, including wearable technologies that can detect an (impending) overdose from physiological signals to signal for help, or trigger a coupled automated injection of naloxone. This project tests the approach of monitoring respiration by detecting the sounds of breathing in the trachea. This proposal aims to develop a machine learning algorithm that could process those sounds, detect the kinds of patterns of reduced breathing that occur during an opioid overdose, and design a miniature wireless sensor that could be used to detect those sounds. Such a sensor and algorithm could be a key component to a device to detect and intervene in overdoses.

Chronic focal neuropathic pain, which includes pain etiologies such as radiculopathy and radiculitis, focal peripheral neuropathies, and low back pain, affects as many as 25 million patients annually in the United States. Chronic focal neuropathic pain is maintained by genome-wide transcription regulation in the dorsal root ganglia (DRG) / spinal cord network. The transcription factors driving this regulation constitute a promising class of targets with the potential to alter the course of pain with a single treatment. DNA decoys are oligonucleotides that specifically inhibit the activity of certain transcription factors. AYX2 binds and inhibits Krüppel-like transcription factors (KLF) in the DRG-spinal cord. The goal of this Phase 1 proposal is to advance AYX2 toward an IND submission, allowing for human clinical trials. We propose in Aim 1 to characterize AYX2 pharmacokinetics in the cerebrospinal fluid and plasma and its distribution in the DRG, spinal cord and brain following an IT injection. With this information, AYX2 will be tested in a panel of complementary toxicology studies in Aim 2 to allow for final IND-enabling studies, supported by Phase 2 of the grant. This research will accelerate development of AYX2 as a novel drug candidate for the non-opioid treatment of pain.

Hesperos uses microphysiological systems in combination with functional readouts to establish systems capable of analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing, with initial emphasis on predictive toxicity. The team constructed physiological systems that represent cardiac, muscle and liver function, and demonstrated a multi-organ functional cardiac/liver module for toxicity studies as well as metabolic activity evaluations. In addition, the team demonstrated multi-organ toxicity in a 4-organ system composed of neuronal, cardiac, liver and muscle components. While much is known about the cells and neural circuitry regulating pain modulation there is limited knowledge regarding the precise mechanism by which peripheral and spinal level antinociceptive drugs function, and no available human-based model reproducing this part of the pain pathway. The ascending pain modulatory pathways provide a well characterized neural architecture for investigating pain regulatory physiology. In this project, the research team propose a human-on-a-chip neuron tri-culture system composed of nociceptive neurons, GABAergic interneurons and glutamatergic dorsal projection neurons (DPN) integrated with a MEMS construct. Using this model, investigators will interrogate pain signaling physiology at three levels, 1) at the site of origin by targeting nociceptive neurons with pain modulating compounds including noxious stimuli and inflammatory mediators, 2) at the inhibitory GABAergic interneuron, and 3) at the ascending spinal level by targeting glutamatergic DPNs. These circuits will be integrated utilizing expertise in patterning neurons as well as integration with BioMEMs devices. This system provides scientists with a better understanding of ascending pain pathway physiology and enable clinicians to consider alternative indications for treating pain at peripheral and spinal levels. 

Chronic pain affects over 100 million Americans, costing society about $600 billion annually. Despite numerous pharmacological and non-pharmacological therapies, over 50% of chronic pain sufferers feel little control over their pain. CognifiSense has developed a patent-pending Virtual Reality Psychological Therapy (VRPT), which is designed to create lasting reduction of chronic pain by addressing the maladaptive learning processes driving pain chronification. VRPT is an experiential learning system, which provides the brain a new set of signals that teaches it that the pain is not as bad as it perceived and that it has greater control over the pain than it perceived. VRPT combines the immersive power and the ability to individualize the therapy of Virtual Reality with well-researched principles of self-distancing, self-efficacy, and extinction to retrain the brain. The goal of this study is to determine the clinical feasibility of VRPT in achieving a lasting reduction of chronic pain, establish brain mechanisms associated with treatment response, and collect comprehensive user feedback to enable further refinement of the current product prototype. CognifiSense's VRPT has the potential to be a significant clinical and business opportunity in the treatment of chronic pain.