Funded Projects

Infants exposed to opioids in the womb may suffer from neonatal opioid withdrawal syndrome (NOWS). They experience symptoms such as excessive crying, irritability, rapid breathing, elevated heart rates, tremors, and sometimes seizures. There is no accepted standard treatment for NOWS; infants are treated with pharmacological (opioid administration and gradual weaning) and nonpharmacological measures. Nonpharmacological care such as swaddling, rocking, frequent feedings, and skin contact, are time consuming, placing a substantial burden on hospitals with limited resources. Prapela, Inc. previously developed a hospital bassinette pad that, using stochastic vibrotactile stimulation (SVS) technology, very gently rocks infants with NOWS to reduce irritability and other symptoms without disturbing sleep patterns. This project will conduct an additional clinical study to determine the SVS bassinette pad’s efficacy in reducing breathing and heart rate, its safety, and its acceptability with clinical staff and parents caring for infants with NOWS.

Chronic pelvic pain affects social and sexual quality of life in up to 20% of women in the United States. It is often managed with physical therapy approaches, but when these measures fail, injection therapies may be indicated. These include injection of botulinum neurotoxin, which leads to muscle relaxation in the pelvic floor and thus pain relief. However, botulinum neurotoxin has dose-dependent side effects and is expensive. Therefore, a precision injection technique to administer botulinum neurotoxin so that it remains effective while minimizing adverse effects and costs is needed. Hillmed Inc. has developed a technique to assess the pelvic floor and choose the optimal injection site, which has improved treatment outcome in initial analyses. They are now aiming to develop a commercializable, personalized precision injection medical device for botulinum toxin and software package that will enable clinicians to optimize botulinum neurotoxin injection. They will then assess the system’s efficacy in a clinical trial of women with chronic pelvic pain and healthy women.

Chronic pain is a major healthcare burden. However, the types and underlying mechanisms of pain vary greatly, as do patient responses to currently available pain medications. Inflammation in the nervous system (neuroinflammation) is involved in several types of pain, and targeting key molecules involved in neuroinflammation is therefore a promising treatment approach. The chemokine receptor system, a complex network of more than 20 different receptors and more than 80 molecules that bind to these receptors, has a central role in neuroinflammation. Researchers do not yet fully understand the functioning of this network and how specific receptors vary in different chronic pain conditions. Therefore, this project aims to further characterize the expression of one specific receptor, using samples collected from participants in clinical trials evaluating a compound that interferes with the receptor’s function. This information should allow researchers to classify pain patients and identify those most likely to benefit from a treatment with compounds targeting the receptor.

Migraines and other headaches are often debilitating for patients, yet few treatment options providing sustained relief exist. All available therapies, including frequently prescribed opioids, have considerable side effects or limitations. Therefore, novel treatment approaches are needed to reduce or eliminate the need to use opiates and other systemic pharmaceuticals. Thermaquil Inc. has developed a new way of stopping migraine and other headache pain by noninvasively blocking pain signal transmission in the head, which in initial studies allowed patients to discontinue use of opioids and other addictive pain medications. Thermaquil will now be conducting a larger randomized controlled trial to demonstrate the safety and effectiveness of this novel approach. After a baseline period, patients will be randomly assigned to the active or control condition and receive a single treatment. The study will continue for 12 weeks with the active versus control arms, before all patients will be given active therapy for an additional 12 weeks.

The need to develop non-opioid therapeutics for chronic pain is greater than ever.  One option being explored is inhibiting the activity of calpains – enzymes that have been shown to cause pain in animal models of chronic pain.  Using an artificial intelligence (AI)-driven drug discovery platform, researchers have uncovered and validated four calpain-1 inhibitors using biochemical assays.  This study by 1910 Genetics Inc. hopes to synthesize multiple analogs of its most potent discovered calpain-1 inhibitor and determine its effectiveness against calpain-2 and certain enzymes that break down proteins.  Findings that successfully significantly inhibit calpain-1 in at least one animal model of chronic pain could lead to the first oral, central nervous system penetrating selective calpain-1 inhibitor [non-opioid therapeutic] for chronic pain.

As prescription opioid drug abuse and overdose-related deaths continue to skyrocket in the United States, the need for new and more effective non-addictive pain drugs to treat chronic pain remains critical. This research is conducting studies in animal models of a small molecule that has high potential to treat chronic pain conditions associated with neuropathy and/or inflammation. The goal of this project is to conduct dosing and other studies leading up to an animal model study of the potential drug in a toxicology study for 28 days. Results may lead to Investigative New Drug regulatory clearance to begin clinical studies to validate the potential drug’s efficacy and safety.

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. Blocking chemokines (rather than opioid receptors) provides an exciting treatment opportunity for both pain and opioid use disorder. This research continues previous work studying the efficacy of RAP-103, a small, orally stable chemokine receptor blocker. The previous research has shown that RAP-103 is safety and effective in preclinical models that mimic human drug-taking. This research will now optimize the dose required to achieve decreased motivation to maintain opioid use, establish manufacturing scale-up feasibility, provide RAP-103 for safety testing in animals, and conduct stability testing of RAP-103 toward the goal of submitting an Investigational New Drug application to the FDA.

While the mu opioid receptor (MOR) antagonist naloxone has proven invaluable as an opioid overdose antidote, naloxone suffers from a very short duration of action (half-life is approximately 1 hour) and has been found to be less effective against newer, long-acting opioids, including fentanyl (half-life is approximately 7–10 hours). This leads to a highly lethal and increasingly prevalent phenomenon known as “renarcotization,” wherein an overdose patient revived with naloxone can re-enter an overdose state from residual fentanyl in the body. Thus, there is a critical need to develop a long-acting MOR antagonist formulation that can address renarcotization by providing multi-hour protection. The goal of this project is to reformulate naloxone using FDA-approved microencapsulation technology into a long-acting injectable (LAI) that can provide 12–24 hours of sustained antagonist activity in vivo. It will employ a proprietary Computational Drug Delivery™ software, called ADSR™, to perform in silico formulation optimization as well as to predict its in vitro dissolution and in vivo pharmacokinetic behavior.

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.

With the exception of the Breathalyzer for alcohol, there is currently no available technology that can immediately identify neurologic impairment related to the use of licit or illicit drugs. The presently available methods for detecting opioids—which rely upon analysis of urine, blood, saliva, or hair—are expensive, time-consuming to implement, and can take days to deliver actionable information to meet the “fitness-for-duty” concerns of employers as well as the needs for immediate detection of drug use in the drug rehabilitation and public safety fields. This project intends to develop a non-invasive means of identifying temporary neurological impairment from prescription opioids using analysis of involuntary eye movements. The resultant biometric signature of opioid impairment will be incorporated into Zverex’s existing product library of oculomotor biosignatures, such as marijuana impairment and fatigue.

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.

Even though pain is a nearly universal experience, objective measurements of pain remain difficult. Given that responding to the opioid crisis will require both better ways to manage pain and better ways to detect drug-seeking behavior, finding approaches to objectively measure pain is crucial. The goal of this project is to develop a product that will objectively measure pain using computer vision and machine learning technologies together with tablet-based self-reported pain data from patients for research or clinical purposes. The product will be low cost, involving one or two cameras to record the video and a computer to analyze the video in almost-real time, and will involve software that can be portable to ordinary personal computers and tablets. The project will capture facial expressions related to genuine pain and integrate it with patients’ self-reported pain data, in order to refine the product and create an objective measure of pain intensity that can be used in clinical settings and test its accuracy. This new tool has the potential to help rectify the poor pain outcomes that still plague Americans with opioid addiction, cancer, and other health conditions in many health care settings.