Funded Projects

According to SAMHSA’s 2017 National Survey on Drug Use and Health (NSDUH), 11.4 million persons in the U.S. report past-year opioid misuse; out of them, only 2.1 million individuals met criteria for an OUD. Very little is known about efficacious interventions for those who do not meet criteria for moderate/severe OUD (i.e., subthreshold OUD). The prevalence of subthreshold OUD in primary care settings is 5 percent to 10 percent, with higher rates (21 percent to 29 percent) among those receiving prescribed opioids. Although they are at high risk of developing moderate/severe OUD and/or dying from an overdose, little or no empirical evidence exists for pragmatic prevention interventions that can be adopted at integrated general medical settings. To study the efficacy of prevention interventions to arrest the progression from risky opioid use, researchers will test the efficacy of a STOP intervention in primary care settings. STOP adopts an early intervention approach, based on a collaborative care model to prevent progression to moderate/severe OUD, and consists of a practice-embedded nurse care manager who provides patient education and supports the primary care provider (PCP) in engaging, monitoring and guiding patients who have risky opioid use; brief advice delivered to patients by their PCP; and phone counseling of patients by behavioral health providers to motivate and support behavior change. Researchers will determine whether STOP reduces risky opioid use and examine the impact of STOP on progression to moderate/severe OUD, overdose risk behavior and overdose events in adults with risky use of illicit or prescription opioids.

There is an unmet need for an effective parenteral/oral analgesic for acute post- operative pain management without the risks of opioid addiction. Salsalate, a dimer or salicylic acid, is currently available in oral dosage for the treatment of osteoarthritis and rheumatoid arthritis. Salsalate works at multiple levels to target multiple steps along the surgical pain pathway. Salsalate through its active metabolite, salicylic acid (SA), reduces NF-?B activation via IKK-kinase beta inhibition, and has no direct binding to cyclooxygenase 1 (Cox-1); therefore, does not affect function of platelets, resulting in a safer hematological and gastrointestinal safety profile. RH Nano proposes a plan for manufacturing and pre- clinical testing of parenteral M-salsalate in two animal models to assess the efficacy and safety in the treatment of acute postoperative pain management. In this proposal, the team will develop the optimal formulation under strict Chemistry Manufacturing and Control guidelines. In Phase II, the team proposes to conduct the pharmacokinetics and toxicology studies of M-salsalate in two species of animals (rodent and non-rodent). Additionally, the project will use an animal pain model for preclinical efficacy studies, and an in vivo Receptor Occupancy assay in animal brain tissues to assess the opioid sparing properties of M-salsalate. 

An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. Researchers have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, researchers anticipate that their compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions.

Sublingual buprenorphine is a standard treatment for opioid use disorder and is considered safe and effective. However, in 2022 the U.S. Food and Drug Administration advised that buprenorphine is linked to oral disease. However, the underlying studies did not measure when oral disease started, how it progressed, or if other risk factors were present. How sublingual buprenorphine may impact oral health also remains unclear. This project will follow adults in two U.S. states who take sublingual buprenorphine or other medications for opioid use disorder to understand if and how these medications increase the extent, onset, and progression of oral disease, accounting for other risk factors.

Current opioid overdose treatment requires administration of naloxone by first responders, which requires timely identification of the overdose, the need for a rescue injection, and immediate availability of the medication. The development of a fail-safe treatment that would provide a life-saving dose of naloxone without the need for intervention by another party could significantly reduce mortality. The researchers aim to develop a new medical device comprising an implantable, closed-loop system that senses the presence of an opioid overdose, automatically administers a life-saving bolus injection of naloxone, and simultaneously alerts first responders.

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.

Exacerbation of health disparities has emerged during the COVID 19 pandemic and highlighted the recognition that minority underrepresentation in clinical research may contribute to racial disparities in health outcomes. In clinical trials related to pain, disparities in trial patient inclusion are documented by white patients often being overrepresented. Mitigating these disparities is an area in which an early-career pain investigator training and contributions may have lasting benefits. The pandemic also drove rapid expansion of telehealth for pain management without knowledge of how social and demographic factors affect utilization patterns of this care delivery model. This supplement supports research to examine the extent to which disparities exist in access to and outcomes of telehealth in socially marginalized pain patients. Findings will be applied to enrich the diversity in clinical trial populations for phase 2 safety trials performed in the HEAL EPPIC Network.

People with diabetes are at risk for painful diabetic peripheral neuropathy. This pain may be experienced as burning, aching, hypersensitivity to touch, or simply as pain, and there are no currently FDA-approved medications that reduce its symptoms. This phase 2 clinical trial, through the EPPIC-NET program, will test a potential new treatment for painful diabetic peripheral neuropathy. The molecule, NRD135S.E1, is a lab-made version of a natural substance traditionally used to brew tea to treat a variety of indications, including pain, in a village in Siberia. In clinical studies, NRD135S.E1 was well tolerated by patients and showed clinically relevant pain relief. Testing within EPPIC-Net will use a master protocol, an innovative study design in which multiple treatments can be tested at the same time with fewer research participants.

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.

The proposed SBIR Phase II program seeks to select a first-in-class, peripherally-restricted, and long-acting somatostatin receptor 4 (LA-SSTR4) agonist clinical candidate for development as a novel non-addictive analgesic able to replace opioids for the treatment of moderate-to-severe chronic pain. The program is based on strong scientific evidence showing that activation of peripheral SSTR4 produces broad spectrum analgesic activity and pursues a unique therapeutic strategy.   Unlike opioids, SSTR4 agonists do not induce constipation, respiratory depression, dependence, addiction, or abuse. Finally, unlike SSTR2 and SSTR5, SSTR4 expression in the pituitary and pancreas is very low, supporting that selective SSTR4 agonists are unlikely to perturb peripheral endocrine functions. The preceding SBIR Phase I program has already established the feasibility of conjugating a short-acting, potent, and selective peptide SSTR4 agonist to the antibody carrier. The resulting LA-SSTR4 agonist lead series has high agonist potency and selectivity for SSTR4 and has demonstrated antinociceptive activity in an animal pain model. The proposed SBIR Phase II program seeks to: optimize the existing lead series and select a clinical candidate for development,  validate and prioritize the indication(s) for clinical development using disease-relevant mouse pain models, and characterize the pharmacokinetics and safety/toxicology profile of the clinical candidate in rat and non-human primates to help design subsequent investigational new drug (IND)-enabling studies.

This project's goal is to develop a completely noninvasive, precise, and durable treatment option for low back pain (LBP). Focused ultrasound (FUS) is a lower-risk, completely noninvasive modality that enables the delivery of spatially confined acoustic energy to a small tissue region (dorsal root ganglion [DRG]) under magnetic resonance (MR) imaging guidance to treat axial low back pain by neuromodulation. The central goal of this study is to demonstrate neuromodulation of the DRG with FUS to decrease nerve conduction; this treatment can be used to attenuate pain sensation. This exploratory study will demonstrate FUS neuromodulation of the DRG in pigs as assessed by somatosensory evoked potential and perform unique behavioral assessments indicative of supraspinal pain sensation, with the ultimate goal of translating this technology to patients with LBP. FUS could potentially replace current invasive or systemically detrimental treatment modalities.

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.