Funded Projects

NOFO Title: HEAL Initiative: Early Phase Pain Investigation Clinical Network - Clinical Coordinating Center (U24 Clinical Trials Not Allowed)
NOFO Number: RFA-NS-19-023
Summary:

The objective of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) and EPPIC- Net initiatives is to rapidly and efficiently translate advances in the neurobiology of pain into treatments for people with chronic and acute pain, conditions associated with a significant burden to both patients and society. The Clinical Coordinating Center (CCC) for EPPIC-Net will promote and facilitate, from initial conception through final analysis, clinical trials in adult and pediatric populations with acute or chronic pain by providing efficient methodological, organizational, and logistical support. The EPPIC-Net-CCC will adopt and establish processes aimed at dramatically increasing the efficiency of multicenter clinical trials, improving the overall quality of clinical trials, promoting patient recruitment and retention as well as increasing the number of clinical investigators and research staff well trained and passionate about leading and conducting multicenter clinical trials.

NOFO Title: NCI Community Oncology Research Program (NCORP) Research Bases (UG1 Clinical Trial Required)
NOFO Number: RFA-CA-18-015
Summary:

Pain Coping Skills Training (PCST) uses a cognitive behavioral therapy (CBT) approach to teach patients cognitive and behavioral coping skills shown to reduce pain and pain interference (e.g., relaxation, distraction, cognitive restructuring, activity pacing). Randomized controlled trials show that PCST and similar CBT-based interventions, when delivered in a traditional in-person format, can improve pain and functioning in people with cancer and other conditions. Yet these interventions are underused in clinical care due to barriers such as high resource costs, a shortage of therapists trained to deliver them, and travel requirements for patients. This trial aims to deliver evidence-based behavioral pain interventions such as PCST with methods capable of overcoming barriers currently limiting patient access. This will be investigated using a two-arm trial comparing pain relief with the following interventions: painTRAINER in clinic with eight web-based follow-up sessions; enhanced usual care.

NOFO Title: HEAL Initiative: Back Pain Consortium (BACPAC) Research Program Technology Research Sites (UH2/UH3 Clinical Trial Optional)
NOFO Number: RFA-AR-19-028
Summary:

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.

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

This project focuses on identifying and validating a new central analgesic circuit in the brain, based on a highly innovative hypothesis that the strong analgesic effects of general anesthesia (GA) are in part carried out by GA-mediated activation of the endogenous analgesic circuits. Preliminary discovery studies found that a subset of GABAergic neurons located in the central amygdala (CeA) become strongly activated and express high levels of the immediate early gene Fos under GA (hereafter referred to as CeAGA neurons). Furthermore, activation of these neurons exert profound pain-suppressing effects in an acute pain model and a chronic orofacial neuropathic pain model in mice. Based on these exciting preliminary findings, this project will identify and validate CeAGA neurons’ analgesic functions utilizing multiple mouse pain models. Identification of these shared common pathways that need to be suppressed by specific subtypes of CeAGA analgesic neurons will be highly critical for developing precise CeAGA-targeted therapies to treat chronic pain.

NOFO Title: Data Coordinating Center for the NICHD Cooperative Multicenter Maternal Fetal Medicine Units Research Network (U10)
NOFO Number: RFA-HD-13-014
Summary:

Cesarean deliveries are the most commonly performed surgical procedure in the United States. Opioids are almost universally used for post-cesarean analgesia management. Studies suggest that most women are prescribed more tablets at discharge than needed. These often go unused, providing an important reservoir contributing to the opioid crisis. Physicians struggle to prescribe and dose postoperative opioids appropriately while tackling the real needs of acute pain from surgery. Without literature to guide obstetric providers on appropriate amounts of opioids to prescribe upon discharge, actual prescription amounts nationally vary widely by up to 65 tablets. To improve post-cesarean opioid prescribing practices without compromising pain management, the study will test an individualized, patient-empowered approach for pain management and opioid prescription quantity. This is a noninferiority randomized trial of 5,500 women with a cesarean delivery who will be randomized prior to discharge.

NOFO Title: HEAL Initiative: Limited Competition: Resource Coordinating Center for Pragmatic and Implementation Studies for the Management of Pain (PRISM) to Reduce Opioid Prescribing (U24 Clinical Trial Not Allowed)
NOFO Number: RFA-AT-19-011
Summary:

Improved pain management and reduction of opioid use could greatly benefit from improved pragmatic clinical trials (PCTs). The PRISM Resource Coordinating Center (CC), as part of the NIH Health Care Systems Research Collaboratory, will support up to nine more embedded PCTs that address pain management and the opioid crisis. Since 2012, the CC has nurtured 15 Demonstration Projects by providing leadership, resources, tools, training, and coordination of diverse elements. The CC will work collaboratively with each PRISM Demonstration Project team supported through the HEAL Initiative, including their partnering health care systems, to develop, test, and implement the projects while providing technical, design, and coordination support. The CC will also develop and refine technical and policy guidelines and best practices for the effective conduct of pain-related research studies in partnership with health care systems and disseminate best strategies for successful embedded PCTs.

NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO Number: NOT-NS-18-073
Summary:

Neuropathic pain is a debilitating affliction present in 26% of diabetic patients, with substantial impact on the quality of life. Despite this significant impact and prevalence, current therapies for painful diabetic neuropathy (PDN) are only partially effective, and the molecular mechanisms underlying neuropathic pain in diabetes are not well understood. Our long-term goal is to elucidate the molecular mechanisms responsible for PDN in order to provide targets for the development of therapeutic agents. Our objective is to identify the molecular cascade linking CXCR4/SDF-1 chemokine signaling to DRG nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration. Our aims will determine: 1) the ion-channel current profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN; 2) the gene expression profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN; and 3) the specific features of nociceptor mitochondrial dysfunction produced by CXCR4/SDF-1 signaling in PDN.

NOFO Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
NOFO Number: PA-18-574
Summary:

 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.

NOFO Title: HEAL Initiative: Integrated Approach to Pain and Opioid Use in Hemodialysis Patients: The Hemodialysis Opioid Prescription Effort (HOPE) Consortium - Clinical Centers (U01 Clinical Trial Required)
NOFO Number: RFA-DK-18-030
Summary:

This study will evaluate novel strategies to reduce opioid use and pain in patients with end-stage renal disease receiving chronic hemodialysis (HD). Specifically, the study will examine the effect of nonpharmacologic (Acceptance and Commitment Therapy [ACT] and acupuncture) and pharmacologic (buprenorphine) interventions in HD patients who are receiving chronic opioid medications due to chronic pain and/or high pain interference. The study will enroll 720 HD patients across U.S. Hemodialysis Opioid Prescription Effort Consortium Clinical Centers to (1) determine the effectiveness of ACT and acupuncture compared with the control condition in reducing opioid dose and improving pain among HD patients; (2) identify the best adaptive intervention sequence for improved outcomes; (3) explore age, sex, and comorbidities as potential moderators of the response to the intervention; and (4) describe facilitators and barriers to the implementation of the intervention using in-depth, semi-structured individual interviews with intervention participants and providers.

NOFO Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
NOFO Number: PA-18-574
Summary:

 Quell Therapeutics uses the Optopatch platform for making all-optical electrophysiology measurements in neurons at a throughput sufficient for phenotypic screening. Using engineered optogenetic proteins, blue and red light can be used to stimulate and record neuronal activity, respectively. Custom microscopes enable electrophysiology recordings from 100’s of individual neurons in parallel with high sensitivity and temporal resolution, a capability currently not available with any other platform screening technology. Here, researchers combine the Optopatch platform with an in vitro model of chronic pain, where dorsal root ganglion (DRG) sensory neurons are bathed in a mixture of inflammatory mediators found in the joints of osteoarthritis patients. The neurons treated with the inflammatory mixture become hyperexcitable, mimicking the anticipated cellular pain response. Investigators calculate the functional phenotype of arthritis pain, which captures the difference in action potential shape and firing rate in response to diverse stimuli. The team will screen for small molecule compounds that reverse the pain phenotype while minimizing perturbation of neuronal behavior orthogonal to the pain phenotype, the in vitro “side effects.” The highest ranking compounds will be chemically optimized and their pharmacokinetic, drug metabolism, and in vivo efficacy will be characterized. The goal is to advance therapeutic discovery for pain, which may ultimately help relieve the US opioid crisis.

NOFO Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
NOFO Number: PA-18-574
Summary:

There is a need for safe, effective, well- tolerated drugs to treat painful neuropathy by halting or reversing the underlying pathology of the disease. One promising approach to treating painful neuropathy without opioids is the use of ghrelin, a 28-amino acid acylated peptide hormone. However, it has a short half-life and must be delivered via a constant intravenous infusion to have a therapeutic effect. Extend Biosciences' D-VITylation platform technology is truly enabling for small peptide-based therapeutics that are rapidly cleared from the bloodstream by renal filtration. The platform harnesses the naturally long half-life of vitamin D and its dedicated binding protein, VDBP. When the vitamin D molecule is conjugated to a biological therapeutic, it dramatically improves the half-life and bioavailability of the drug. Use of the technology should also allow the drug to be self-administered by subcutaneous injection. This would be of significant benefit to patients. In this project, the team will test the efficacy of EXT405 in a cell-based model of neuropathy as well as in animal models of CIPN and diabetes- induced neuropathy.

NOFO Title: HEAL Initiative: Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM)(UG3/UH3 Clinical Trial Optional)
NOFO Number: RFA-AT-19-004
Summary:

Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain, tenderness, and stiffness associated with fatigue and sleep disturbance. The investigators have recently completed a trial that demonstrated efficacy of active transcutaneous electrical nerve stimulation (TENS) compared with placebo TENS or no treatment in women with FM. While physical therapists are trained in using TENS, it is underused in clinical practice. This application proposes a pragmatic clinical trial of TENS for patients with FM to determine if the addition of TENS to physical therapy (PT) reduces pain, increases PT adherence, and helps achieve functional goals with less drug use. This study will address the critical need for strategies to implement effective nonpharmacologic treatments for FM. Successful completion of this trial will provide generalizable effectiveness data for referring providers, physical therapists, and insurers and will inform future pragmatic trials of nonpharmacologic treatments conducted in PT practices.

NOFO Title: HEAL Initiative: Tissue Chips to Model Nociception, Addiction, and Overdose (UG3/UH3 Clinical Trial Not Allowed)
NOFO Number: RFA-TR-19-003
Summary:

This project will build overdose models for fentanyl, methadone, codeine, and morphine in a multi-organ system and evaluate the acute and repeat dose, or chronic effects, of overdose treatments as well as off-target toxicity. Researchers developed a system using human cells in a pumpless multi-organ platform that allows continuous recirculation of a blood surrogate for up to 28 days. They will develop two overdose models for male and female phenotypes based on pre-B?tzinger Complex neurons and will integrate functional immune components that enable organ-specific or systemic monocyte actuation. Models for cardiomyopathy and infection will be utilized. Researchers will establish a pharmacokinetic/pharmacodynamic model of overdose and treatment to enable prediction for a range of variables. We will use a serum-free medium with microelectrode arrays and cantilever systems integrated on chip that allow noninvasive electronic and mechanical readouts of organ function.