Funded Projects

There are currently no reliable tools to measure pain objectively, and health care providers must rely on patient’s subjective reports and observations of patient behavior to determine the level of pain a person experiences. This hampers both effective pain management and the development of new pain medications. This project will assess an imaging technology called Radiocaine that in animal studies has been able to identify the origin of pain as well as its intensity. The goal is to use Radiocaine in clinical trials for pain treatments, thereby enhancing treatment effectiveness and facilitating development of new treatments.

Despite the need for non-opioid treatments for chronic pain, few alternative treatment approaches exist. Transcutaneous auricular neurostimulation (tAN) is a safe and effective treatment for pain during opioid withdrawal; however, researchers do not understand how tAN reduces pain, which limits its clinical use. A better understanding of how tAN affects neurophysiological processes to provide pain relief would likely expand tAN development and use. This interdisciplinary project will conduct research in both healthy adults and those with chronic pain to explain the neurochemical and neurophysiological mechanisms for tAN-based pain relief, and also help optimize treatments and their use.

Head and neck cancer is particularly susceptible to nociceptive and neuropathic pains because it is dense with sensitive anatomic structures and richly innervated. Transcranial magnetic resonance imaging–guided focused ultrasound (FUS) is a new stereotactic modality capable of delivering high-intensity energy through the intact human skull with submillimeter precision. This clinical trial will target the spinothalamic and spinoreticular pain circuits by unilateral FUS mesencephalotomy, an effective procedure for cancer pain but limited by the accuracy of its era. The primary aim is to assess the safety and preliminary effectiveness in six head and neck cancer patients with opioid-resistant pain. Researchers will investigate the potential mechanism of pain relief as the mesencephalotomy target involves the confluence of the ascending and descending pain systems. Aims 2 and 3 will investigate these systems with electrophysiology specific for the spinothalamic tract and carfentenil positron emission tomography imaging that measures the brain’s endogenous opioids.

Chronic pain diminishes the quality of life for millions of patients, and new drugs that have better efficacy and/or fewer side effects are needed. A promising target is the sphingosine-1-phosphate (S1P) receptor system, which mediates central nervous system (CNS) neuromodulatory functions. FTY720-phosphate, the active metabolite of FTY720 (FTY), acts as an agonist at four of the five S1P receptors (S1P1, 3, 4, 5). We propose that the S1P1 receptor is a target for treatment of neuropathic pain. We will test whether S1P1 receptors mediate anti-hyperalgesic effects in a mouse neuropathic pain model. The specific aims are to: 1) determine the role of S1P1Rs in alleviation of neuropathic pain by S1PR ligands; 2) determine the role of FTY-induced S1PR adaptation in FTY-mediated reversal of neuropathic pain; and 3) determine the role of S1P and S1P1 receptors in spinal glia in CCI-induced neuropathic pain and its reversal by FTY.

The MGH EPPIC-Net hub will utilize two well-established collaborative entities in both patient care and clinical research at the Massachusetts General Hospital (MGH): 1) MGH Division of Pain Medicine and 2) MGH Center for Translational Pain Research. This hub-spoke network at MGH will include four core spokes consisting of both academic centers and community health care organizations, as well as over a dozen spokes that can be recruited as needed based on special requirements of phase II trials and research studies. The responsibilities of this hub-spoke network at MGH include a) coordinating phase II trials/clinical biomarker validation studies; b) recruiting well-phenotyped subjects in a timely manner; c) collecting clinical data and targeted outcome data tailored to meet the needs of each clinical trial/study; and d) maintaining communications within and outside the hub, including the NIH EPPIC-Net.

Immune checkpoint proteins regulate the immune system to prevent it from indiscriminately attacking cells. Some cancers activate these immune checkpoints to avoid attack, and drugs that target certain immune checkpoints are approved for cancer treatment. The same pathway may also be involved in pain because immune checkpoint proteins, such as programmed death 1 (PD-1) and the molecule that binds to it (programmed death ligand 1 [PD-L1]), also are found in sensory neurons, microglia, and macrophages. This project will investigate PD-1/PD-L1 in different cell populations to determine their contribution to pain and to the effects of opioids such as morphine. This knowledge may help identify new drugs for pain management that modify immune checkpoint activity.

Chronic post-traumatic headache (PTH) is highly debilitating, poorly understood, and difficult to treat. This project aims to identify proteins located in the membrane of certain neurons that are critical for the development, maintenance, and/or resolution of PTH. These proteins may be targets for novel treatment approaches that are nonaddictive and have minimal side effects.

Throughout clinical pain research, there is a need to increase the workforce of researchers familiar with individualized treatment strategies known as precision pain medicine. This mentoring award will leverage EPPIC-Net’s Clinical Coordinating Center resources to encourage interest in clinical pain management, in particular through multidisciplinary pain research projects. A selected clinician-researcher  will mentor early career investigators and provide them with hands-on training activities and other skill-building experiences in clinical pain research, with a focus on precision pain medicine, biomarker development, and pain assessment. Mentoring activities will include formal educational coursework, inclusion in EPPIC-Net working groups, and collaborative writing experiences.

As many as 64% of patients with Temporomandibular Joint Disorders (TMJDs) report symptoms consistent with Irritable Bowel Syndrome (IBS). However the underlying connection between these comorbid conditions is unclear and treatment options are poor. As such, pain management for these Chronic Overlapping Pain Conditions (COPCs) is a challenge for physicians and patients. This project will determine whether the convergence of pain from different peripheral tissues and perceived stress occurs in the brain and elicits a change in central neural processing of painful stimuli. This project will identify and validate specific lipids, enzymes and metabolic pathways that change expression in the brain during the transition from acute to chronic overlapping pain that can be therapeutically targeted to treat COPCs. Multi-disciplinary approaches will be used to combine brain imaging, visualization of spatial distribution of molecules, genetics, pharmacological and behavioral research techniques.

Efforts to identify non-opioid analgesics for treatment of chronic pain have identified a protein, carbonic anhydrase-8 (CA8), in pain-sensing nerve cells in the spinal cord (dorsal root ganglion cells) whose expression regulates analgesic responses. Gene therapy delivering CA8 to dorsal root ganglion cells through clinically relevant routes of administration functions as a “local anesthetic” that induces long-lasting pain relief in animal models of chronic pain. This project will further develop CA8 gene therapy with the goal of treating chronic knee osteoarthritis pain. It will assess several gene therapy constructs to determine the doses needed, safety, efficacy, and specificity to nerve cells for each construct. It will then select the safest and most effective construct that can be administered via the least invasive route for further development. The project will include all steps necessary to identify one candidate gene therapy construct that will be suitable to begin clinical trials in patients with chronic knee osteoarthritis pain.

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.

Neuropilin 1 receptor (NRP1) is a protein receptor that is active in neurons and is hypothesized to be a key mediator of sensory neuron sensitization that can lead to pain. This project will study the cellular mechanisms by which NRP1 leads to sensitization and which cell types—sensory neurons, microglia, or both—are responsible for NRP1’s role in pain. The findings can help validate NRP1 in sensory neurons and the spinal cord as a target to treat pain following nerve injury.