Funded Projects

The research team will develop HD64—a high-resolution, 64-channel spinal cord stimulation therapy to provide more pain relief for those suffering from chronic neuropathic pain and opioid dependence. HD64 provides an ultra-thin conformal blanket of stimulation contacts across the width of the spinal cord and enables more precise targeting of the lateral structures of the spinal cord to enhance pain relief. A cadaveric pilot run followed by a non-significant risk intraoperative study will be performed to inform the design parameters of HD64 arrays. The study will evaluate activation of medial and lateral spinal targets. At the end of Phase 1, the clinical feasibility of HD64 surgical leads will be established. In Phase 2, researchers will develop an external active lead pulse generator and charger. They will perform an early feasibility study human trial using active HD64 and mechanical and electrical design verification testing and chronic safety studies in large animals.

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.

The development of non-addictive pain therapeutics can help counter opioid addiction and benefit patients, including those who suffer from neuropathic pain, in particular diabetic neuropathic pain (DNP). This project’s goal is to develop a safe, efficacious, and non-addictive small-molecule drug that activates Kv7 voltage-gated potassium channels to address overactive neuronal activity in DNP. Researchers will discover Kv7 activators that favor Kv7 isoforms altered in DNP and found in dorsal root ganglia, decrease off-target side effects observed with the use of earlier non-biased Kv7 activators, and optimize the absorption, distribution, metabolism, excretion, and toxicity profiles of these activators. This screening paradigm is intended to establish a clinic-ready, well-tolerated, and widely effective product to treat neuropathic pain.

There are currently few effective therapies available for chronic nerve injury-induced pain, associated anxiety, and depression. This project aims to extend previous research aiming to uncover the mechanism of action of artificially modified immune molecules (humanized cholecystokinin-2 receptor [CCKBR] single-chain variable fragments [scFv]) on human neurons and how it reverses chronic pain and anxiety-like behaviors in mouse models. This potential treatment approach offers important advantages over existing therapies, including extreme specificity, higher affinity, brain/nerve penetrance, safety, and reduced self-immunogenicity.

EPPIC-Net will provide a robust and readily accessible infrastructure for the rapid implementation and performance of high-quality comprehensive studies of patients with well-defined pain conditions, and the rapid design and performance of high-quality Phase 2 clinical trials to test promising novel therapeutics for pain. Using the Hospital of the University of Pennsylvania as a hub and five additional centers that are part of the UPenn Health System and the Children’s Hospital of Philadelphia (CHOP) as spokes, studies will be conducted as designed by the expertise of the EPPIC Network, which intends to bring intense focus to relatively small numbers of patients with clinically well-defined pain conditions and high unmet therapeutic needs. The UPenn Specialized Clinical Center (SCC) will test novel, efficient study designs including adaptive and platform designs, validation studies of biomarkers, and biomarker-informed proof of principle or target engagement studies in Phase 2 trials of interventions from academic and industry partners.

Up to 5 percent of adolescents suffer from high-impact chronic musculoskeletal (MSK) pain, and only about 50 percent with chronic MSK pain who present for treatment recover. Current treatments for chronic MSK pain are suboptimal and have been tied to the opioid crisis. Discovery of robust markers of the recovery versus persistence of pain and disability is essential to develop more resourceful and patient-specific treatment strategies, requiring measurements across multiple dimensions in the same patient cohort in combination with a suitable computational analysis pipeline. Preliminary data has implicated novel candidates for neuroimaging, immune, quantitative sensory, and psychological markers for discovery. In addition, a standardized specimen collection, processing, storage, and distribution system is in place, along with expertise in machine learning approaches to extract reliable and prognostic bio-signatures from a large and complex data set. This project will facilitate risk stratification and a resourceful selection of patients who are likely to respond to current multidisciplinary pain treatment approaches.

Epidural/spinal administration of analgesics such as opioids, ziconotide and local anesthetics have profound efficacy in some of the most intractable pain conditions such as severe neuropathic pain after failed back surgery, cancer pain and post-operative pain after major abdominal/thoracic surgeries. Contulakin G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin and was shown to be safe in humans in preliminary studies. A small pilot study demonstrated CGX?s analgesic effect in some patients with spinal cord injury-associated pain. Preliminary findings from mechanistic studies in rodents identified neurotensin receptor 2 (NTSR2) as the mediator for analgesic effects of CGX. This project aims to validate spinal NTSR2 as an analgesic target utilizing three species (rat, mice and human), and two pain models (neuropathic pain and post-surgical pain). The project will utilize pharmacological and gene editing tools such as CRISPR-Cas9 and will include assessment of both sensory and affective measures of pain. A two-site parallel confirmation study is designed based on multisite clinical trials to further authenticate spinal NTSR2 as an analgesic target. Successful completion of this project could lead to the development of a non-opioid spinal analgesic that has high translational potential.

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.

There is a clear public health imperative to improve the care and outcomes of people who experience severe acute and chronic pain. The Early Phase Pain Investigation Clinical Network (EPPIC-Net) is charged with conducting deep phenotyping and biomarker studies for specific pain conditions – and with conducting high-quality phase II clinical trials to test novel non-opioid pain treatments with academic and industry partners. This research will extend EPPIC-Net’s current portfolio to develop novel and efficient data-analytic methodologies for complex medical data, such as those that are expected to be generated by the clinical trials conducted by EPPIC-Net.

Enhancing the workforce of pain investigators and practitioners is a key goal of the NIH HEAL Initiative. This mentoring award leverages the resources at one of EPPIC-Net’s Specialized Clinical Centers to encourage interest in clinical pain management, in particular through multidisciplinary pain research projects. A selected investigator will train early career clinical researchers on how to develop and validate relevant pain measures and outcomes in chronic pain conditions, including chemotherapy-induced peripheral neuropathy and neuropathic chronic low back pain. Mentoring activities will include formal research and analysis, active inclusion in EPPIC-Net working groups, and collaborative writing experiences.

Managing persistent pain has long been a difficult challenge, one that is heightened by the recent opioid crisis. Although many potential solutions may exist, demonstrating their efficacy in a multicenter trial is a considerable obstacle. There is broad consensus that a nationwide clinical research network is necessary to promote innovation. A hub-spoke complex of academic medical centers with considerable experience in pain management clinical trials and biomarker validation will leverage existing resources to make clinical trial execution efficient and rapid. Together, spokes will provide maximum flexibility, ready to accommodate studies in any well-characterized pain condition.

A main goal of the NIH HEAL Initiative and the Early Phase Pain Intervention Clinical Network (EPPIC-Net) is to improve non-opioid pain management. This award will leverage the resources at one of EPPIC-Net’s Specialized Clinical Centers by implementing and evaluating strategies to improve the engagement, recruitment, and retention of individuals from underserved racial/ethnic minority populations to participate in EPPIC-Net clinical trials. Since environmental, cultural, and genetic factors may account for observed differences in pain responses between racial and ethnic groups, enrollment of a diverse sample in pain research is crucial to obtain a complete understanding of the effectiveness of any proposed pain therapeutic intervention. The success of these activities will be evaluated, and a toolkit will be created to define best practices that can be by other EPPIC-Net sites and additional trials.

Pain associated with surgery is experienced by millions of patients every year. Although post-surgical pain usually resolves as the surgical site heals, up to half of the patients develop chronic pain after surgery. Opioids remain the mainstay treatment for post-surgical pain which are fraught with serious side-effects and abuse liabilities. The endogenous mechanism that leads to the resolution of post-surgical pain remain unclear, specifically the effects of surgery on the metabolism of sensory neurons and how those changes influence the resolution of post-surgical pain are not known. Preliminary findings suggest that surgical trauma suppresses pyruvate oxidation while increased glutamine catabolism was associated with the resolution of post-surgical pain. This project will test the hypothesis that tissue incision and surgery disrupt the expression of the glutamine transporter ASCT2, which then prevents the resolution of post-incisional pain and aims to validate ASCT2 as a therapeutic target. This project will also employ pharmacological, genetic and animal pain model studies test a novel RNA expression-based strategy to enhance ASCT2 expression in DRG sensory neurons and alleviate postoperative pain in animal model systems. Successful completion of this project would validate ASCT2 as a novel endogenous non-opioid and non-addictive mechanism-based target for the resolution of postoperative pain.