Funded Projects

African American adults are less likely to receive analgesics, particularly opioids. Research in the pediatric surgical population is limited, but the pattern of disparate use of opioids appears consistent with adults. Furthermore, adolescent access to prescribed opioids has increased, both through physician prescribing and misuse of medications prescribed to family members or friends. This study will explore the interrelated impacts of policy, clinical need, and sociodemographic factors by combining Medicaid claims and electronic health record data with findings from a statewide opioid policy inventory. We will focus on discharge prescribing of opioids in three high-volume pediatric surgical procedures: tonsillectomy/adenoidectomy, supracondylar fracture, and appendectomy. We aim to 1) determine the extent of racial disparities in postoperative discharge opioid prescribing since the 2011 onset of enhanced opioid prescription reduction activities and 2) develop an expanded model to assess the linkage between differential opioid use for pediatric postoperative pain and opioid use-related outcomes.

Ethnic groups show substantial variability in the experience of acute and clinical pain, with African Americans (AAs) having more clinical pain conditions and higher levels of pain severity and pain-related disability compared to non-Hispanic whites (NHW). Ethnic differences in opioid neurotransmitters suggest that these systems function less efficiently among AAs and may account for differences in pain and analgesic responses. The overwhelming majority of clinically used opioids elicit their effects through activation of the mu-opioid receptor, making it a relevant target for investigation. We propose to examine ethnic differences in the supraspinal endogenous opioid system using positron emission tomography (PET) imaging of mu-opioid receptors employing the mu-selective agonist [11C]carfentanil. Healthy AAs and sex-, age-, SES-matched NHW participants will undergo one baseline (non-pain) and one capsaicin-induced pain PET session using [11C]carfentanil. The current proposal will measure µ-opioid binding potential and examine its role in ethnic group differences in pain sensitivity.

Previous studies found that African American (AA) and low socioeconomic status (SES) patients are less likely to receive guideline-concordant pain care relative to White and high SES patients. According to research and theory, enhancing clinician perspective-taking is a promising strategy for improving the care of AA and low SES patients. We have developed an innovative methodology that utilizes computer-simulated patients and environments to assess, understand, and remediate pain treatment disparities. Our approach allows for the intervention to be individually tailored to each trainee, thereby enhancing its impact. It also allows for individual trainees to gain exposure to a greater range of racially and socioeconomically diverse patients than can normally be obtained in traditional training settings. We hypothesize that our perspective-taking intervention will increase trainees’ knowledge of their own biases, enhance trainees’ empathy toward patients, and reduce trainees’ anxiety/threat toward patients, and that these changes will reduce pain treatment disparities.

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.

Neuropathic corneal pain (NCP) causes patients to have severe discomfort and a compromised quality of life (QoL). The lack of signs observed by standard examination has resulted in misdiagnosis as dry eye disease (DED). An optical biopsy using laser in vivo confocal microscopy (IVCM) revealed that microneuromas (bulbs at the ends of severed nerves caused by buildup of molecular constituents) are present in NCP but not DED and may serve as a biomarker for NCP. The aims are to (1) use a database of more than 2,000 DED/NCP subjects and more than 500,000 IVCM images to confirm that the presence of microneuromas is an appropriate biomarker for NCP, (2) provide biological validation of microneuromas, (3) develop a validated artificial intelligence (AI) program for automated identification of microneuromas, and (4) establish the clinical utility of microneuromas observed by IVCM as a biomarker for NCP in a prospective, multicenter study.

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.

Cataract surgery is commonly performed in older adults; however, some patients subsequently experience chronic eye pain that is difficult to treat. One promising approach that is effective in some, but not all, patients uses the patient's own serum (a component of blood) as eye drops. This project seeks to identify markers that can help predict which patients will respond to serum treatment and monitor their progress. Using advanced technology and data analysis to evaluate patient histories, questionnaires, and different genetic and other molecular characteristics in the eyes and serum it aims to identify potential markers that can then be tested in a clinical study.

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.

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.

Current medications for chronic pain are largely ineffective and rely heavily on opioids, one contributor to the nation’s opioid crisis. The endocannabinoid system that consists of cannabinoid receptors (CB1R and CB2R) and their endogenous ligands is a natural pathway in the human body and has emerged as an alternative target for developing new pain medications with few side effects. Current molecules that bind to CB1R in the brain and spinal cord have psychoactive side effects, limiting their therapeutic use for treating chronic pain. This study aims to develop new molecules to bind to CB1R tightly and selectively, are metabolically stable, and are also unable to enter the brain.

Over-the-counter medicines such as non-steroidal anti-inflammatory drugs are ineffective for treating severe chronic pain and may have serious side effects from continued use, which limits treatment options. A kinase (an enzyme whose activity targets a specific molecule) called TAK1 is involved in the chronic pain process. This research will develop a molecule previously shown to be effective in a model of inflammatory pain that also inhibits TAK1. A main goal will be to determine if this inhibitor (takinib analog HS-276) can cross the blood-brain barrier and, if successful, pursue FDA  Investigative New Drug-enabling safety studies leading to a Phase I clinical trial and a potential new chronic pain treatment.