Funded Projects

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.

Despite the significance of spine disorders, there are few reliable methods to determine appropriate patient care and evaluate intervention effectiveness. The Back Pain Consortium Research Program
(BACPAC) is developing machine learning-based methods to obtain disease-related features from biological images. This project supports a scientist from a group underrepresented in biomedicine to expand ongoing research to improve ways to interpret medical data about spine disorders and associated pain.

Mismanagement of orofacial chronic pain, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, substantially contributes to opioid overuse; overdose-related deaths; and cardiovascular, renal, and neurological complications at epidemic proportions. The current paradigm implies that orofacial conditions could trigger maladaptation of the immune system and plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LT?), members of the tumor necrosis factor superfamily, provide a balance between protective immunity and immunopathology during chronic inflammatory diseases. This project will test the hypothesis that targeting LIGHT and LT? signaling could prevent the development and inhibit the maintenance of chronic pain produced by TMJD and oral cancer, via peripheral mechanisms involving plasticity of immune, stromal, and tumor cells, as well as sensory neurons. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain and offers new therapeutic targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer.

Chronic pain affects over 100 million Americans, costing society about $600 billion annually. Despite numerous pharmacological and non-pharmacological therapies, over 50% of chronic pain sufferers feel little control over their pain. CognifiSense has developed a patent-pending Virtual Reality Psychological Therapy (VRPT), which is designed to create lasting reduction of chronic pain by addressing the maladaptive learning processes driving pain chronification. VRPT is an experiential learning system, which provides the brain a new set of signals that teaches it that the pain is not as bad as it perceived and that it has greater control over the pain than it perceived. VRPT combines the immersive power and the ability to individualize the therapy of Virtual Reality with well-researched principles of self-distancing, self-efficacy, and extinction to retrain the brain. The goal of this study is to determine the clinical feasibility of VRPT in achieving a lasting reduction of chronic pain, establish brain mechanisms associated with treatment response, and collect comprehensive user feedback to enable further refinement of the current product prototype. CognifiSense's VRPT has the potential to be a significant clinical and business opportunity in the treatment of chronic pain.

Research on optimal long-term opioid therapy (LTOT) tapering strategies has lagged behind clinical needs. Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) may be especially vulnerable. This study will adapt the Collaborative Opioid Reassessment Program (CORP) and Cooperative Pain Education and Self-Management (COPES) interventions for patients receiving HD and LTOT and test their effectiveness in a pragmatic sequential multiple assignment randomized trial (SMART) design. Initial randomization will be to compare CORP-supported taper with (CORP-B) and without (CORP) buprenorphine rotation on the six-month composite outcome of LTOT dose reduction and pain response. This design will allow determination of which of the eight adaptive treatment strategies leads to the greatest reduction in six-month opioid dose and pain interference.

There is increasing evidence that satellite glial cells (SGCs) surrounding neurons in the dorsal root ganglia modulate sensory processing and are important for chronic pain. Tissue inhibitor of metalloproteinase 3 (TIMP3) signaling occurs in SGCs and has unique plethoric functions in inhibiting matrix metalloproteinases, the tumor necrosis factor-?-converting enzyme, and the vascular endothelial growth factor receptor 2, all of which have been implicated in inflammation and pain. This study will test the hypothesis that expression of TIMP3 in SGCs is critical for the neuroimmune homeostasis in sensory ganglia, as well as for the development of pain, and therefore could be a novel therapeutic target for acute and chronic pain. Given the expression of TIMP3 in human SGCs and the strong validation of multiple small molecules targeting TIMP3 signaling, including FDA-approved drugs, in various animal models of pain and in cultured human SGCs, the successful completion of this research project has a high likelihood of rapid translation into therapeutic testing in inflammatory pain conditions that are a risk for opioid abuse.

Researchers will develop an innovative three-dimensional (3D) model of acute and chronic nociception using human induced pluripotent stem cell (hiPSC) sensory neurons and satellite glial cell surrogates. They will develop a tissue chip for modeling acute and chronic nociception based on 3D hiPSC-based dorsal root ganglion tissue mimics and a high-content, moderate-throughput microelectrode array. Researchers will demonstrate stable spontaneous and noxious stimulus-evoked behavior in response to thermal, chemical, and electrical stimulation challenges. They aim to demonstrate sensitivity to translational control via ligand receptor interactions between neuronal and non-neuronal cell types. They also will demonstrate the quantitative efficiency and preclinical efficacy of our system by detecting known ligand-based modulators of translational control and voltage-gated ion channel antagonists in a sensitized model of chronic nociception. Researchers will leverage the high-throughput nature of our tissue chip model to screen Food and Drug Administration–approved bioactive compounds.

Chronic low back pain (cLBP) is recurrent and often nonresponsive to conservative treatments. Biomechanists, physical therapists, and surgeons each utilize a variety of tools and techniques to assess and interpret qualitative movement changes to understand potential mechanical and neurological sources of low back pain and as critical elements in their treatment paradigm. However, objectively characterizing and communicating this information is currently impossible, since clinically feasible (i.e., cost-effective, objective, and accurate) tools and quantitative benchmarks do not exist. This research addresses the challenge to improve cLBP outcomes through the use of unique, inexpensive, screen-printable, elastomer-based, nanocomposite, piezoresponsive sensors, which will be integrated into a SPInal Nanosensor Environment (SPINE) sense system to measure lumbar kinematics and provide an objective, quantitative platform for diagnosis, monitoring, and follow-up assessment of cLBP.

Debilitating pain is the most common complication of sickle cell disease (SCD), but there is significant variability in pain expression in these patients. Currently, there is no plasma biomarker that can prognosticate which patients are likely to experience pain. The overall goal of this proposed research is to develop a biomarker that prognosticates the clinical expression of pain in SCD. Project aims are to (1) derive the inflammatory index for pain by identifying inflammatory and immune regulatory gene probe sets that will distinguish healthy controls, patients with SCD in baseline health, and patients with SCD in acute pain and (2) determine whether co-expressed genes from patients with SCD correlate with clinical pain data. Subsequent aims are to (1) determine the clinically meaningful changes of the index in patients with SCD and (2) investigate the preliminary clinical validity of the index as a prognostic biomarker for pain in patients with SCD.

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.

TWIK-related spinal cord K+ (TRESK) channel is abundantly expressed in all primary afferent neurons (PANs) in trigeminal ganglion (TG) and dorsal root ganglion (DRG), mediating background K+ currents and controlling the excitability of PANs. TRESK mutations cause migraine headache but not body pain in humans, suggesting that TG neurons are more vulnerable to TRESK dysfunctions. TRESK knock out (KO) mice exhibit more robust behavioral responses than wild-type controls in mouse models of trigeminal pain, especially headache. We will investigate the mechanisms through which TRESK dysfunction differentially affects TG and DRG neurons. Based on our preliminary finding that changes of endogenous TRESK activity correlate with changes of the excitability of TG neurons during estrous cycles in female mice, we will examine whether estrogen increases migraine susceptibility in women through inhibition of TRESK activity in TG neurons. We will test the hypothesis that frequent migraine attacks reduce TG TRESK currents.

This study will collaborate with diverse stakeholders to design and conduct a multisite trial evaluating innovative strategies to reduce opioid dosing and improve quality of life and experience with care specific to pain management among adults receiving in-center hemodialysis. A pragmatic parallel arm trial will test the impact of adding a 12-week interactive video cognitive behavioral therapy (IV-CBT) intervention program, compared with CDC guideline-concordant shared decision-making (SDM) for NCCP pharmacotherapy management. The specific aims are to (1) conduct a multisite randomized trial to receive IV-CBT and SDM versus SDM alone over 15 months; (2) investigate and describe barriers and facilitators of the implementation of IV-CBT and also SDM among patients, clinicians, and dialysis staff; and (3) create a collaborative network of investigators and dialysis facilities for efficient recruitment and for dissemination of successful strategies to optimize pain care in dialysis.