Funded Projects

Many barriers exist in primary care offices where socioeconomically disadvantaged patients are most often treated. This project seeks to address chronic pain disparities that affect racially diverse, socioeconomically disadvantaged individuals. The study aims to optimize multimodal pain management in primary care clinics for low-income populations. This study includes two group-based models: integrative group medical visits and group acupuncture. These two interventions will be compared to typical treatment to measure both pain interference and social isolation. National experts and patient stakeholders will refine and optimize the design of the study with English- or Spanish-speaking patients with chronic pain in two primary care clinics for low-income populations.

The opioid crisis has underscored the urgency of alleviating patients’ chronic low back pain (cLBP) with effective therapies, including evidence-based nonpharmacologic approaches. Mindfulness-based stress reduction (MBSR) is now recommended by the American College of Physicians for initial treatment of cLBP. A pragmatic clinical trial (PCT) will inform health care decision makers about whether this program can be implemented in a real-life clinical setting and measure its impact on outcomes. The OPTIMUM (Optimizing Pain Treatment In Medical settings Using Mindfulness) program will integrate and test an evidence-based mindfulness clinical pain program for patients with cLBP in the primary care provider (PCP) setting. It will be conducted with three health care system sites. Four hundred and fifty persons ? 18 years of age with cLBP will be randomized to OPTIMUM + PCP Usual Care or PCP Usual Care.

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.

The University of Pittsburgh Low Back Pain: Biological, Biomechanical, and Behavioral Phenotypes (LB3P) Mechanistic Research Center (MRC) will to perform in-depth phenotyping of patients with chronic low back pain (cLBP), using a multimodal approach to characterize patients and provide insight into the phenotypes associated with experience of cLBP to direct targeted and improved treatments. The LB3P MRC will be formed of three Research Cores, three support cores, and one research project. This approach will leverage and integrate distinctive resources at the University of Pittsburgh laboratories to deliver quantified biomechanical, biological, and behavioral characteristics; functional assessments; and patient-reported outcomes, coupled with advanced data analytics using a novel Network Phenotyping Strategy (NPS). By eliminating isolated and disconnected approaches to treatment and focusing on personalized patient-centric approaches, this approach will yield improved outcomes and patient satisfaction.

Identifying optimal chronic low back pain treatments on a patient-specific basis is an important and unresolved challenge. Tailoring interventions according to patient movement characteristics is one option. This research is characterizing patients based on spinal motion during functional tasks and daily activities and will use artificial intelligence to objectively characterize motions of the spine during both clinical assessments and day-to-day life. During clinical assessments, participants will be asked to perform functional tasks while wearing motion sensors. Data collected from the sensors will be used to identify tasks of interest, such as activities of daily living and aberrant/painful motions. An artificial intelligence approach will then interpret data collected continuously during assessment in patients’ homes over a 7-day testing period. Ultimately, this data could be used to help clinicians tailor treatments that are responsive to a patient’s real-world functional impairments.

This project aims to develop and clinically validate a 64-channel spinal cord stimulation therapy for treating chronic neuropathic pain of the lower extremities, groin, and lower back. With an increased channel count and the ability to precisely target medial and lateral structures of the spinal cord, the system will treat chronic pain with greater efficacy and reduced side effects. This project will pursue a safe, effective, and non-addictive treatment for neuropathic pain through the testing of enhanced HD64 active leads to be manufactured under GMP regulations. The leads will then undergo electrical, mechanical, biocompatibility, and sterilization testing before being tested in a 10-subject early feasibility study.

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.

This project will develop a human cell-based model of the afferent pain pathway in the dorsal horn of the spinal cord. The research team’s approach utilizes novel human pluripotent stem cell (hPSC)-derived phenotypes in a model that combines 3D organoid culture with microfabricated systems on an integrated, three-dimensional (3D) microelectrode array. Researchers will establish the feasibility of a physiologically relevant, human 3D model of the afferent pain pathway that will be useful for evaluation of candidate analgesic drugs. They will then improve the physiological relevance of the system by promoting neural network maturation before demonstrating the system’s utility in modeling adverse effects of opioids and screening compounds to validate the model. Completion of the study objective will establish novel protocols for deriving dorsal horn neurons from hPSCs and create the first human microphysiological model of the spinal cord dorsal horn afferent sensory pathway.

In the US, approximately 100,000 people, mainly of African and Hispanic background have Sickle Cell Disease (SCD). Pain is a constant companion and chronic disabling symptom for those with SCD. It is increasingly clear that adults with chronic SCD pain also experience periods of acute worsening of their pain. The evaluation of nonpharmacological therapies that reduce chronic pain and the need for opioid medication among individuals with SCD is critically needed to address lack of adequate pain control to prevent periods of acute deterioration and high opioid use with negative sequelae. The investigators will conduct a hybrid type 1 effectiveness-implementation trial to assess the effectiveness of acupuncture and guided relaxation in patients with SCD while observing and gathering information on implementation in three health systems. The study will utilize a 3-arm, 3-site pragmatic randomized controlled SMART trial design that evaluates adaptive interventions, in which selection of interventions responds to patients? characteristics and evolving clinical status. The investigators will use the Consolidated Framework for Implementation Research to plan, execute, and evaluate implementation processes.

Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN accounts for significant dose reductions and/or discontinuation of these life-saving treatments. Unfortunately CIPN can also persist in cancer-survivors, adversely affecting their quality of life. CIPN is not well-managed with existing pain therapeutics. Recent preliminary findings suggest that the transcription factor hypoxia-inducible factor alpha (HIF1A) is the target for the chemotherapeutic bortezomib, a proteasome inhibitor. This project will test the hypothesis that bortezomib chemotherapy-induced expression of HIF1A, PDHK1 and LDHA constitute an altered metabolic state known as aerobic glycolysis (AG) that leads to the initiation and maintenance of peripheral neuropathy and pain using a novel tumor-bearing animal model of CIPN. This project aims to validate HIF1A as a therapeutic target for the prevention of CIPN, as well as validate PDHK1 and LDHA as non-opioid therapeutic targets for chronic or established CIPN in animal models.

Inhibitors of the epigenetic enzymes histone deacetylases (HDACs) produce analgesic responses and are therefore therapeutic targets for pain. The research team recently resolved a PET imaging agent, [11C]Martinostat, that selectively binds to a subset of HDAC enzymes. A series of initial proof-of-concept clinical validation studies will be conducted to evaluate whether [11C]Martinostat PET is a sensitive biomarker to detect the typical (axial) chronic low back pain (cLBP). The research team will validate [11C]Martinostat PET’s ability to differentiate subtypes of pain by comparing axial cLBP and other cLBP patients with radiculopathy and longitudinally study subacute LBP patients (sLBP) to investigate whether there is a unique imaging signature that differentiates patients who develop cLBP and those who recover from low back pain. Using [11C]Martinostat to understand HDAC expression changes in chronic pain patients will validate an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism in developing novel analgesics.

The research team will develop an implantable neural stimulation system to provide natural and intuitive sensation for prosthesis users. The nerve cuff technology meets the requirements for a sensory feedback system capable of providing consistent and controlled electrical stimulation. Coupled with a multichannel implantable stimulator, this electrode array will offer substantial improvement over existing options to treat phantom limb pain (PLP). In Phase I, researchers will finalize array architectures for evaluation in cadaver studies, complete integration of electrodes with our stimulator, conduct benchtop verification of electrical and mechanical performance, send implants for third-party evaluation of system biocompatibility, and complete a Good Laboratory Practice animal study to validate safety and efficacy. In Phase II, researchers will conduct a 5-subject clinical study to test the implantable stimulation system. Each unilateral prosthesis user will be implanted for one year as researchers evaluate the safety and efficacy of this implantable device to treat PLP.