Funded Projects

Migraine is the most common neurological disorder. Currently available treatments fail to effectively manage migraine in most patients. Development of new therapeutics has been slow due in large part to a poor understanding of the underlying pathology of migraine. Endogenous proteases, released in the meninges by resident mast cells, have been proposed as a potential driver of migraine pain via an action on protease activated receptor type 2 (PAR2). The central hypothesis is that PAR2 expression in nociceptors that project to the meninges plays a key role in the pathogenesis of migraine pain. The aims are to: 1) use the established PAR2 development pipeline to design new PAR2 antagonists with improved drug-like properties; 2) use pharmacological tools in a novel mouse migraine model to further understand the potential role of PAR2 in migraine; and 3) use mouse genetics to study the cell type–specific role of PAR2 in migraine pain.

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.

Fifty million Americans experience chronic pain, including about 25 million who report pain that substantially interferes with daily activities and reduces quality of life. Mental health problems, including depression, anxiety, and post-traumatic stress disorder, increase risk for severe chronic pain. This project will use genetic data, information about observable characteristics (phenotypic data), and neuroimaging data from three large databases to identify psychosocial factors that predict chronic pain, assess differences across diverse U.S. populations, and determine whether risk profiles predict post-surgical chronic pain.

The Interagency Pain Research Coordinating Committee has identified a need for organized opportunities for early-stage pain researchers to meet and learn from more experienced pain researchers and mentors – who are exiting the field at a faster rate than they are being replaced. This project will create a coordinating center for early-stage pain researchers, with an online networking platform to encourage interactions and collaboration among these scientists. The research will also develop a training curriculum and make it accessible to NIH funded, early-stage pain scientists.

The increased presence of fentanyl in cocaine has drastically increased cocaine-related overdoses, yet there is no research quantifying how cocaine users respond to fentanyl adulteration. In this online study, a modification of a behavioral economics measure, the Cocaine Purchase Task, will quantify for the first time how cocaine users respond to fentanyl contamination in cocaine. This study aims to 1) Determine how possible fentanyl adulteration affects cocaine demand, and 2) Determine which individual characteristics moderate the relationship between fentanyl adulteration and cocaine demand. Determining how possible fentanyl adulteration affects cocaine demand can help inform the development of effective harm reduction interventions for people who use cocaine to address the worsening crisis of opioid related deaths.

For many individuals in recovery from a substance use disorder, certain cues—including stress and drug-related cues—can trigger a physiological state in which they are more likely to relapse. In this SBIR project, the investigators intend to deploy a system—consisting of a wearable sensor, a smartphone app, and a clinical portal—to provide individuals in recovery and their treatment providers with an opportunity to identify moments of high risk for relapse and to access real-time intervention opportunities. The sensors will identify signals of stress or drug use, interface with a smartphone app, and provide options for annotations, stress-reduction techniques, or contact with an individual’s support system and treatment providers, as well as log and encourage healthy behaviors. This study will deploy and optimize the system, as well as test its effects on addiction-related outcomes, such as rate of relapse.

For patients with end-stage renal disease treated with long-term hemodialysis (HD), the safety and efficacy of behavioral interventions alone or augmented by safer drugs remain untested. This study will perform a multicenter parallel group randomized controlled trial to test the efficacy of two interventions to reduce opioid use in HD patients. Seven hundred and twenty HD patients with significant and ongoing opioid use will be randomly assigned to (1) telehealth cognitive behavioral therapy (CBT) alone, (2) telehealth CBT augmented by transdermal buprenorphine, and (3) usual care, with follow-up for up to one year. The primary outcome will be prescribed morphine milligram equivalent (MME) over the preceding four weeks. Three patient-reported outcomes (interference by pain, functional status, and quality of life) will comprise the secondary outcomes.

Although digital health technologies are now widely available for both therapeutic and monitoring applications, there are wide variations in patient knowledge, attitudes, beliefs, and preferences regarding their uptake and effectiveness. There are also sociodemographic variations in willingness to participate in digital health research studies, both for chronic pain and other common disorders. However, few efforts have systematically examined patient-level predictors of digital health uptake and benefit among diverse individuals who experience chronic pain. This research will employ mixed methods to examine variations in engagement and benefit among diverse participants in a large clinical trial examining the benefits of virtual reality for treatment of chronic lower back pain.

To respond quickly and effectively to the constantly changing dynamics of the opioid crisis, public health agencies and organizations need timely state and local data to make critical decisions about where to allocate resources and target responses. This project creates the Rapid Actionable Data for Opioid Response in Kentucky system, a near real-time statewide surveillance system. This resource will combine data from multiple state agencies to provide actionable and timely information to support opioid overdose prevention, harm reduction, evidence-based treatment, and recovery services. The project will also develop user-driven reporting and visualization tools (mobile and web-based apps) that provide immediate access to near real-time community or state level data, reports, and visual analytics.

This project addresses the significant challenge of providing evidence-based, non-pharmacologic pain management to veterans with chronic pain living in rural regions. This research will test whether an innovative, virtual complementary and integrative group-based treatment will improve rural veterans’ pain management, function, and well-being. The research will also devise, evaluate, and adapt strategies for implementing this intervention while working with the health care system, veteran patients, and communities. The scalable, 12-week intervention includes pain education, mindfulness, pain-specific exercises, and cognitive behavioral strategies.

Because pain is a multidimensional phenomenon with physical and psychosocial components, a pain management approach relying solely on analgesics is unlikely to be efficacious. Nonpharmacologic therapies for co-occurring chronic pain and opioid use in hemodialysis patients should target and alter cognitive-affective circuits that govern responses elicited by pain, stress, mood disorders, and opioid-related cues. These domains are directly addressed through the behavioral therapy program known as MORE (Mindfulness-Oriented Recovery Enhancement)—a multipronged mindfulness-oriented individualized group therapy that integrates mindfulness training, cognitive reappraisal, and enhancement of natural reward processing. The specific aims are 1) to determine the impact of MORE on chronic pain and opioid use in hemodialysis patients and 2) to determine predictors of chronic pain, opioid use, and response to MORE.

Lumbar spinal surgery, an increasingly common surgery in adults with severe chronic back pain, is associated with acute post-surgical pain, costly postoperative opioid-related adverse effects, long hospital stays, high-risk for chronic post-surgical back pain, and persistent opioid use and dependence. Each individual responds differently to opioids based on their unique genetic and clinical factors, and the current trial-and-error approach to opioid use and prescribing promotes excessive opioid use, costly adverse outcomes, and poor surgical pain management. To address this issue, this research project will develop a preoperative diagnostic test that will use genetic and clinical information to proactively assess each person’s risk for opioid-related adverse events and chronic post-operative pain. The results will help clinicians provide personalized pain management to maximize pain relief while minimizing opioid-related safety risks, including opioid dependence.