Funded Projects

Negative Affect (NA) and stress are key features of Opioid Use Disorder (OUD) and often lead to drug use and relapse. The Autonomic Nervous System (ANS) dominates physiological responses to emotions and stress, yet its function and how it unfolds over time and in real-world settings remains understudied in the context of OUD. With new wearable technologies, ANS function can be measured through heart rate variability (HRV) and can be recorded continuously via wearable sensors, providing a non-invasive method to examine physiological mechanisms underlying stress and NA in real-world settings and in real-time. The present research will serve as a pilot study to assess 1. The role of autonomic function (indexed by HRV) as a marker of NA and stress in people with OUD 2. Participants’ adherence to wearing sensor devices and response rates to daily questionnaires. To achieve these objectives, we will monitor participants for 14 days and quantify self-reports measures of stress, overall daytime HRV patterns, and the magnitude, frequency, and duration of reduced HRV instances. Our findings can help advance technologies to address the opioid epidemic, and our understanding of physiological markers as objective measures and predictors of NA and stress in OUD.

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.

The University of California, San Francisco, as part of the Back Pain Consortium (BACPAC) Research Program, has established a Core Center for Patient-centric Mechanistic Phenotyping in Chronic Low Back Pain (REACH). The main goal of REACH is to define different subtypes (phenotypes) of chronic low back pain as well as to identify underlying pain mechanisms that can lead to effective, personalized treatments for patients across all population subgroups. To achieve this goal, REACH is, or will be, participating in several clinical trials, and it is imperative that the patients participating in these trials reflect the diversity of the U.S. population. Therefore, this project seeks to adapt methods that have successfully improved minority participation in other settings as well as to develop and deploy digital strategies that can promote recruitment and engagement of patients from marginalized populations.

The HEAL Initiative is establishing a HEAL Data Ecosystem to help investigators manage and share HEAL-generated data. A key principle underlying the HEAL Data Ecosystem strategy is to make those data findable, accessible, interoperable, and reusable (FAIR). Renascence Computing Institute at the University of North Carolina Chapel Hill (RENCI) and RTI, International (RTI) [RENCI/RTI] are serving as the HEAL Data Stewardship Group to guide HEAL investigators as they prepare their data to connect to the HEAL Platform, a secure data access and computing environment that will leverage metadata query to provide access to data and digital assets stored in various disparate repositories. The HEAL Data Stewardship Group is engaging HEAL investigators to understand and enhance data management needs, provide tools, training, and best practices for making data FAIR, and understand and support valuable uses and reuses of HEAL data sharing via the Platform The HEAL Data Stewardship Group will collaborate closely with the HEAL Platform team at the University of Chicago to meet the needs and goals of the HEAL Data Ecosystem.

Mindfulness has been shown to be effective in treating chronic low back pain, but it has not been embedded into routine clinical care. The OPTIMUM study (Optimizing Pain Treatment In Medical settings Using Mindfulness) will address barriers to delivering mindfulness in primary care and determine the effectiveness in this setting. This project extends the stakeholder engagement efforts of the OPTIMUM study by increasing the size and responsibilities of the Community Advisory Board, adding focus groups for participants in both study arms, and collecting stories from study nonparticipants about their experience seeking care for chronic low back pain and their views on participating in research. This expanded effort will optimize recruitment of a diverse and underrepresented sample, maximize retention, and prepare for future implementation and dissemination.

Approximately 3.6 million Americans live with an amputated extremity, and the majority of these individuals are likely to suffer from chronic post-amputation pain. There is no consensus as to a recommended therapy for such pain, and many treatments do not provide sufficient pain control. Some studies have shown effective pain suppression from delivering an anesthetic agent directly to an injured nerve. This research aims to develop a device that can be implanted near the injured nerves of an amputated limb to deliver an anesthetic. Findings from this preclinical study will optimize design and delivery features to maximize its effect on pain control for as long as possible without needing a drug refill. The research is expected to advance eligibility for further testing in large animals and humans.

The parent project’s Housing First initiative can be divided into two interconnected goals: (1) to reduce the likelihood of substance misuse and the development of an opioid use disorder and (2) to provide youth with housing stability and opioid and related risk prevention services that will assist them in exiting homelessness. The proposed supplement project complements the goals of the parent grant project by exploring two additional components that are related to exiting homelessness and reducing substance misuse or the development of opioid use disorder: (1) to further investigate youth’s interactions with social service providers, via qualitative methods, with the goal of cultivating a detail understanding actionable practices as it relates to fostering successful interactions between substance using homeless youth and service providers and (2) to evaluate, via quantitative methods, the extent to which ethnic identity protects youth from the negative effects of discrimination, substance misuse, and the development of a opioid use disorder.

Disruptions in make-up of the microbiome are associated with disorders characterized by chronic pain and inflammation, such as rheumatoid arthritis and fibromyalgia. The gut microbiome has immune and metabolic effects, and human gut-derived bacteria may be a source of novel, safe, and non-addictive pain treatments. However, connections between gut and pain signals, known as the “gut–pain axis,” are still poorly understood. This study aims to identify human-gut-native bacteria that i) interact with known pain targets in lab studies, ii) test their activity and analgesic/anti-inflammatory potential in an animal model, and iii) develop a computational approach to predict microbial-genetic effects on pain signals.

The need to develop non-opioid therapeutics for chronic pain is greater than ever.  One option being explored is inhibiting the activity of calpains – enzymes that have been shown to cause pain in animal models of chronic pain.  Using an artificial intelligence (AI)-driven drug discovery platform, researchers have uncovered and validated four calpain-1 inhibitors using biochemical assays.  This study by 1910 Genetics Inc. hopes to synthesize multiple analogs of its most potent discovered calpain-1 inhibitor and determine its effectiveness against calpain-2 and certain enzymes that break down proteins.  Findings that successfully significantly inhibit calpain-1 in at least one animal model of chronic pain could lead to the first oral, central nervous system penetrating selective calpain-1 inhibitor [non-opioid therapeutic] for chronic pain.

Knee osteoarthritis is one of the leading causes of disability worldwide, particularly among older adults. Despite multiple guidelines for care, most patients do not receive adequate treatment, and about 30% are prescribed long-term opioids. This award will be used to recruit and support an early career faculty member from a group underrepresented in biomedicine. This research, part of the Pain Management Effectiveness Research Network will evaluate conservative and more aggressive treatments for knee osteoarthritis and determine which individual-level factors contribute to treatment outcomes.

Patients with severe, intractable chronic pain primarily receive treatment with opioids, and non-opioid treatment options are urgently needed. These patients may be candidates for treatment using other types of pain medications administered via intrathecal injection—that is, injection directly into the fluid-filled space between the membranes surrounding the brain and spinal cord. Intrathecal injection requires much lower medication doses than systemic administration. Centrexion Therapeutics Corporation seeks to develop CNTX-3100, a highly selective and highly potent novel small molecule that activates the nociception receptor (NOPr), for intrathecal administration using a pump approved by the U.S. Food and Drug Administration. In animal studies, such NOPr agonists had powerful analgesic effects when delivered directly to the spinal cord by intrathecal administration. CNTX-3100 has ideal properties for intrathecal delivery and in animal studies provided pain relief and a safety profile that was superior to intrathecally administered morphine. This project will scale up the drug, develop a formulation that ensures a stable product for intrathecal delivery, and conduct preclinical toxicity studies to prepare for a Phase 1 clinical trial.

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.