Funded Projects

Recent studies have reported that neuropathic pain involves changes in the central nervous system that are linked to necroptosis (programmed necrotic cell death) and release of cellular components that create neuroinflammation. Necroptosis is a type of necrotic cell death affected by the protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1 or RIP1). Preliminary studies also indicate that pain increases levels of RIPK1 in key brain regions implicated in pain processing. This project aims to further validate RIPK1 as a target for neuropathic pain using a newly developed positron emission tomography imaging approach. The work will pave the way for new brain-penetrant RIPK1 inhibitors as a safe, effective, and nonaddictive treatment approach for neuropathic pain.

Chronic pain from tissue injury often stems from long-term changes in spinal cord circuits that change nerve sensation. Reversing these changes may provide better pain therapeutics. Previous work in animal models showed that activating G protein-coupled receptor 37 (GPR37) dampens nerve signal intensity after long-term stimulation and alleviates pain behavioral responses. This project aims to validate GPR37 in the spinal cord as a useful target for new treatments for neuropathic pain. The work will facilitate screening and identification of new molecules that activate GPR37, which can then be tested for efficacy and safety in further research in animal models of pain.

There is a need to improve access to treatments and address the stigma, bias, and mistrust that harm and isolate people with chronic pain, especially those from ethnic and racial minority populations. The Integrating Nonpharmacologic Strategies for Pain with Inclusion, Respect, and Equity (INSPIRE) Chronic Pain (CP) intervention blends cognitive-behavioral therapy, physical therapy, mindfulness, and pain education, and is delivered by a trilingual mobile app and supported by a telehealth pain coach who coordinates with doctors. The coach will collect and summarize patient reports on pain, depression, anxiety, substance use, and social factors, and share them with healthcare providers. In this project, researchers will create the digital tool and coaching protocol, develop educational and implementation strategies for healthcare providers, and conduct a pilot test. They will then perform a randomized clinical trial to compare INSPIRE to current treatment, analyze its effects, and evaluate outcomes.

It is unclear what changes in the brain mediate the development of chronic pain from acute pain and how chronic pain may change responses to opioid reward for the altered liability of opioid abuse under chronic pain. Preliminary studies have found that Dnmt3a, a DNA methyltransferase that catalyzes DNA methylation for gene repression, is significantly downregulated in the brain in a time-dependent manner during the development of chronic pain and after repeated opioid treatment. This project will investigate whether Dnmt3a acts as a key protein in the brain for the development of chronic pain, and whether Dnmt3a could be a novel epigenetic target for the development of new drugs and therapeutic options for the treatment of chronic pain while decreasing abuse liability of opioids.

Effective treatments are elusive for the majority of patients with neuropathic pain. Reactive oxygen and nitrogen species (ROS/RNS) are involved in neuropathic pain, because they drive mitochondrial dysfunction, cytokine production, and neuronal hyperexcitability; therefore, stimulation of endogenous antioxidants is predicted to simultaneously resolve multiple neuropathic pain mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is a potential therapeutic target because it regulates the expression of a large number of endogenous antioxidant-related genes and can be activated with a single drug. This project will test the hypothesis that Nrf2 activation increases multiple endogenous antioxidants, therefore reversing neuropathic pain behaviors and counteracting neuropathic pain mechanisms that are driven by ROS/RNS and could provide an effective pain therapy, with minimal abuse/addictive potential.

An important component of neuropathic pain is spontaneous or ongoing pain, such as burning pain or intermittent paroxysms of sharp and shooting pain, which may result from abnormal spontaneous activity in sensory nerves. However, due to technical limitations, spontaneous activity in sensory neurons in vivo has not been well studied. Using in vivo imaging in genetically-modified mice, preliminary findings identified spontaneously-firing clusters of neurons formed within the dorsal root ganglia (DRG) after traumatic nerve injury that exhibits increased spontaneous pain behaviors. Furthermore, preliminary evidence has been collected that cluster firing may be related to abnormal sympathetic sprouting in the sensory ganglia. This project will test the hypothesis that cluster firing is triggered by abnormal sympathetic inputs to sensory neurons, and that it underpins spontaneous paroxysmal pain in neuropathic pain models. Findings from this project will identify potential novel therapeutic targets for the treatment of neuropathic pain.

Complex regional pain syndrome is a difficult-to-treat chronic condition that causes excess and prolonged pain and inflammation after injury to an arm or leg and includes damage to skin of affected limbs. Although it is known that aberrant immune system function plays a role in this condition, the details remain unclear about how this occurs – in particular, through the adaptive immune system that relies on specialized immune cells and antibodies to protect the body from harm.  This project will study the role of certain immune cells (T cells) that circulate throughout the body or reside in bone using both rat or human bone samples from patients with complex regional pain syndrome.

Chronic pain is a debilitating condition for which there is a pressing need for safe, effective treatments. Neurostimulation therapies that target nerve structures such as the dorsal root ganglion (DRG) and the spinal cord, have shown promising results for treating chronic pain, but researchers don’t know how they work. This project focuses on two prevailing models used to explain the therapeutic effects of neurostimulation: the gate-control model in which pain signals are blocked from reaching the brain and the T-junction filtering model in which pain signals are blocked from reaching the spinal cord. Strategies will include innovative behavioral, electrophysiological, imaging, and computational modeling techniques. The results of these studies will help explain why neurostimulation therapies work and potentially offer new treatment strategies for improved pain relief.

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.

The Pain Reduction and Opioid Medication Safety in ESRD (PROMISE) study aims to improve the safety of opioid use and pain management in end-stage renal disease (ESRD) patients on hemodialysis (HD) using a Type I effectiveness-implementation hybrid design. A multisite randomized controlled trial of HD patients from the Hemodialysis Opioid Prescription Effort (HOPE) Consortium will examine the effectiveness of two separate nine-month evidence-based interventions: 1) Opioid Tapering Management (OTM) and 2) Behavioral Pain Management (BPM). We will examine the effectiveness of OTM (versus no OTM, Aim 1) and BPM (versus no BPM) over nine months for reducing opioid use (primary outcome) and improving pain severity (secondary outcome) in HD patients on chronic opioids. The implementation goal will take advantage of the diverse patient, provider, and organizational settings in the HOPE Consortium to evaluate process outcomes.

In this study, 600 to 700 hemodialysis patients receiving chronic opioids will be randomized across the Hemodialysis Opioid Prescription Effort (HOPE) Consortium to enhanced treatment as usual, buprenorphine therapy, or buprenorphine plus mindfulness-based cognitive therapy intervention delivered by telephone and adapted for pain (MBCT-TP). The following specific aims will be assessed: Aim 1—to assess the effectiveness of buprenorphine in reducing chronic opioid use and prescriptions in hemodialysis patients on opioids at baseline, compared with an enhanced treatment as usual intervention and to assess the effectiveness of buprenorphine in improving pain intensity, quality of life measures, and hospitalizations; Aim 2—to assess the incremental effectiveness of MBCT-TP added to buprenorphine compared with buprenorphine alone on pain interference with physical, social, and mental functioning, opioid use, pain intensity, other quality of life measures, hospitalizations, and mortality.

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.

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.