Funded Projects

Neuropathic pain is characterized by neuronal hyperexcitability and spontaneous activity, properties associated with activity of hyperpolarization-activated, cyclic nucleotide-regulated (HCN1-4) channels, the source of the pacemaker current, Ih. Inhibition of HCN1-mediated Ih elicits marked antihyperalgesia in multiple animal models of neuropathic pain, including models for direct nerve injury and chemotherapy-induced peripheral neuropathy, and does so with little or no disruption to either normal pain processing or baseline behaviors and activities. The overall objective is to develop a peripherally restricted HCN1 inverse-agonist as a therapeutic for neuropathic pain. Researchers have generated a novel small molecule that combines an antihyperalgesic HCN1 inhibitor with a motif that controls distribution and membrane presentation and is a potential non-opioid antihyperalgesic treatment for peripheral neuropathic pain.

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.

Severe tissue injury generates central sensitization. Latent sensitization (LS) is a silent form of central sensitization that persists after tissue has healed and overt signs of hyperalgesia have resolved. Pain remission during LS is likely maintained by tonic opioid receptor activity. The opioid receptor inverse agonist, naloxone, can reinstate experimental pain when delivered one week after the resolution of secondary hyperalgesia following first degree thermal injury. Our aims are to test: 1) the hypothesis that burn or surgery triggers LS and long-term opioid analgesia in humans; 2) the hypothesis that mu-opioid receptor (MOR) constitutive activity (MORCA) receptors by opioid peptides maintains endogenous analgesia and restricts LS to a state of pain remission; 3) the extent to which MORs inhibit neural activity in the DH and synaptic strength in presynaptic terminals of primary afferent nociceptors during LS; and 4) whether MORs inhibit spinal NMDA receptor subunits to block pain during LS.

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.

To enhance availability of cognitive behavioral therapy for chronic pain (CBT-CP), this study will 1) refine strategies to identify and recruit patients, finalize intervention procedures, and ensure data infrastructure and quality; 2) determine the effectiveness of online and telephonic CBT-CP on patients and pain severity and secondary outcomes, including depression, sleep, quality of life, and pain-related health care utilization, from the electronic health record; and 3) assess the cost and incremental cost-effectiveness of online and telephonic CBT-CP compared with usual care. Eligible participants will be randomized to one of two painTRAINER interventions or usual care. Interventions will be eight weekly 45-minute sessions of the online program or telehealth-style phone coaching by trained behavioral health specialists. Self-reported pain severity and secondary outcomes will be assessed at baseline and at three, six, and 12 months.

There is a compelling need to develop a front line, non-opioid-based acute pain management strategy for outpatient oral surgical procedures. LaunchPad Medical has developed Tetranite® (TN), a novel bone regenerative mineral-organic self-setting adhesive biomaterial. TN has been extensively studied in vivo in a canine jaw model and shown to be effective and well-tolerated. In this project, researchers will demonstrate that drug-loaded TN can be a novel route to providing localized and time release pain medication following wisdom tooth extraction by determining the release profile of various pain medications from TN at different concentrations. The ability to release pain therapeutics in a controlled fashion and directly at the site of injury offers improved pain control following oral surgical procedures without exposing the patient to opioids. This novel approach to pain management can be extended to more invasive orthopedic procedures such as joint replacement, spinal fusions or reconstructive trauma surgery. In Phase II the team will conduct an in vivo study to assess efficacy of medicated TN to address post-operative pain following wisdom tooth odontectomy, optimize incorporation and release of medications in TN formulations, develop cGMP manufacturing process for the compounded product, and ultimately conduct clinical trials for bone void filler using medicated TN.

We propose to develop a safe and effective nonopioid analgesic to treat neuropathic pain that targets an isoform of the voltage-gated sodium ion channel, NaV1.7. Voltage-gated sodium channels are involved in the transmission of nociceptive signals from their site of origin in the peripheral terminals of DRG neurons to the synaptic terminals in the dorsal horn. NaV1.7 is the most abundant tetrodotoxin-sensitive sodium channel in small diameter myelinated and unmyelinated afferents, where it has been shown to modulate excitability and set the threshold for action potentials. Development of systemic NaV1.7 inhibitors has been complicated by the challenge of achieving selectivity over other NaV isoforms expressed throughout the body. We have discovered a series of potent, state-independent NaV1.7 inhibitors that exhibit >1000-fold selectivity over other human isoforms. Work conducted under this program will support advancement of a lead candidate into clinical development as a therapeutic for neuropathic pain.

Most of the 200k Americans who undergo thoracotomy each year receive opiates to reduce postoperative pain because clinicians have few non-addictive, cost-effective choices to control the severe pain patients often experience in the first two weeks after surgery. Managing pain post-thoracotomy is critical to enable patients to take deep breaths and remove (via coughing) lung secretions that otherwise significantly increase risk of pneumonia and collapsed lung, hospital re-admission and morbidity. The most severe pain associated with thoracotomy is transmitted along the intercostal nerves, but no long-term analgesic or nerve block device exists that can provide safe and effective long-term reduction of pain. A reversible, patient-controlled, non- addictive, intercostal nerve block device would reduce suffering due to thoracotomy, broken ribs and herpes zoster. In this Phase I project, the team will develop a minimally invasive thermal nerve block device that can control nerve conduction by gently warming and cooling a short nerve segment between room temperature and warm water temperature. This novel approach is based on the discovery that warm and cool temperature mechanisms of nerve block are different and additive, enabling moderate-temperature nerve block by cycling neural tissues slightly above and below body temperature. Reversible thermal nerve blocks represent a completely new approach to managing pain.  

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.

This project will design and test optimized temporal patterns of stimulation to improve the efficacy of commercially available spinal cord stimulation (SCS) systems to treat chronic neuropathic pain. Researchers will build upon a validated biophysical model of the effects of SCS on sensory signal processing in neurons within the dorsal horn of the spinal cord to better understand how to improve the electrical stimulus patterns applied to the spinal cord. They will use sensitivity analyses to determine the robustness of stimulation patterns to variations in electrode positioning, selectivity of stimulation, and biophysical properties of the dorsal horn neural network. Researchers will demonstrate improvements from these new stimulus patterns by 1) measuring their effects on pain-related behavioral outcomes in a rat model of chronic neuropathic pain and by 2) quantifying the effects of optimized temporal patterns on spinal cord neuron activity. The outcome will be mechanistically derived and validated stimulus patterns that are significantly more efficacious than the phenomenologically derived standard of care patterns; these patterns could be implemented with either a software update or minor hardware modifications to existing SCS products.

Chronic focal neuropathic pain, which includes pain etiologies such as radiculopathy and radiculitis, focal peripheral neuropathies, and low back pain, affects as many as 25 million patients annually in the United States. Chronic focal neuropathic pain is maintained by genome-wide transcription regulation in the dorsal root ganglia (DRG) / spinal cord network. The transcription factors driving this regulation constitute a promising class of targets with the potential to alter the course of pain with a single treatment. DNA decoys are oligonucleotides that specifically inhibit the activity of certain transcription factors. AYX2 binds and inhibits Krüppel-like transcription factors (KLF) in the DRG-spinal cord. The goal of this Phase 1 proposal is to advance AYX2 toward an IND submission, allowing for human clinical trials. We propose in Aim 1 to characterize AYX2 pharmacokinetics in the cerebrospinal fluid and plasma and its distribution in the DRG, spinal cord and brain following an IT injection. With this information, AYX2 will be tested in a panel of complementary toxicology studies in Aim 2 to allow for final IND-enabling studies, supported by Phase 2 of the grant. This research will accelerate development of AYX2 as a novel drug candidate for the non-opioid treatment of pain.

Neuropathic pain conditions are exceedingly difficult to treat, and novel non-opioid analgesics are desperately needed. Receptomic and unbiased transcriptomic approaches recently identified the orphan G-protein coupled receptor (oGPCR), GPR160, as a major oGPCR whose transcript is significantly increased in the dorsal horn of the spinal cord (DH-SC) ipsilateral to nerve injury, in a model of traumatic nerve-injury induced neuropathic pain caused by constriction of the sciatic nerve in rats (CCI). De-orphanization of GPR160 led to the identification of cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand which activates pathways crucial to persistent pain sensitization. This project will test the hypothesis that CARTp/GPR160 signaling in the spinal cord is essential for the development and maintenance of neuropathic pain states. It will also validate GPR160 as a non-opioid receptor target for therapeutic intervention in neuropathic pain, and characterize GPR160 coupling and downstream molecular signaling pathways underlying chronic neuropathic pain.