Funded Projects

Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous adverse effects, including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor agonist could be combined with small amounts of an opioid to treat pain, thereby lowering the risk associated with larger doses. Unfortunately, very little is known about interactions between 5-HT2 receptor agonists and other opioids. The proposed studies will evaluate the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well-established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive-reinforcing (leading to misuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of chronic treatment on the development of tolerance to and physical dependence on opioids. If successful, these studies will provide proof-of-concept for this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic drug development.

There is a need for longer-acting prophylactic pharmacologic options for opioid use disorder (OUD) patients during maintenance therapy. This study tests a titanium implant loaded with a formulation of naltrexone and a naturally occurring carboxylic acid. The device is implanted subcutaneously with local anesthetic during an in-office procedure. The technology is based on a unique formulation that keeps the pH within the reservoir low and promotes passive diffusion of naltrexone. The benefits of the product include complete medication adherence for one year after administration, fewer relapses, smooth profile ensuring complete prophylaxis without sub-therapeutic plasma troughs, full reversibility, and similar efficacy with less drug exposure. This technology has been validated clinically with another drug and tested preclinically with naltrexone. This project will finalize the chemistry manufacturing and controls, produce IND supplies, conduct an IND-enabling safety study, and submit the IND.

Novel therapies that could alleviate the severe symptoms of opioid withdrawal and/or reduce risk of relapse could help address the devastating opioid crisis. Memantine, an FDA-approved NMDA receptor antagonist, has shown encouraging results as an adjunct to existing opioid use therapies. Its therapeutic efficacy likely derives from its preferential binding to NMDA receptors located outside the synapse, since broad spectrum NMDA receptor antagonists are associated with multiple clinical side effects. This project will use a preclinical model to evaluate a nanostructured version of memantine (AuM) that physically prevents its binding to synaptic NMDA receptors but allows activation of extrasynaptic receptors with potency exceeding that of free memantine.

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.

A major barrier to developing new pain treatments has been the absence of infrastructure to facilitate well-designed and carefully conducted clinical trials to test the efficacy of promising treatments. The UF Health Specialized Clinical Center Network will include UF Health as “hub” and statewide partners serving as spokes as part of the EPPIC Network. The University of Florida (UF) has the capability to reach more than 50% of the population of Florida, the third most populous state of the United States, and the capacity to successfully enroll patients with varying pain conditions into clinical trial protocols through its hub and spoke infrastructure as part of EPPIC-Net.

Current opioid overdose treatment requires administration of naloxone by first responders, which requires timely identification of the overdose, the need for a rescue injection, and immediate availability of the medication. The development of a fail-safe treatment that would provide a life-saving dose of naloxone without the need for intervention by another party could significantly reduce mortality. The researchers aim to develop a new medical device comprising an implantable, closed-loop system that senses the presence of an opioid overdose, automatically administers a life-saving bolus injection of naloxone, and simultaneously alerts first responders.

MNK-eIF4E signaling is activated in nociceptors upon exposure to pain or peripheral nerve injury, promoting cytokines and growth factors and increasing nociceptor excitability, which leads to neuropathic pain. Genetic or pharmacological inhibition of MNK signaling blocks and reverses nociceptor hyperexcitability as well as behavioral signs of neuropathic pain. A clinical phase drug for cancer shows strong specificity as an MNK inhibitor but requires optimization because MNK inhibition in the central nervous system (CNS) may lead to depression, an unacceptable side effect for a neuropathic pain drug. The research team plans a targeted medicinal chemistry and screening campaign directed at generating a MNK-inhibitor-based neuropathic pain treatment with the goal of restricting its CNS penetration while retaining potency, specificity, and in vivo bioavailability and efficacy.

Justice-involved young adults are one of the highest-risk populations for the development of opioid use disorder (OUD) and other significant public health problems, but they usually lack access to evidence-based practices that could potentially prevent this trajectory. The risk of unintentional death and other deleterious outcomes and long-term costs for opioid misuse for young adults, their communities and society (costs estimated at more than $115 billion annually) make this a priority, with rural areas in need of the most attention and assistance. The overriding purpose of the proposed pilot study is to prevent the onset of OUD by improving young adult offenders’ access to evidence-based risk reduction interventions, like contingency management (CM), by testing whether officers in the adult probation and parole setting can deliver such an intervention to their young adult substance using probationers who have not yet developed OUD. The primary motivation for this pilot is the clear public health need for improving and expanding delivery of substance use risk reduction interventions for young adults in the justice system. The ultimate outcome would be prevention of OUD in this high-risk population.

According to SAMHSA’s 2017 National Survey on Drug Use and Health (NSDUH), 11.4 million persons in the U.S. report past-year opioid misuse; out of them, only 2.1 million individuals met criteria for an OUD. Very little is known about efficacious interventions for those who do not meet criteria for moderate/severe OUD (i.e., subthreshold OUD). The prevalence of subthreshold OUD in primary care settings is 5 percent to 10 percent, with higher rates (21 percent to 29 percent) among those receiving prescribed opioids. Although they are at high risk of developing moderate/severe OUD and/or dying from an overdose, little or no empirical evidence exists for pragmatic prevention interventions that can be adopted at integrated general medical settings. To study the efficacy of prevention interventions to arrest the progression from risky opioid use, researchers will test the efficacy of a STOP intervention in primary care settings. STOP adopts an early intervention approach, based on a collaborative care model to prevent progression to moderate/severe OUD, and consists of a practice-embedded nurse care manager who provides patient education and supports the primary care provider (PCP) in engaging, monitoring and guiding patients who have risky opioid use; brief advice delivered to patients by their PCP; and phone counseling of patients by behavioral health providers to motivate and support behavior change. Researchers will determine whether STOP reduces risky opioid use and examine the impact of STOP on progression to moderate/severe OUD, overdose risk behavior and overdose events in adults with risky use of illicit or prescription opioids.

Identification of new targets and mechanisms underlying chronic neuropathic pain is essential for the discovery of novel treatments and preventative tactics for better neuropathic pain management. A recent exploration of next-generation RNA sequencing identified a large, native, full-length long noncoding RNA (lncRNA) in mouse and human dorsal root ganglion (DRG). It was named as nerve injury-specific lncRNA (NIS-lncRNA), since its expression was found increased in injured DRGs, in response to peripheral nerve injury, but not in response to inflammation. Preliminary findings revealed that blocking the nerve injury-induced increases in DRG NIS-lncRNA levels ameliorated neuropathic pain. This project will validate NIS-lncRNA as a therapeutic target in animal models of neuropathic pain and in cell-based functional assays utilizing human DRG neurons. Completion of this proposal will advance neuropathic pain management and might provide a novel, non-opioid pain therapeutic target.

There is a significant treatment gap between patients diagnosed with OUD and those who seek treatment, and only a small proportion of those seeking treatment receive MOUD. Primary care is the most common point of health care contact in the U.S. and is an important venue to address stigma, improve access to treatment and improve quality of care. Over the past decade, electronic health record (EHR)-linked Web-based point-of-care clinical decision support (CDS) systems designed to improve quality of chronic disease care have become increasingly sophisticated and successful. A Web-based and EHR-integrated OUD CDS system to offer expert guidance to primary care providers (PCPs) on the diagnosis and management of OUD was developed and piloted. This project will implement the OUD clinical decision support system in three large diverse health care systems and randomize a minimum of 30 clinics to receive the OUD-CDS intervention or usual care (UC). The project will evaluate the impact of OUD CDS on practice process measures and patient outcomes. The study will also prepare for scalability and dissemination by evaluating facilitators and barriers to implementation, determining the costs of implementation and maintenance and assessing the short-term cost impacts of the OUD-CDS.

The California Clinical and Translational Pain Research Consortium (CCTPRC) consists of four University of California academic medical centers with considerable experience in pain management clinical trials, phenotyping, and biomarker validation. The network will leverage solid existing Clinical and Translational Science Award (CTSA) resources to make clinical trial execution efficient and rapid. The hub will be located at the University of California, San Diego, with spokes located on the other three campuses to provide maximum flexibility, ready to accommodate studies in a variety of pain conditions and provide successful recruitment and high-quality data collection.