Funded Projects

Fentanyl and its analogs are synthetic opioids that are 100 to 10,000 times more potent than morphine. Overdose from these opioids is extremely dangerous due to their ultra-potency and longer half-life than naloxone, the front-line treatment for fentanyl overdose. This research study will develop novel mu opioid receptor antagonists that bind to the same receptor as the opioid drugs and specifically counteract fentanyl and its analogs, thereby reversing the drugs’ acute toxicity more effectively and with fewer side effects than current treatments. The researchers will characterize novel fentanyl derivatives, identify promising compounds, and pursue preclinical development of these compounds as novel reversal agents against the acute toxicity of fentanyl. The goal is to file an Investigational New Drug application with the U.S. Food and Drug Administration.

Novel treatments for opioid use disorder are urgently needed. Previous research has shown that angiotensin-converting enzyme (ACE) can control levels and activity of natural, “endogenous,” opioids in a way that might reduce the rewarding effects of opioids like fentanyl. ACE inhibitors have been used to treat hypertension for decades, with no evidence of addiction or dependence. This research will evaluate ACE effects on endogenous opioids toward generating new, domain-specific ACE inhibitors with optimized properties for treating opioid use disorder. The research will also test the behavioral impact of these compounds in preclinical models of opioid use disorder. 

Buprenorphine is commonly used in medication-assisted treatment of opioid use disorders. The U.S. Food and Drug Administration recently issued a warning that the drug may lead to serious tooth damage in some patients. It is thought that high concentrations of the drug in saliva may contribute to tooth damage and decay. This project will use a mouse model of dental caries to explore the mechanism leading to high buprenorphine concentrations in saliva and examine ways to reduce concentrations in the mouth but not the rest of the body; it will also examine buprenorphine’s effects on the bacteria that lead to caries development.

A recent FDA public meeting identified sleep disturbance as a primary contributor to opioid use disorder (OUD) treatment failure. Suvorexant (SUVO; Belsomra®) is a dual orexin receptor antagonist that is FDA-approved for insomnia, with low addiction liability, that improves sleep continuity with a single dose, has an extremely safe and mild side-effect profile, has clear interactions with the opioid system, and has not yet been evaluated in OUD patients. The hypothesis is that SUVO will improve total sleep time during withdrawal, have no addiction liability, and be more efficacious than trazodone, a common OUD-associated insomnia medication. Primary outcomes will be objective sleep measures and addiction liability. Secondary measures will include objective, biological, and self-report measures of opioid withdrawal severity, treatment retention, craving, and stress. Results will advance the treatment of OUD, the understanding of sleep and opioids, and the use of SUVO in clinical populations.

New medication treatment approaches are needed to help address the severe epidemic of opioid use disorder (OUD) and opioid overdose deaths in the U.S. Currently available medications, such as methadone, buprenorphine, and extended release injection naltrexone (XR-NTX; trade name: Vivitrol), are highly efficacious, but their effectiveness in practice is limited by poor adherence, with many patients stopping treatment prematurely and relapsing. The goal of this proposal is to develop an innovative long-acting subcutaneous implanted formulation of naltrexone, the O’Neil Long-Acting Naltrexone Implant (OLANI), toward FDA approval. Expected to produce naltrexone blood levels sufficient to block the effects of opioids for 6 months after implant, OLANI circumvents the need for adherence to monthly injections with XR-NTX and could represent an important new addition to the medical armamentarium for treatment of OUD.

There are currently no FDA-approved treatments for cocaine use disorder (CUD) or co-occurring substance use disorder. High relapse rates pose a major obstacle to treatment, and this is due in part to the way that high drug cravings reduce individuals’ cognitive flexibility in situations where they are stressed or exposed to drug-related cues. These effects appear to be stronger in women with CUD than in men. Building on preliminary data that a drug called Guanfacine reverses these effects in women, but not in men, this 3-year pilot clinical study will test whether Guanfacine will reduce cocaine use and increase abstinence and will use laboratory challenges to determine whether it reduces cravings and enhances cognitive flexibility in stressful or drug-cue-related situations.

The ongoing opioid crisis has led to renewed concerns about the clinical prescription of addictive opioid analgesics. However, there are currently no suitable alternatives for treating severe or malignant pain. Studies of opioid signaling mechanisms in mice deficient in ?-arrestin have suggested that biased agonists displaying preferential activation of G-protein signaling over ?-arrestin signaling could offer a promising avenue for the development of opioid analgesics with a reduced adverse effects profile. However, there is no concluding evidence showing that such biased signaling can indeed be associated with reduced opioid side effects and, consequently, an improved safety profile. This research will address the need for preclinical data to rigorously evaluate this hypothesis with a program of in vivo studies to compare the effects of “balanced” opioids (morphine, oxycodone, and fentanyl) with that of the “biased” agonists PZM21 and two novel ligands provided by colleagues at the NIDA IRP in nonhuman primates. The results of these studies will provide critical information regarding the dependence liability of “biased” agonists that, in clinical practice, might be given on a repeated, or chronic, basis, potentially adding a powerful new tool for the safer management of severe or malignant pain.

Naltrexone (NTX) has been proven as an important, safe, and effective therapy in helping patients overcome opioid addition and in preventing overdose. Unfortunately, the therapeutic potential of NTX has been blunted by poor adherence. To combat this issue, a system must be developed to deliver NTX for longer durations than are currently available with a more patient-friendly format. The goal of this research is to optimize and scale up our laboratory PLGA-based microparticle formulations of NTX delivery (either 2 months or 7–10 days) and bridge it to a Phase 1 clinical trial. This innovation will result in a more patient-friendly format consisting of less painful injections and improved release kinetics. PLGA-based drug delivery systems have been used successfully in a number of small-molecule products and are the most widely utilized and studied biocompatible polymer systems in controlled release. Thus, the regulatory and development hurdles with the FDA will be lower than with other novel excipients or technologies. The significance of this research and product development is that the final outcome of this project will ultimately provide a new, readily viable, essential tool to help patients overcome opioid dependence.

Safe and effective options are urgently needed to prevent and treat opioid use disorder and polysubstance use disorders. Previous research in humans and animals suggests that activating the calcium-activated potassium channel KCa2.2 is a promising therapeutic approach for treating substance use disorders and associated health conditions. This project will perform a virtual high-throughput screen using novel machine learning approaches to discover new molecules that interact with the KCa2.2 channel. The newly discovered molecules help develop novel drugs for the treatment of opioid use disorder and associated health conditions.

This U54 Center will use translational research from brain to bedside as a tool for medication development in cocaine use disorder. Preclinical and early phase I clinical PK/PD data will provide information for go/no-go decisions on phase II–III clinical trials with medications that show promise for cocaine use disorder. The overall goal of this research is to create a center that can provide important preclinical and early phase I clinical data to NIDA and pharmaceutical industry partners on novel compounds for cocaine use disorder. The aims related to the theme of the center will be achieved through two cores and three projects: The Administrative Core serves as a general resource for the other projects and the Educational Core, including oversight of fiscal and compliance matters, and will oversee interactions with outside entities, including NIDA and the pharmaceutical industry. The Educational Core will focus on training translational researchers for medication development for addictions across the two institutions.

Tens of thousands of people die each year from opioid overdose. Many of these people began taking opioids for pain. A critical treatment goal is to reduce the development of opioid dependence either by enhancing opioid analgesia so lower doses can be used or by blocking withdrawal symptoms. Current pharmacological treatments in these two categories, although effective, present serious limitations. The recent finding that reducing the signaling through mu-delta opioid heterodimers appears to enhance opioid antinociception and reduce dependence suggests that a blocker of mixed mu-delta receptors (MDOR antagonist) could be effective in reducing dependence by limiting opioid tolerance and preventing opioid withdrawal. This research group has developed a compound with that characteristic, called D24M, which preliminary studies have shown could reduce opioid dependence by enhancing opioid antinociception, reducing opioid tolerance, or directly inhibiting opioid withdrawal. They propose to extend this research by investigating whether it can reduce chronic pain in an animal model that mimics the clinical situation of pain patients who transition to dependence. If these studies are successful, they could lead to the development of an optimized drug ready for Investigational New Drug (IND) application and enable translational and clinical testing.