Funded Projects

Opioid overdoses result from reduced oxygen in the bloodstream. Although the opioid blocker naloxone can reverse the immediate harmful effects of opioids, it also has limitations. It does not last very long, blocks pain relief, and may induce withdrawal. This project will characterize and test the effectiveness of a novel, potent, and long-lasting respiratory stimulant. The study will use a freely behaving, large animal model with physiology similar to humans.

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.

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.

The current studies are designed to examine a novel approach to treating OUD, namely use of a vaccine (OXY-KLH) targeted against oxycodone, one of the most commonly misused prescription opioids, and a vaccine (M-KLH) targeted against heroin/morphine. The researchers will evaluate the safety, immunogenicity, and preliminary efficacy of OXY-KLH and M-KLH. Overall, the proposed studies will provide a great deal of information about the safety and potential efficacy of the vaccines in reducing the addiction liability of opioids, which will be administered in a controlled laboratory setting. If the outcomes of the proposed studies with OXY-KLH and M-KLH are favorable, development of the bivalent vaccine (OXY-KLH plus M-KLH) that will target oxycodone and heroin will proceed. The long-term goal of this research is to develop a multivalent vaccine directed against oxycodone, heroin, and other relevant opioids.

The ongoing epidemic of opioid use disorder (OUD), overdose, and death is unprecedented. Available pharmacologic therapies for OUD have failed to stem the tide, plagued by poor adherence and retention, the principal factors associated with relapse and treatment failure. More than 80 percent of individuals with OUD are untreated. More treatment options are needed. This proposal seeks to develop a better antagonist-based OUD pharmacotherapy for populations highly motivated to achieve abstinence, such as military personnel, criminal justice clients, and the currently employed. A series of novel and proprietary small molecules will be designed and synthesized to address the adherence problem by inducing effective opioid antagonism with a single injection lasting at least 2 months, and up to 4 months or more. The goal of this project is to advance to Phase 3 clinical trials toward FDA approval of our lead compound. If successful, this project could lead to a novel therapeutic with superior adherence and retention, resulting in a significant public health impact by reducing rates of relapse, overdose, and death.

Currently there are no effective treatments approved by the U.S. Food and Drug Administration for cocaine use disorder. This project will explore the use of a novel class of small molecules that selectively block the molecule phosphodiesterase 7 (PDE7). Past research suggests that the PDE7 class of compounds helps restore normal functions of the dopamine reward system altered by chronic exposure to cocaine. This research will use both preclinical and clinical research studies to develop and test a PDE7 blocker, toward development of the first oral treatment for cocaine use disorder. 

There is an urgent need for improved medications to treat OUD. This project will test cebranopadol, a novel synthetic medication that interacts in a new way with the human opioid system as a safe and potentially effective alternative treatment for OUD. The research will test the safety and efficacy of cebranopadol in preclinical and clinical studies, toward guiding future research to support potential approval of this medication by the U.S. Food and Drug Administration.

High relapse rates among people with opioid use disorder (OUD) indicate that addiction involves appetitive pathways. Peripheral stimulation of the glucagon-like peptide-1 receptor (GLP-1R) “satiety” pathway could reduce heroin seeking and taking. Pretreatment with a GLP-1R agonist reduces heroin taking, seeking, and drug-induced reinstatement in rats. This project tests whether GLP-1R agonists can reduce relapse in humans with OUD. A pilot study will be conducted to determine whether once-daily treatment with the shorter acting GLP-1R agonist, liraglutide, can safely and effectively reduce cravings among OUD patients. Animal models will be used to test the efficacy and safety of a longer-acting GLP-1R agonist, semaglutide, and then a clinical trial will be conducted to test whether semaglutide will reduce relapse and use in animal models. If successful, the study will show that treatment with GLP-1R agonists can safely and effectively reduce opioid craving, seeking, and relapse.

Naloxone is a safe and effective opioid antagonist, but currently available products are burdened with high cost and limited accessibility due to a need for a prescription or being kept behind-the-counter. In response to the FDA putting out an unprecedented call for an over the counter naloxone product, Pocket Naloxone Corp. is developing a novel intranasal delivery method for naloxone intended to be low-priced and widely accessible. This project will culminate in a New Drug Application to the FDA for over-the-counter approval to meet the urgent need for widespread access to a reliable, easy-to-use naloxone product for use in an emergency by non-medical individuals.

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.

Opioids can be effective analgesics but can also be fatal due to opioid-induced respiratory depression after overdose. This project will use cutting-edge molecular, physiological, behavioral, and imaging techniques to better understand and distinguish opioid-induced respiratory depression and opioid-mediated analgesia. Nerve cell-specific, single-cell transcriptomic analysis will be used to identify functional markers expressed in nerve cells that play a specific role in opioid-induced respiratory depression, but not opioid analgesia. This research study will help to identify novel therapeutic targets that could selectively rescue opioid-induced respiratory depression while maintaining the beneficial pain-relieving effects of opioids. 

Given recent increases in co-use of opioids and methamphetamine, there is a dire need for novel treatment strategies that prevent relapse to drug use in both opioid use disorder (OUD) and methamphetamine use disorder (MUD). The localization of certain receptors for the neurotransmitter glutamate—metabotropic glutamate receptor subtypes 2 and 3 (mGlu2/3)—and the mechanism through which they transmit signals, strongly suggest that activation of both of these receptors will effectively treat multiple symptoms that contribute to relapse, such as responsiveness to drug cues, physical withdrawal symptoms, neuroinflammation, and sleep disturbances. This project seeks to evaluate molecules that can activate mGlu2/3 receptors without binding to the same site as glutamate (i.e., positive allosteric modulators) as a novel pharmacological treatment for preventing relapse to OUD. The research also will examine the potential of such modulators for treating MUD.

The sodium channel NaV1.8 is a promising target for the development of effective, non-addictive pain medications. Recent evidence from clinical studies indicates that medications that target NaV1.8 are effective at managing postoperative, neuropathic, and inflammatory pain, but with side effects and prohibitively high cost. This project will test the safety and compatibility in the body of an NaV1.8-targeted molecule, toward developing an effective, non-addictive, once daily oral medication for the treatment of acute postsurgical pain and chronic neuropathic.