Funded Projects

There is an urgent need to prevent and reduce opioid use disorder (OUD) by reducing the need for opioid analgesia and preventing the escalation of opioid dosing in patients at greater risk of using more opioids following surgery. Brivoligide is a non-opioid drug candidate that can alter the course of postoperative pain for patients most likely to suffer increased pain and utilize more opioids following surgery. A single administration of brivoligide at the time of surgery can reduce acute postoperative pain in these patients by 30 percent to 40 percent beyond what can be achieved with the current standard of care for at least 28 days and reduce opioid utilization by 40 percent over a 3-month period following surgery. This project will support the research necessary to achieve regulatory approval of brivoligide with a broad indication, which will initially focus on the reduction of postoperative pain following mastectomy, a soft-tissue surgery model suitable to detect long-term pain and opioid reduction benefits. Brivoligide appears to be a very promising pharmacotherapy with the potential to greatly contribute to stemming the tide in the opioid crisis.

Chronic pain and opioid use disorder often occur together, but there are a striking lack of integrated treatments accessible to people in need, particularly Black and Hispanic individuals living and seeking care in under resourced settings. This research will examine multi-modal, evidence-based practices in diverse health care settings and among diverse populations with both chronic pain and opioid misuse/disorder. The first project will examine the effects of yoga and physical therapy onsite at methadone opioid treatment clinics. The second project will test Acceptance and Commitment Therapy and a care-management smartphone app for individuals in primary-care based buprenorphine treatment. The third project will compare microdosing versus standard doses/timing of buprenorphine for hospitalized patients. All three projects will improve access to care for Black and Hispanic individuals in under resourced settings by bringing integrated treatments to them. The interventions have high potential to be used broadly.

Millions of Americans undergo surgery each year, with fewer than half of patients reporting adequate postoperative pain relief and approximately 75 percent reporting moderate to severe postoperative pain. Gaps in postoperative pain management that lead to the unnecessary introduction and over-prescription of opioids continue to exacerbate the opioid crisis, but virtual reality (VR) has been demonstrated to be an effective strategy for pain management. This project will enhance and improve the functionality of a VR-based technology, AppliedVR, to provide acute perioperative pain management through a new software-based VR medical device, RelieVRx™. As a non-opioid alternative intended to reduce postoperative pain, RelieVRx can potentially reduce the need for and utilization of opioids in the postoperative setting.

The objective of the HEALthy Brain and Child Development (HBCD) Prenatal Experiences and Longitudinal Development (PRELUDE) multi-site consortium is to characterize typical brain development from birth through childhood. All sites in this consortium will measure the influence of key biological and environmental factors on child social, cognitive, and emotional development. Researchers will assess how prenatal exposure to opioids and other substances, as well as other adverse environmental factors, affect brain development and other child health outcomes. The Arkansas Children’s Research Institute site is in a predominantly rural state with the second highest rate of opioid prescriptions in the U.S.

Chronic pain affects an estimated 100 million Americans, or one third of the U.S. population, and it is the primary reason Americans are on disability. Although many treatments are available for pain, the most potent class of analgesics relies on opioid analogs, whose limitations and well-known adverse effects have contributed to the present opioid crisis. New pharmacotherapies for pain management are sorely needed. MTX1604, a synthetic endomorphin analog, has emerged as a highly effective analgesic that exhibits reduced reward potential and respiratory suppression, and a robust duration of efficacy in a variety of validated animal models of acute, neuropathic, inflammatory, post-operative, and visceral pain. This project will generate additional preclinical characterization data of MTX1604 and advance clinical development toward FDA approval. If successful, this medication development project could offer patients a novel non-addictive, potent, and safe analgesic and thus have a direct impact on the opioid crisis.

Although effective, current pharmacotherapies for opioid use disorder (OUD) present serious limitations. For example, methadone, a mu opioid receptor (MOP) full agonist, has significant abuse liability and causes withdrawal after chronic use, while buprenorphine (Bup), an MOP partial agonist and kappa opioid receptor (KOP) antagonist, produces limited respiratory depression and is less effective than methadone in reducing drug use, craving, and relapse. To address the limitation of currently available MATs, this project uses a phased plan that will fast-track the IND development of a next-generation medication for OUD based on small-molecule compounds targeting the nociception opioid receptor (NOP)—with no misuse or dependence liability—that have shown promising efficacy in reducing oxycodone intake in rhesus monkeys trained to self-administer, with efficacies similar to that of buprenorphine. The project’s ultimate goal is to file an IND application for an NOP agonist as a promising new approach to treat illicit and prescription OUD that may offer an alternative to buprenorphine.

Despite increased efforts to understand the neurodevelopmental sequelae of in utero opioid and other substance exposure on long-term behavioral, cognitive, and societal outcomes, important questions remain, specifically, 1) How is brain growth disrupted by fetal substance and related pre- and post-natal exposures? and 2) How are these disrupted growth patterns causally related to later cognitive and behavioral outcomes? This project seeks to formulate an approach to addressing these key questions and decipher the individual and cumulative effect of these intertwined pre- and post-natal exposures on child neurodevelopment. First, researchers will address the legal, ethical, and mother-child care and support concerns implicit in this study. Next, they will integrate across our areas of neuroimaging expertise to develop, implement, and harmonize a multi-modal MRI and EEG protocol to assess maturing brain structure, function, and connectivity. Finally, researchers will develop and test advanced statistical approaches to model and analyze this multidimensional and longitudinal data.

Rates of neonatal abstinence syndrome (NAS) have skyrocketed during the last decade, and estimates suggest that 5% of mothers use at least one addictive drug during their pregnancy. To address this public health crisis, multiple groups—including the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics—recommend universal screening of substance use in pregnancy using standardized behavioral scoring tools. Unfortunately, such tools are often biased due to subjective scoring or self-reporting errors, and fail to identify babies who did not receive proper prenatal care. This project will develop a fast and accurate NAS screening tool that pairs a simple sample preparation protocol with a high-sensitivity panel of homogeneous enzyme immunoassays recognizing five common classes of drugs: fentanyl, morphine, amphetamine/methamphetamine, cocaine, and benzodiazepines. The potential benefits of such a system include reduced length of hospitalization for unaffected newborns, accelerated time to confirmatory results (under 2 hours), faster resolution of acute withdrawal symptoms, and improved referral to family/maternal support services.

Chronic opioid use results in tolerance, a primary driver for opioid misuse and overdose that directly contribute to increased morbidity and mortality. Changes in neuronal connectivity known as synaptic plasticity are a key determinant of opioid tolerance, but the underlying molecular mechanisms remain unclear. Tiam1 is a protein known to control the development of nerve cells and their connections and is also involved in morphine-induced neuronal changes. This research will examine Tiam1-mediated synaptic plasticity underlying opioid tolerance and validate Tiam1 as a potential therapeutic target for prevention of tolerance development.

A major driver of the U.S. opioid crisis is limited access to effective medications for opioid use disorder (MOUD) that reduce the risk of overdose. Traditionally, jails and prisons in the U.S. do not initiate or maintain MOUD for inmates with OUD prior to their return to the community, which places them at high risk for fatal overdose. The Massachusetts Justice Community Opioid Innovation Network (JCOIN) will study the outcomes and implementation of a 2018 state law that seven county jails must provide all approved forms of medication for OUD. The Chapter 208 initiative has important implications for future policy and practice in the justice and OUD treatment systems at the local, state, and national levels.

With the entwined crises of opioid use and chronic pain, there is a need for alternative, safe therapies to manage opioid use disorder, opioid withdrawal symptoms, chronic pain, and/or associated anxiety and depression. A proof-of-concept preclinical study has already been conducted of a cannabinoid-opioid combination that demonstrated opioid-sparing and synergistic analgesic effects, with the combination providing greater analgesia in a rodent model of chronic pain than a standard dose of the opioid alone. This proposal aims to develop a fixed-dose combination (FDC) of the cannabinoid-opioid that may have improved analgesia with lower opioid doses and thereby lower the risk of dependence, withdrawal, diversion, abuse, and overdose. Preclinical pharmacokinetic and ?in vivo ?safety studies will help determine if co-administration alters the pharmacokinetics and/or respiratory depression related to either compound in rodents.

A critical line of defense against opioid use disorder (OUD), one of the nation’s leading preventable causes of death, must be standardized screening provided by the patient’s primary care physician, psychiatrist, and/or counselor. Standardized screening methods for opioids, however, are simply inferior and no gold standards exist. This project aims to develop a validated, theoretically guided tool that provides clinicians with information beyond OUD symptoms using reinforcer pathology, a measure of severity derived from the synergy between excessive delay discounting and high behavioral economic demand. The Behavioral Economic Screening Tool (BEST-OUD) will use these combined measures in a mobile tablet application to enable clinicians to screen for OUD.

The opioid antagonist naltrexone (NTX) is a proven treatment for opioid use disorder (OUD); however, lack of adherence is a serious limitation that has prevented NTX from reaching its maximum therapeutic potential. To address this limitation, BioCorRx is developing BICX102, a subcutaneous solid depot pellet of NTX, a single implantation of which can provide continual blockade of opioid receptors for up to 3 months. This can prevent patients from being adversely affected by almost any opioid relapse event, while improving efficacy and adherence to behavioral programs that support long-term management and recovery. This proposal comprises the steps required to achieve FDA approval. Successful development of BICX102 would result in a safe and effective 3-month subcutaneous depot pellet/implant containing NTX (1,000 mg) that would be far less reliant on patient compliance.