Funded Projects

The expansion of opioid prescribing in recent years to better treat pain has markedly increased their usage and availability and fueled an epidemic of abuse. Up to 80 percent of addicts reported initiating their habit through prescriptions drugs. Decreasing opioid prescriptions would lower opioid exposure, with fewer people receiving the drugs and less drug available for diversion. Study investigators have identified a novel target in the brain, distinct from any of the traditional opioid receptors capable of mediating potent analgesia without the reward behavior and side effects seen with traditional opioids. They targeted this site with a series of arylepoxamides and have identified a clinical candidate (MP1000) and backup compound. MP1000 is a potent analgesic in a range of thermal, inflammatory, and neuropathic analgesic assays. It fails to show reward behavior and does not produce respiratory depression at doses 5-fold greater than its analgesic ED50. Chronic administration does not produce physical dependence or withdrawal when challenged with an antagonist. It shows no cross tolerance to morphine and can be co-administered to subjects already on opioids for pain to lower their opioid usage (i.e., opioid sparing), facilitating the eventual discontinuation of the opioid. If successful, this project could lead to the development of a viable alternative to current opioid-based analgesics with reduced side effects (such as reward and respiratory depression) compared to opioids.

Postoperative pain is a major contributor to the current opioid epidemic. Novel objective measures capable of personalizing pain care will enhance medical precision in prevention and treatment of postoperative pain. This project seeks to discover and validate a novel biosignature of the human pain experience, based on underlying IL-1 family cytokine activity and associated brain endogenous opioid function, that is readily quantifiable and clinically translatable to prevention and treatment of postoperative pain states. Specific aims will assess whether the novel biosignature will predict 1) experimentally induced pain during an experimental nociceptive pain challenge; 2) postoperative pain states with accuracy >75%, accounting for a wide range of variance in the human pain experience; and 3) postoperative pain states in an expanded clinically enriched sample.

Though prenatal exposure to opioids and other substances have adverse effects on neurodevelopment, advances in neuroimaging and developmentally sensitive phenotypic measurement now enable characterization of typical and atypical brain-behavior pathways on an unprecedented scale. The Brains Begin Before Birth (B4) Midwest Consortium, a partnership of neuroscience, substance use, perinatal mental health, and child welfare scientists at Washington University School of Medicine (WUSM) and neuroscience, bioethics, pediatric population health, maternal-fetal, and addiction scientists at Northwestern University (NU). This regional consortium will leverage the contrasting approaches of Illinois (punitive) and Missouri (non-punitive) to prenatal opioid use, providing a platform for examining the impact of jurisdictional variations on science and practice. The consortium provide a framework for addressing three major areas of challenge: (1) legal/ethical, (2) recruitment/retention, and (3) imaging/assessment methods.

Neonatal abstinence syndrome (NAS) rates have increased since 2000. To determine multifactorial genetic, psychosocial predictors of opioid-related maternal and infant outcomes using rigorous prospective longitudinal design, innovative combinatorial pharmacogenetic approach, fetal MRI, and neonatal brain resting state functional MRI analysis, we hypothesize that a combination of maternal and infant genetic profiles, maternal psychosocial factors, maternal opioid treatment response, fetal and neonatal neurodevelopment, and NAS treatment will affect maternal and childhood outcomes with prenatal opioid exposure. The specific aims are to (1) Identify high-risk genetic profiles and psychosocial factors in pregnant women with opioid use disorder (OUD) and predisposing to poor maternal opioid maintenance treatment outcomes; (2) Determine maternal-infant genetic profiles and maternal opioid treatment factors predicting adverse fetal development, severity of NAS, and neonatal brain function; and (3) Develop predictive models for maternal opioid relapse and poor long-term neurodevelopmental outcomes in children with in utero opioid exposure.

Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of myriad cellular signals. In particular, many ion channels are clustered either with the receptors that modulate them, or with other ion channels whose activities are linked. Often the clustering is mediated by scaffolding proteins, such as the AKAP79/150 protein that is a focus of this research. This research will focus on three different channels critical to nervous function. One is the"M-type" (KCNQ, Kv7) K+ channel that plays fundamental roles in the regulation of excitability in nerve and muscle. It is thought to associate with Gq/11- coupled receptors, protein kinases, calcineurin (CaN), calmodulin (CaM) and phosphoinositides via AKAP79/150. Another channel of focus is TRPV1, a nociceptive channel in sensory neurons that is also thought to be regulated by signaling proteins recruited by AKAP79/150. The third are L-type Ca2+ (CaV1.2) channels that are critical to synaptic plasticity, gene regulation and neuronal firing. This research will probe complexes containing AKAP79/150 and these three channels using"super-resolution" STORM imaging of primary sensory neurons and heterologously-expressed tissue-culture cells, in which individual complexes can be visualized at 10-20 nm resolution with visible light, breaking the diffraction barrier of physics. The researchers hypothesize that AKAP79/150 brings several of these channels together to enable functional coupling, which the researchers will examine by patch-clamp electrophysiology of the neurons. Förster resonance energy transfer (FRET) will also be performed under total internal reflection fluorescence (TIRF) or confocal microscopy, further testing for complexes containing KCNQ, TRPV1 and CaV1.2 channels. Since all three of these channels bind to AKAP79/150, the researchers hypothesize that they co-assemble into complexes in neurons, together with certain G protein-coupled receptors. Furthermore, the researchers hypothesize these complexes to not be static, but rather to be dynamically regulated by other cellular signals, which the researchers will examine using rapid activation of kinases or phosphatases. Several types of mouse colonies of genetically altered AKAP150 knock-out or knock-in mice will be utilized.

This project aims to develop a novel abuse deterrent formulation (ADF) that will be uniquely designed to prevent abuse of the prescription pill. The study will focus on the development of the ADF with design aspects specifically focused on abuse through insufflation, smoking, injection, and taking multiple pills. The study will also validate the design by putting the pill through a rigorous test following the procedures outlined by the FDA Abuse-Deterrent-Opioids-Evaluation and Labeling guidelines. The study could result in the development of a novel ADF that will be resistant to a wide range of tampering, resulting in a safer formulation and pill design.

More than 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10 percent of the world’s population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids, and the use of opioids for pain treatment has resulted in what has been called an “epidemic” of opioid abuse, addiction, and lethal overdoses. Through a process of rational drug design, the research team has generated a new chemical entity (NCE) and have given it the name Kindolor, a non-opiate, non-addicting molecule that was shown to reduce or eliminate chronic pain in five animal models at doses compatible with use of Kindolor in humans. This project intends to complete the pre-clinical studies required for an IND application, which, if approved, would allow for proceeding onto the Phase 1 and 2 studies to assess safety and efficacy of the compound against osteoarthritic pain.

Very little research has been conducted on better understanding of phenotypic characterization of individuals with OUD (beyond DSM-5 diagnoses) and how these features predict illness severity, treatment retention or outcomes. The primary objective of the deep phenotyping study is to provide a comprehensive phenotypic characterization (e.g., domains of negative affect, reward salience, cognitive control, mental health) of a heterogeneous sample of individuals (n = 1,000) who currently meet one or more DSM-5 diagnostic criteria for OUD and are in treatment for OUD. In a subset of this sample (n = 100), the investigators conduct digital phenotyping to examine the utility of ecological momentary assessment (EMA), digital sensing and social media to predict retention, medication adherence and opioid use outcomes in patients receiving buprenorphine for OUD. It is anticipated that this foundational study will inform the feasibility and utility of such assessments that can be successfully embedded into imminent and future CTN and other OUD clinical trials.

Morbidity and mortality related to prescription opioids are accelerating in the United States. Identifying the factors that lead to new opioid dependence among opioid naïve patients is a critical opportunity to reduce prescription opioid dependence and unintended diversion. In the United States, the majority of individuals who become opioid dependent receive their first opioid prescription following surgical procedures, yet there are no clinical guidelines to inform appropriate postoperative opioid use. We will examine the patient factors that are associated with postoperative pain and opioid consumption among a cohort of patients undergoing common elective abdominal procedures. We will identify the provider characteristics in postoperative opioid prescribing practices, and design and implement a provider-directed intervention to optimize postoperative opioid prescribing. Findings will inform patients and providers regarding the risk of opioid dependence following surgery, and will establish a patient-centered data infrastructure that yields continuous feedback to providers regarding appropriate opioid prescribing practices.

This study will (1) test pharmacologic and behavioral strategies to improve OUD pharmacotherapy treatment retention and to improve outcomes among patients who have been successfully stabilized on OUD medications and want to stop medication and (2) identify predictors of successful outcome and develop a stage model of relapse risk.

Levo-alpha-acetylmethadol (LAAM) offers numerous behavioral and clinical advantages for select opioid use disorder (OUD) patients who do not respond to standard treatment. While LAAM was withdrawn from the market despite being approved for OUD treatment, this project seeks to develop novel, patentable, convenient dosage forms of LAAM, including novel LAAM oral dosage formulations and novel buccal film formulations of LAAM. Morphology, mechanical property, drug release kinetics, and stability of the oral dosage and buccal film formulations will be characterized to determine the instant release or steady release of LAAM, respectively. The two lead LAAM formulations with adequate release and stability profiles will be chosen through optimization studies both in vitro and in vivo. A human pharmacokinetic/pharmacodynamic study will then be carried out on the two selected formulations.

Neurostimulation techniques, such as transcranial direct current stimulation (tDCS), have been used as interventions for substance use disorders. This is a supplement to the currently NIDA-funded UG3 DA047793, “tDCS to Decrease Opioid Relapse,” which will measure behavioral and brain responses following tDCS stimulation delivered during tasks that use a particular brain network involved in cognitive control, and utilizing FMRI to assess the effects. This supplement allows the researchers to add an EEG measurement to the study, to get a complete picture of how tDCS might affect the function of key brain networks in ways that could be helpful for SUDs.

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.