Funded Projects

This project seeks to develop and test a “train-the-trainer” curriculum and training experience that will facilitate the spread and use of the 6BBs by adapting the 6BBs framework and toolkit for health systems and other organizations, training personnel to facilitate its implementation and monitoring results of this implementation.

FDA-approved medications for treating opioid use disorder are effective, but there is a significant unmet need for alternatives, especially relapse prevention. NIDA and the FDA have encouraged investigators to expand the range of therapeutic outcomes, beyond measurement of abstinence. Insomnia is a clinically significant, but understudied, correlate/predictor of relapse to substance use. Yet most medications for treating insomnia have limited efficacy and can produce side effects. The orexin (OX) system plays a key role in sleep and substance use, offering a promising avenue for study. This project will address whether OX-1/2 antagonism is a mechanism that can directly improve outpatient opioid abstinence, or whether OX antagonism corrects sleep deficiencies and indirectly improves opioid abstinence. Specific aims are to determine whether nightly treatment with the OX-1/2 antagonist suvorexant, relative to placebo, 1) increases outpatient opioid abstinence and 2) improves sleep efficiency on the residential detoxification unit. The study will also determine 3) whether improved sleep efficiency predicts greater opioid abstinence (regardless of group assignment).

Evidence suggests that homeless youth have the highest rates of opioid use among youth subgroups in the country (Brands et al., 2005). Resolution of youth homelessness through housing and prevention services, often referred to as “Housing First”, has great potential to reduce the likelihood for the development of an opioid use disorder as well as other problem behaviors associated with living on the streets. However, only 20 percent to 30 percent of homeless youth samples report ever having stayed at a crisis shelter, 9 percent report having ever accessed mental health services, and 15 percent report ever having received treatment for substance use disorder (Ray, 2006), indicating a need to reach and engage youth in services that are feasible and acceptable. The results of this study will provide essential information for researchers and providers on the efficacy of housing plus opioid and related risk prevention services in a randomized controlled trial on opioid use, how moderators affect the response, and mechanisms underlying change.

Among the most common symptoms experienced by individuals suffering with opioid use disorder (OUD) are severe sleep and circadian disruptions. The relationship between opioid dependence and sleep and circadian systems is not well understood. A circadian-dependent mechanism has been shown to modulate fentanyl reward-related behaviors in the nucleus accumbens (NAc). The study team will use a combination of behavioral, slice electrophysiology, and molecular approaches to 1) investigate the role of the circadian transcription factor NPAS2 in medium spiny neurons with dopamine 1 (D1R-MSNs); 2) assess the impact of fentanyl on synaptic plasticity at D1R-MSNs and investigate whether NPAS2 mediates the potentiation of excitatory synapses at specific diurnal phases; 3) elucidate the cell-type-specific NPAS2-dependent transcriptional mechanisms of fentanyl-seeking and relapse behaviors; and 4) investigate whether NPAS2 rescue and buprenorphine medication-assisted treatment (MAT) improve fentanyl-induced sleep disturbances. This study will define the role for circadian-dependent transcriptional mechanisms and uncover the therapeutic potential of NPAS2 for opioid dependence and relapse.

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.

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.

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.

The first ten years of life are accompanied by rapid changes to the developing brain and cognitive abilities. Complex interacting factors including genetics, early-life exposure to substances, family and social interactions, and home and community environments can affect brain and cognitive development. Three linked projects aim to develop effective research protocols to lay a foundation for a future HEALthy Brain and Cognitive Development (HBCD) birth cohort study. Project 1 will develop protocols for recruitment and retention of a diverse sample of pregnant and postpartum women with oversampling of mothers with prenatal opioid use. Project 2 will identify ethical, legal, and regulatory challenges for investigations in this vulnerable population and define effective solutions to enable recruitment and study of these participants. Project 3 will develop and evaluate protocols for acquiring high-quality, quantitative neuroimaging measures with magnetic resonance imaging and functional near infrared spectroscopy and assess effective strategies for measuring cognitive performance in young children, including those exposed to opioids.

Neonatal opioid withdrawal syndrome (NOWS) has emerged as a tragic by-product of the opioid epidemic. Newborns whose mothers used opioids while pregnant can experience symptoms of opioid withdrawal in the days following birth, such as tremors, irritability, seizures, sleep, digestive, and feeding problems. However, little is known about the effect of antenatal opioid exposure on longer-term infant development over time. To address this gap in understanding, the ACT NOW Longitudinal study is examining a crucial developmental period from birth to two years of life through a comprehensive battery of assessments, including MRI imaging, neurodevelopmental behavioral assessments, and family report measures. This longitudinal cohort study is projected to include a total of 375 infants, 250 who were exposed to opioids and 125 matched controls.

Neonatal opioid withdrawal syndrome (NOWS) has emerged as a tragic by-product of the opioid epidemic. Newborns whose mothers used opioids while pregnant can experience symptoms of opioid withdrawal in the days following birth, such as tremors, irritability, seizures, sleep, digestive, and feeding problems. However, little is known about the effect of antenatal opioid exposure on longer-term infant development over time. To address this gap in understanding, the ACT NOW Longitudinal study is examining a crucial developmental period from birth to two years of life through a comprehensive battery of assessments, including MRI imaging, neurodevelopmental behavioral assessments, and family report measures. This longitudinal cohort study is projected to include a total of 375 infants, 250 who were exposed to opioids and 125 matched controls.

Due to the opioid misuse epidemic across the nation, more infants are being exposed to narcotics during fetal life and developing neonatal opioid withdrawal syndrome (NOWS) in the neonatal period. Critical gaps remain in our knowledge with respect to best practices for identifying and managing infants with NOWS and no large-scale studies have been published on treatments undertaken and later outcomes of infants with NOWS. To address these gaps in knowledge, the Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW) study will evaluate treatment options and improve clinical care of infants with NAS/NOWS. This collaborative effort will conduct two trials: 1) Eating, Sleeping, Consoling for Neonatal Withdrawal (ESC-NOW): a Function-Based Assessment and Management Approach (ESC Study); and 2) Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS) (Weaning Study).

While advances in cancer treatment have increased survival rates, these patients often suffer from chronic cancer pain. Prescription opioids are often prescribed during active cancer treatment, but their long-term use for chronic cancer pain is associated with risk for opioid use disorder and risk for stigmatization associated with emotional distress, suboptimal health behaviors and coping strategies, and difficult patient-provider communication. This study aims to conduct qualitative interviews exploring prescription opioid and chronic pain stigma in cancer survivors with moderate-to-severe pain, caregivers, and clinicians who treat patients with chronic cancer pain, including oncologists, primary care providers, pain management specialists, and palliative care physicians. An analysis of potential contributors to stigma in cancer survivors will be completed to support development of multi-level behavioral interventions to reduce stigma and explore long-term health outcomes from such interventions.

Medication-based treatment for opioid use disorder OUD aids in reducing mortality, opioid withdrawal, intake and opioid-seeking behaviors, however there is a clear need to increase the armamentarium of therapeutics for OUD. The ?non-classical? NOcicePtin receptor (NOPr) binds the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) and is a promising target based on the evidence for its function in the regulation of the rewarding and motivational effects of opioids and alcohol. This study plans to assess the ability of the novel and selective NOPr antagonist BTRX-246040 to block oxycodone intake without abuse liability, and to suppress oxycodone withdrawal and relapse-like behaviors in rats. The study will also determine Drug Metabolism and Pharmacokinetics interactions (DMPK) between oxycodone and BTRX-246040 and brain penetrability in male and female rats. If successful, these preclinical studies will be followed by a Phase 1 clinical trial in non-treatment seeking OUD participants. These investigations will advance the prospects of validating a novel medication for OUD.