Funded Projects

The widespread misuse of opioids has underscored the need to develop nonaddicting pain medications. Chronic pain is a major factor contributing to insomnia, and sleep disruption due to chronic pain causes patients to seek relief, exacerbating the drive for prescription opioids. In opioid use disorder, withdrawal from opiates induces insomnia, posing an additional challenge for successful abstinence. This study aims to determine whether treatment of opioid withdrawal-induced insomnia with nociceptin/orphanin FQ receptor (NOPR) agonists will mitigate the drive for opiate use. A major component of the arousal/withdrawal circuitries resides in the locus coeruleus (LC), which expresses MOPRs. The study will determine whether and how the NOPR system engages LC circuits to reduce arousal and insomnia-related phenotypes and assess the hypotheses that 1) the NOPR system is a component of the endogenous sleep/wake regulatory system and 2) NOPR agonists can act as therapeutic interventions to reduce opiate use.

The UCSF Core Center for Patient-centric Mechanistic Phenotyping in Chronic Low Back Pain (UCSF REACH) is an interdisciplinary consortium of basic and clinical scientists dedicated to understanding and clarifying the biopsychosocial mechanisms of chronic low back pain (cLBP). The goal of REACH is to define cLBP phenotypes and pain mechanisms that can lead to effective, personalized treatments for patients across the population. UCSF REACH has six cores that will support a single research project that is focused on the challenge of developing validated and adoptable tools that enable comprehensive yet routine clinical assessment and treatment of cLBP patients. Overall, the object of REACH is to make optimum use of all available resources to catalyze discovery and translation of novel diagnostics and therapeutics that improve outcomes of cLBP patients.

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.

For many reasons, the emergency department (ED) is a critical venue to initiate opioid use disorder (OUD) interventions. ED patients have a disproportionately high prevalence of substance use disorders and are at an elevated risk of overdose, and many do not access health care elsewhere. Despite this, OUD interventions are rarely initiated in EDs. The Emergency Department Connection to Care with Buprenorphine for Opioid Use Disorder study (CTN-0079) will assess the feasibility, acceptability and impact of introducing clinical protocols for screening for OUD, buprenorphine treatment initiation, and referral for ongoing treatment in ED settings with high need, limited resources and different staffing structures. This extension study will use the existing infrastructure to evaluate the adoption and sustainability of the clinical protocols introduced at each of the study sites and to identify factors influencing their diffusion and effectiveness.

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.

Rescue of victims of opioid overdose is accomplished by treatment with antagonist drugs, such as naloxone, that can reverse the respiratory depression. However, naloxone has serious liver toxicity and a short half-life, and its complete antagonism results in a withdrawal effect. Nalmefene is an FDA-approved opioid derivative that is an antagonist of the MOR and a weak agonist of the k-opioid receptors (KOR). An immediate release intravenous injectable formulation was approved by the FDA in 1995 for opioid overdose; however, the requirement for intravenous administration has limited its clinical use. This project, in partnership with Avior, aims to develop a fast-onset, rapidly-dissolving, mucoadhesive thin film formulation that carries uniformly distributed nalmefene nanoparticles on the surface of the film. This film, produced using Avior’s proprietary Speedit™ transmucosal drug delivery technology, rapidly delivers nalmefene when the film is placed in contact with the lower lining of the inner lip. This project will generate non-clinical data to support critical human clinical trials to determine if a transmucosal film can be developed with a rapid onset of action that is required for rescue of opioid overdose patients or taken prophylactically to prevent respiratory depression, to assess whether the effective speed of delivery is sufficient to conduct a human clinical trial.

Community pharmacies are optimal—yet underutilized—settings for identifying individuals with opioid use disorder (OUD) and increasing their access to treatment. Approximately 93 percent of individuals in the U.S. live within 5 miles of a community pharmacy. The most common opioid-related tool available to pharmacists is the prescription drug monitoring program (PDMP), which provides highly limited information and support for clinical decision making. Appriss Health, the largest U.S. PDMP vendor, covering 42 states, has developed an opioid risk measure, the NarxScore. This study will clinically validate the NarxScore metric and identify high, moderate and low opioid risk thresholds to inform OUD care management within urban and rural community pharmacies. This is a prospective cross-sectional comprehensive OUD risk and behavioral/physical health survey administered electronically with patients (n = 1,523) filling opioid medications in urban/rural community pharmacies in Ohio (pharmacy sites: n = 12) and Indiana (pharmacy sites: n = 3), states that continue to have disproportionately high rates of overdose and opioid prescribing. Correlation, regression and kappa statistics will be calculated for validation; receiver operating curves with sensitivity/specificity values will be employed for threshold identification (with >95 percent power to detect an area of 0.7 under the curve value).

Although medications are available to treat opioid use disorder (OUD), adherence with treatment programs remains a problem. Nalmefene is an opioid receptor antagonist that was previously approved for treatment of opioid overdose–induced respiratory depression that has a longer duration of action than naloxone. AP007 is a unique formulation of nalmefene-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles that when injected intramuscularly continually releases an effective dose of nalmefene and thus reduces opioid cravings in OUD patients. This group is developing AP007 and will have a lead formulation selected based on in vitro release kinetics data and in vivo pharmacokinetics data in rats. The objectives of the project are to determine safety and efficacy of AP007 in a swine opioid use/withdrawal model, preliminary safety in a first-in-human Phase 1 study, and preliminary efficacy in a Phase 2a multidose study. These results will be used to develop Phase 2 human and Phase 3 clinical studies.

This proposal would address barriers to the NP’s ability to prescribe buprenorphine by incorporating waiver education into NP final semester curriculum. The initial eight hours of training would be provided to students in a face-to-face classroom setting or via live video streaming. The remaining 16 hours would be completed by the NP students through online modules offered by the AANP. Trained NP students would be eligible for one year of peer-to-peer mentorship and inclusion in the MUSC Project ECHO tele-mentoring for new providers. Outcomes to be tracked would be the number of NPs trained who obtain their waiver and the number of individuals treated with MOUD by the NPs trained. Secondary data collected would offer insight into wavier obtainment process and determine need for mentorship for newly waivered providers.

There is a great deal of research aimed at better understanding transitions in alcohol and other drug (AOD) use patterns from early to late adolescence and from late adolescence to emerging adulthood. However, no studies to date have (a) assessments of AOD use from ages 10 to 24 across all developmental periods (middle school, high school, and emerging adulthood); (b) a large sample with substantial racial and ethnic diversity, particularly among Hispanic and Asian youth; (c) in-depth coverage of 10 areas of functioning across three key domains; (d) subjective and objective neighborhood data; or (e) the capacity to examine developmental trajectories for more than one substance. The current proposal is a continuation of previous projects that assessed AOD use across nine waves of data from age 10 to age 19. The proposed study capitalizes on the longitudinal data on protective and risk factors we have collected since age 10 in an ethnically diverse cohort by continuing to annually assess these youth in order to capture important transitions to emerging adulthood (through age 24). By advancing the epidemiology of alcohol use during adolescence and emerging adulthood, our findings can affect prevention and intervention programming for young people and address critical issues of public health policy.

Rates of opioid use (OU), opioid use disorder (OUD), and overdose (OD) disproportionately affect those in the justice system. Yet, despite such high rates of misuse and associated negative outcomes of untreated OUD, screening and the availability or use of evidence-based treatments for OU and OUD—including medication to treat OUD—are substantially underused in justice populations. This project will leverage the unique, real-time scale-up of a new opioid court model (OCM) to address a critical public and correctional health problem by developing and evaluating an implementation intervention (OCM RISE), designed to build cross-system partnerships to permit the development of generalizable yet tailored strategies that allow the OCM to be scaled up across a variety of contexts.

The Coordinating Center (CC) will provide centralized logistical support and facilitate communication and coordination of activities across the cooperative. The CC will provide scientific leadership, which will include providing scientific expertise in the areas of implementation research and economic evaluation. The CC will establish an infrastructure for cross-site data collection, management, harmonization, and data sharing and provide expert methodological and statistical consultation.