Funded Projects

The increased risk of maternal, obstetric, and newborn morbidity and mortality associated with perinatal prescription opioid (PO) misuse and opioid use disorder (OUD) is well established. Despite clear advances in maternal, fetal, and newborn health with treatment of perinatal opioid misuse and OUD, much work remains. Preliminary data has demonstrated significant reductions in opioid misuse as a result of our Cognitive Behavioral Therapy (CBT) program for pain combined with shared decision making for medication management for pregnant women misusing POs or with OUD (including heroin). However, access to the program is still limited and several obstacles to its expansion remain. This proposal will fill this critical gap by converting their CBT intervention from in-person sessions to a web-based interface. The proposed research will result in a critical advance in the management of opioid use and abuse during pregnancy and prevent both the acute and long-term risks associated with pre- and perinatal PO misuse and OUD, including overdose and death.

A persistent problem in the dissemination of medications for opioid use disorder (MOUD) is patient dropout, and matching patients to suitable medication early has the potential to minimize dropout. The overall objective of this secondary data analysis study is to develop and disseminate individual level risk prediction models using harmonized data collected from three multi-site clinical trials from the CTN, in order to predict specific clinical outcomes (e.g., dropout, relapse) for patients treated with MOUD, including methadone, buprenorphine or extended-release depot naltrexone. The relative importance of predictors in the best predictive models will be estimated, which may facilitate refinement of common data elements for future OUD studies. The comprehensive, harmonized database of treatment data created in this study can be used for future secondary data analysis studies and will provide a replicable data pipeline to process and validate OUD data in future protocols.

Infants exposed to opioids in the womb may suffer from neonatal opioid withdrawal syndrome (NOWS). They experience symptoms such as excessive crying, irritability, rapid breathing, elevated heart rates, tremors, and sometimes seizures. There is no accepted standard treatment for NOWS; infants are treated with pharmacological (opioid administration and gradual weaning) and nonpharmacological measures. Nonpharmacological care such as swaddling, rocking, frequent feedings, and skin contact, are time consuming, placing a substantial burden on hospitals with limited resources. Prapela, Inc. previously developed a hospital bassinette pad that, using stochastic vibrotactile stimulation (SVS) technology, very gently rocks infants with NOWS to reduce irritability and other symptoms without disturbing sleep patterns. This project will conduct an additional clinical study to determine the SVS bassinette pad’s efficacy in reducing breathing and heart rate, its safety, and its acceptability with clinical staff and parents caring for infants with NOWS.

Adolescents and young adults in justice settings (AYAJS) have some of the highest rates of opioid use disorder (OUD), with national rates approaching 20%. Multiple studies have established effectiveness of the Adolescent Community Reinforcement Approach with Assertive Continuing Care (ACRA/ACC) in reducing non-opioid substance use disorder (SUD); however, none have evaluated it as an OUD prevention strategy. SUD is common and costly among AYAJS; thus, ACRA/ACC-based approaches are likely to be effective and cost-beneficial OUD prevention strategies for this group. However, the optimal intensity of an ACRA/ACC-based OUD prevention intervention for AYAJS with and without non-opioid SUD is not known, as these groups are likely to have differing prevention needs. Seattle Children’s Hospital (SCH), University of Washington (UW), and Washington State Juvenile Rehabilitation (WSJR) will collaboratively evaluate ACRA/ACC-based OUD prevention strategies of different intensity levels among SUD and non-SUD youth.

Since 2002, persons with opioid use disorders who desire medication-assisted treatment can be treated with buprenorphine, which has been shown to be efficacious. Buprenorphine treatment can occur in any medical office-based setting, is prescribed by any physician who seeks to become waivered, and is taken by patients at home unsupervised. However, without visual confirmation of medication ingestion, providers remain unsure if patients divert part or all of their buprenorphine medication. This project will develop the technical and logistical workflow needed to implement a video-­based application, miDOT, for office-­based buprenorphine monitoring during the initial months of care, which will allow health care providers to monitor whether patients ingest the drug and adhere to treatment. The project will configure a video-based DOT platform, evaluate its effectiveness in securing medication ingestion and care retention for illicit opiate users, and solidify routes of sustainable commercial viability with commercial partners.

The HEALthy Brain and Child Development National Consortium (HBCD-NC) will establish a normative template of developmental trajectories over the first 10 years of life. All sites in the HBCD-NC will carry out a common research protocol and will assemble and distribute a comprehensive research dataset to the scientific community. The HBCD-NC will collect neural, behavioral, physiological, and psychological measures, as well as biospecimens, to characterize neurodevelopmental trajectories. Most participants will be recruited in the second trimester of pregnancy, with a smaller subset recruited at birth, and followed for the first 10 years of life. The Northwestern University study site is in Chicago where rates of prenatal substance use are rising and consistent with the national trend. This site will recruit a diverse urban sample of mother-infant pairs reflecting the population of Chicago.

Opioid dependence is a leading cause of premature illness and death. Previous research suggests that a protein called G-protein coupled receptor (GPR88) controls many addiction-relevant behavioral and physiological actions of opioids. This research study will validate GPR88 as a drug target for opioid use disorder as well as develop novel, brain-penetrant GPR88-binding molecules with properties optimized for treating opioid dependence. This research is an initial step toward the goal of developing GPR88-binding molecules as novel therapeutics to facilitate abstinence in people dependent on opioids.

To tackle the national public health emergency posed by opioid misuse, addiction, and overdose deaths, the development of effective new medications and the FDA drug approval process must be accelerated. In response to this call, INSYS Development Company, Inc. (INSYS) has developed a cannabidiol (CBD) oral solution that shows promise as a novel medication for prevention of relapse that addresses one of the five opportunities specified in the HEAL Initiative to improve treatment options. The first phase of this project involves clinical trials of CBD on cue-induced cravings, modulation of withdrawal, alterations of negative affect states, relapse to opioid use, and treatment retention in patients with OUD receiving buprenorphine treatment in a residential drug treatment facility. The findings from this phase will inform further studies in an outpatient setting. If successful, this project could advance to the development of a new monotherapy for the treatment of OUD.

A more than 5-fold increase in the incidence of neonatal abstinence syndrome has been reported since 2000. Preliminary studies show that prenatal opioid exposure is associated with increased risk of impaired neurodevelopment. Five institutions (Duke University, Arkansas Children’s Research Institute, Cincinnati Children’s Hospital, University of Illinois at Urbana–Champaign, and University of North Carolina at Chapel Hill) have formed a consortium to develop strategies for the Phase II HEALthy Brain and Child Development Study. Research teams will develop instruments and strategies (recruitment/retention protocols, assessment batteries, and novel tools); conduct pilot studies (fetal and postnatal imaging, advanced imaging harmonization and quality control, assessment administration, biosampling) to evaluate instruments; and analyze available data, including imaging, behavioral, cognitive, and maternal data from studies on early brain development, to guide the Phase II study design. Upon completion, the consortium aims to conduct the Phase II study.

The excruciating multiday experience of opioid withdrawal syndrome (OWS), is exacerbated by the opioid antagonist drugs naloxone and naltrexone. This industry-academia collaboration will explore the potential of the glutamate AMPA receptor antagonist Tezampanel (TZP). Animal studies have shown reduced hyperactivity in brain circuits involved in OWS, without relying on direct stimulation or antagonism of the opioid system ,and has already been delivered to over 500 human subjects and found to be safe for a potential migraine indication. This proposal will build up the evidence needed to apply for and conduct open label and blinded placebo-controlled human trials of TZP safety and efficacy for OWS. If successful, this project will allow planning for a pivotal registration trial for TZP for OWS, and as a transitional treatment to long-term recovery on naltrexone and help us stem the tide of the opioid crisis.

There is an urgent need for longer acting opioid overdose reversal medications to treat acute fentanyl intoxication and overdose. This project will develop a novel molecule (CS-1103) that sticks to fentanyl and removes it from the body. Previous research with animal models shows that CS-1103 has several features that make it attractive for a new medication. It can reverse fentanyl-induced respiratory depression, preventing another overdose; work in combination with naloxone; and appears to be safe and well-tolerated. The research will continue exploration of CS-1103 toward testing CS-1103 in human research participants.

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.

The adverse effects of morphine and other mu-opioid receptor (MOR) agonists are linked to the ?-arrestin pathway, while analgesia is tied to the G-protein pathway. Pathway specific or “biased” drug development can target G-protein specific agonists that avoid the negative consequences of ?-arrestin signaling activation and produce analgesia. Highly “biased” MOR agonists have promise as effective analgesics but devoid of opioid-induced adverse effects. Preclinical studies compared two compounds, MEB-1166 and MEB-1170, against Oliceridine and morphine. Both compounds displayed no respiratory depression, even at high doses, while morphine and Oliceridine significantly reduced respiratory function. In contrast to morphine, neither MEB-1166 nor MEB-1170 produced conditioned place preference, suggesting an absence of abuse liability. This study will characterize the pharmaceutical and pharmacological profiles and perform liability studies for these compounds.