Funded Projects

Many individuals with opioid use disorder (OUD) pass through the criminal justice system over the course of their life. Improved access to high-quality, evidence-based addiction treatment in justice settings will be critical to addressing the opioid crisis. Through the Justice Community Opioid Innovation Network (JCOIN), the National Institutes of Health will study approaches to increase high-quality care for people with opioid misuse and OUD in justice populations. The Mason Coordination and Translation Center (MCTC) will manage logistics, stakeholder engagement, and dissemination of findings and products from the JCOIN network. This will include establishing infrastructure to support research education and rapid response and pilot research.

The project will address gaps in both risk identification and clinical management by utilizing comprehensive clinical data from a mature health information exchange containing more than 2.3 million patients across the spectrum of clinical care (hospitals, primary care, specialty care, community health centers, urgent care) to develop a statistically robust method to measure suicide risk associated with prescription opioid use. First, the team will couple data fusion techniques with machine learning-based approaches in identifying the clinical and demographic characteristics associated with elevated risk of suicidal behavior among prescription opioid users. Second, the team will develop clinical profiles of patients with higher risk of suicidal behavior associated with prescription opioids, and to incorporate these profiles in a clinical decision support platform that can be used for identification and intervention at the point of care. The clinical decision support tool developed under this proposal will provide a generalizable platform that could be extended to other more conventional opioid related outcomes such as OUD and overdose.

One of the current critical needs in addressing the opioid crisis is the development of new overdose-reversal interventions, including wearable technologies that can detect an (impending) overdose from physiological signals to signal for help, or trigger a coupled automated injection of naloxone. This project tests the approach of monitoring respiration by detecting the sounds of breathing in the trachea. This proposal aims to develop a machine learning algorithm that could process those sounds, detect the kinds of patterns of reduced breathing that occur during an opioid overdose, and design a miniature wireless sensor that could be used to detect those sounds. Such a sensor and algorithm could be a key component to a device to detect and intervene in overdoses.

NIH is supporting the Justice Community Opioid Innovation Network (JCOIN), a collaboration of justice and behavioral health stakeholders that will study approaches to increase high-quality care for people with opioid misuse and opioid use disorder in justice populations. This multi-site clinical research center aims to improve local community public health and safety outcomes for reentering justice- involved individuals who have a history of (or are at risk for) using opioids by comparing two implementation strategies and two interventions at the client and system levels. The study will also examine which implementation strategy is most effective for increasing service linkage and initiation, services retention, and improved opioid-related public health safety outcomes.

Opioids have been significantly over-prescribed and are associated with numerous deaths, resulting in the nation’s current opioid crisis. The FDA recently approved the ?2 adrenergic agonist lofexidine as a non-addictive, non-opioid treatment for opioid use disorder (OUD), but there is a continued, urgent need to develop additional pharmacological alternatives to address both pain and OUD. The psychoactive, natural product, Mitragyna speciosa (kratom), has triggered significant interest in this space because Mitragynine, its main alkaloid, can interact with both mu opioid and ?2 receptors, offering a totally new approach for treating OUD. This project involves the synthesis and research of a series of Mitragynine analogs to better understand the pharmacological mechanisms that underlie Mitragynine’s opioid and adrenergic activities. If successful, this project will result in templates for the design of novel opioid receptor ligands. This advance would greatly improve the knowledge of interactions of these structurally novel compounds with opioid receptors and facilitate the development of these ligands as treatments for OUD.

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.

To address the need for novel therapeutics for opioid use disorder (OUD), this research group identified ghrelin as an endogenous regulator of the mesocorticostriatal circuit, which contributes to the enhanced motivational attributes of addictive drugs and drug-associated cues. Ghrelin binds to the growth hormone secretagogue receptor 1? (GHS1?R) to transduce several physiological and behavioral processes, including the reward-related effects of opioid agonists. Systemic administration of a GHS1?R antagonist/inverse agonist dose-dependently attenuated self-administration of the addictive opioid analgesic oxycodone as well as oxycodone-seeking. This project proposes to employ a suite of validated rodent OUD models to define the preclinical profile for PF5190457, a selective GHS1?R antagonist/inverse agonist. PF5190457’s abuse liability, ability to suppress withdrawal and relapse-like behaviors, drug metabolism and pharmacokinetics, and brain penetrability in rats will be assessed. Phase 1 clinical studies in non–treatment seeking OUD participants will follow to assess the safety and tolerability of PF5190457.

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.

People who use opioids in rural areas suffer worse health and less insurance coverage. The opioid problem in rural areas is of particular concern, as rural areas have higher overdose rates despite equivalent rates of OUD. This is because rural areas have a scant number of clinics and clinicians who provide medication treatment for OUD. Thus, people living in rural areas must travel long distances to access clinics that may or may not have expertise in providing treatment to patients with OUD. Telemedicine (TM) could efficiently increase capacity for delivery of buprenorphine in rural areas and may increase the number of patients receiving medication treatment and improve treatment retention and outcomes. While the development of medication treatments for opioid use disorder (MOUD) capacity in primary care settings with optimal/comprehensive services is desirable, the current opioid crisis with escalating overdose death rates in rural areas suggests a need to implement an efficient, cost-effective system of MOUD services that can be scaled up quickly. The use of a centralized and Medicare-covered TM vendor utilizing a developed methodology and established organizational infrastructure offers the great potential for a rapid rollout to increase access to MOUD and improve treatment retention in rural areas. This cluster randomized clinical trial with two phases will test expanded treatment access to improve retention on MOUD in highly affected rural areas. Phase I will include implementing telemedicine in a limited number of rural sites with varying levels of office-based opioid treatment (OBOT) to inform implementation strategies for the main trial, and Phase II will include evaluate comparative effectiveness between OBOT alone and OBOT + TM at 30 sites.

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.

Opioid use disorder, a chronic and relapsing disease, is a significant and escalating public health concern. But, despite the availability of approved pharmacotherapies and promising therapeutic interventions, the high rates of relapse indicate a critical need for a better understanding of the factors that contribute to relapse to opioids, and for the development of new treatment approaches. Sleep problems are a common symptom in most substance use disorder syndromes, including opioid use disorder (OUD), but they are severely undertreated, partly because the standard hypnotic medications used to treat sleep disorders are themselves addictive. This study will investigate whether activating the glucagon-like peptide-1 receptor pathway can help reduce craving while improving sleep in OUD patients. The FDA-approved medication liraglutide, a GLP-1R agonist, is currently approved to treat Type II diabetes mellitus and obesity in humans. This proposal for a supplemental study will add polysomnography, the gold-standard for evaluating sleep architecture, to an ongoing study. If successful, this study will provide a strong rationale for conducting a full multi-site, Phase III clinical trial.