Funded Projects

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.

The U.S. is in the midst of a devastating opioid epidemic. Since 1999, the number of overdose (OD) deaths involving opioids has quadrupled. These trends are magnified among American Indians/Alaska Natives (AI/ANs) compared to other racial/ethnic groups. AI/ANs are second only to Whites in the rate of OD mortality (8/100,000 versus 12/100,000 deaths, respectively). Medications for opioid use disorder (OUD; i.e., methadone, buprenorphine and naltrexone) are considered the most effective treatment, reducing mortality and increasing abstinence and retention. However, numerous barriers limit the uptake of medications for OUD in tribal communities and within urban treatment settings serving AI/AN individuals. This is a two-phase formative research study to develop and test an implementation intervention for programs to provide medications to treat OUD specifically with AI/AN consumers. The objective of Phase I (12 months) is to develop a culturally centered implementation intervention to integrate medications for opioid use disorder (MOUD) into health care/addiction specialty settings. The objective of Phase II (24 months) is to conduct a preliminary test of the implementation intervention at four sites serving AI/AN communities. Community-based participatory research (CBPR) methods will be used throughout both phases. This study will help with decreasing stigma and increase the utilization of MOUD in health care settings that serve AI/AN populations.

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.

MCAM is a novel opioid antagonist that can be used for opioid overdose reversal and has advantages over naloxone, including a pseudo-irreversible interaction with the ?-opioid receptor and a longer duration of action. Studies in animal models demonstrate MCAM’s long duration of action against the reinforcing and respiratory-depressant effects of remifentanil and heroin, indicating that could be a better treatment option for opioid use disorder. This project studies the pharmacodynamics of MCAM through animal toxicity and safety studies to establish the necessary and sufficient conditions from which to establish MCAM’s safety and antagonist activity in animals and humans. MCAM may be able to prevent all actions of any ?-receptor opioid drug in humans for a longer period of time than any other antagonist given acutely.

This supplement supports the goals of the current award, “An Evaluation of the National Zero Suicide Model Across Learning Healthcare Systems” (U01MH114087). Safety planning is a highly recommended practice within the Zero Suicide framework, but little is known about the effectiveness of the individual elements that can make up a safety plan, such as lethal means assessment, identification of supportive contacts, coping skills, warning signs, and sources of distraction. All of the documentation lives in text-based clinical narratives. This supplement will support development of new metrics using natural language processing to determine baseline rates, from which we can quantify the change in safety planning and lethal means assessment practice longitudinally after implementation of new safety planning templates using our Zero Suicide main award.

Acute and chronic low back pain are among the most common sources of short- and long-term disability. Fear of pain and disability, or “catastrophizing,” increases opioid use, but is reduced when patients have effective options and feel control over pain. The goal of this project is to develop an opioid-sparing therapeutic consumer device for low back pain, with multiple patient-controlled effective neuromodulatory pain relief options, including vibration, pressure, cold, and heat. After proving that providing a multimodal device is effective for pain, the project will determine whether the availability of an effective home therapy device reduces opioid use for patients with acute and chronic low back pain.

The growing opioid use epidemic in the U.S. has been associated with a significant increase in the prevalence of pregnant opioid-dependent women and neonatal abstinence syndrome, which is associated with adverse health effects for the infant and with costly hospitalizations. Maintenance with sublingual (SL) buprenorphine (BUP) is efficacious for opioid use disorder but has disadvantages that may be heightened in pregnant women, including the potential for poor adherence, treatment dropout, and negative maternal/fetal effects associated with daily BUP peak-trough cycles. Extended release (XR) formulations may address some of these disadvantages. The primary objective of CTN-0080 is to evaluate the impact of treating opioid use disorder in pregnant women (n = 300) with BUP-XR, compared to BUP-SL, on maternal-infant outcomes. Other objectives include testing a conceptual model of the mechanisms by which BUP-XR may improve maternal-infant outcomes, relative to BUP-SL; determining the economic value of BUP-XR, compared with BUP-SL, to treat OUD in pregnant women; and evaluating the impact of BUP-XR, relative to BUP-SL, on neurodevelopment when the infant/child is approximately 12 and 24 months of age. Ultimately, this study will help in increasing access to treatment as well as provide quality care for pregnant/postpartum women.

This study will challenge current clinical approaches to managing the pregnant woman with opioid use disorder. Dosing of buprenorphine (BUP) in pregnant women is based on studies in non-pregnant subjects, which suggests that symptoms of withdrawal occur when plasma BUP concentrations are < 1ng/ml. No such data exist for pregnant women, but this is a prerequisite for defining an appropriate dosing regimen of BUP in pregnant women. We will define this threshold by monitoring women undergoing mild, medically directed withdrawal. The Clinical Opioid Withdrawal Scale score and the Finnegan score for NAS are key to defining when withdrawal occurs and thus dictate treatment in mother and baby. Neither scoring system is based on plasma BUP concentrations and thus, may not reflect true opioid withdrawal. This proposal aims to develop physiologic-based scoring systems that refine the accuracy of diagnosis and optimize treatment.

One of the most widely used treatments for chronic pain is opioid analgesics. Importantly, there is evidence of a pathological interaction between opioids and the immune system that can contribute to both opioid tolerance and elevated levels of pain. Chronic pain conditions for which opioids are most often prescribed have been shown to involve dysregulation of the immune system, which may contribute to pathological effects of opioid use in these patients. To address this unmet need, this study aims to develop a reliable, cost-effective, and non-invasive in vitro diagnostic assay for chronic pain with an underlying inflammatory pathology, as a blood test available in primary care settings, with the hope that doctors can use the test to identify which patients might benefit less from opioids and be more likely to become addicted.

Quality implementation of evidence-based programs (EBPs) in community settings for youth is critical for reducing the burden of alcohol, tobacco and other drug (ATOD) use and its consequences. EBPs delivered in schools are an efficient way to reach large populations of young people, including those underserved by other settings, and reduce and prevent ATOD use. Yet youth rarely receive EBPs as intended in community settings, including schools. This training and research plan will prepare the investigator to become an independent scholar in the implementation of theories and frameworks to better understand factors related to program delivery—approaches to enhancing ATOD programs for youth in community settings. More specifically, the training will allow him to expand the application of Consolidated Framework for Implementation Research (CFIR) to inform approaches to enhancing effective EBP delivery. The proposed training and research plan extends current implementation research to focus applying implementation theories, frameworks and strategies in other community settings (schools) and on economic evaluation of implementation strategies. The results are expected to improve current efforts to deliver EBPs in diverse community settings and aid in applying evidence-based implementation strategies in the school context to ultimately reduce and prevent ATOD use among youth.

Deaths from opioid overdose continue to rise; from 2015 to 2016, there was a 28 percent increase in the number of fatal overdoses. Currently available pharmacotherapies include MOR agonists (e.g., buprenorphine) and antagonists (e.g., naloxone), all of which suffer from specific and clear limitations. To address the main deficits in these treatments, the researchers will develop and optimize medications with longer duration of action that prevent and reverse the effects of opioids in a manner that is not surmounted by increasing doses of agonist. Their pilot studies in monkeys show that the pseudo irreversible MOR selective antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for remifentanil in a food/drug choice procedure, and reverses—as well as protects against—respiratory depression by heroin, with a single injection being effective for a week or longer. Bringing a medication like this to marketable fruition could significantly improve the treatment of OUD and save lives by providing insurmountable extended protection after rescue from overdose, including from ultra-potent fentanyl analogs.