Funded Projects

This project will support consortium hypothesis generation in Phase II in order to disentangle how complex environmental factors impact brain development and function — from fetal period through the first decade — to shape cognitive, social, and emotional development. The project will develop the strategies to recruit and retain a racially and ethnically diverse sample of pregnant women (and their fetuses), who are oversampled for adverse environmental risk factors and exposure to substances of abuse; develop the strategies for managing potential legal and ethical challenges to ensure that the mother–child dyads have access to legal, social, and psychological support services as needed; and determine the optimal study protocol for the planned, phase II study — balancing the need for high quality, longitudinal data collection with the need to minimize burden on the mother–child dyads.

The Appalachian Node of NIDA Clinical Trials Network (CTN) will address clinical research questions that arise from Central Appalachia, an epicenter of the current opioid epidemic. Its rural geography, culture of independence, strained economy, and lack of access to substance use treatment have all contributed to the epidemic. The three aims of the node are to (1) conduct multi-site trials that address the current opioid crisis, with an emphasis on conducting studies among rural and other underserved populations; (2) propose studies to test innovative uses of existing resources to implement evidence-based practices that will extend state-of-the-art care into resource-poor regions, both rural and urban; and (3) disseminate CTN findings to regional payers and policymakers, practitioners, and the community. Proposed studies built on the work of node investigators include “Serious Bacterial Infections Related to Injection Drug Use: Quality Metrics and Intervention” and “Pharmacist-Assisted Buprenorphine Treatment,” among others.

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.

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.

New Hampshire can anticipate as many as 1,000 infants born with prenatal opioid exposure each year. Pain management is complicated for pregnant women with opioid use disorder (OUD), and undermanagement of pain is a strong risk factor for relapse. Contemplative interventions, such as yoga and mindfulness, may reduce risks for relapse for pregnant and parenting women with OUD. This project represents a partnership with New Hampshire stakeholders to develop and pilot evaluation of a trauma-informed yoga and mindfulness relapse prevention intervention (Mindful Moms in Recovery: MMORE). It aims to: 1) identify needs and areas of adaptation of trauma-informed yoga and mindfulness-based relapse prevention protocols through formative work with pregnant and parenting woman; 2) develop an integrated 10-session intervention protocol with iterative feedback from client stakeholders; and 3) evaluate feasibility, acceptability, and efficacy trends of MMORE in a pre-post pilot with pregnant women.

Chronic pain is a significant public health problem associated with tremendous personal and economic burden. First-line treatment consists of opioid medications, but despite only moderate efficacy and unpleasant side effects, rates of opioid prescriptions have quadrupled over the past 15 years, and this has contributed to high rates of misuse, overdose, and mortality. Clearly, alternative, or non-opioid strategies for treating pain are needed. In this context, “opioid-sparing” medications refer to compounds that can be combined with and enhance the analgesic effects of lower-dose opioids without increasing the rewarding properties of either drug. There is preclinical evidence suggesting that cannabidiol (CBD) may have the potential to function as “opioid-sparing” medications, but its ability to alter opioid-mediated analgesia in humans has yet to be determined. This proposal will fill this gap by conducting a double-blind, placebo-controlled, within-subject randomized crossover study of the effects of CBD and morphine co-administration on pain sensitivity and subjective reinforcement on 28 healthy males and females. This is the first known study to investigate the ability of CBD to alter morphine’s analgesic effects in humans. If successful, the model will have a lasting impact on our ability to develop and test medications that reduce our reliance on chronic use of opioid medications for pain relief.

Kinoxis has developed a novel small-molecule lead, KNX100, that reduces the severity of opioid withdrawal symptoms in preclinical animal models of opioid use disorder (OUD). KNX100 was discovered from a phenotypic screen of compounds derived from a fragment-based drug discovery program targeting the brain oxytocin system. KNX100 has a favorable pharmacokinetic and safety profile and has undergone testing for efficacy signals in two rodents and two non-human primate species. The proposed activity is to progress the development of KNX100 to treat opioid withdrawal in OUD. The overall objective of the project is to establish the safety and tolerability of KNX100 to enable human efficacy testing to commence in patients requiring treatment for opioid withdrawal. The long-term objective for this development program is to generate human efficacy data to support KNX100 as a potential treatment for opioid withdrawal symptoms and ultimately enable a New Drug Application to the FDA.

Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous adverse effects, including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor agonist could be combined with small amounts of an opioid to treat pain, thereby lowering the risk associated with larger doses. Unfortunately, very little is known about interactions between 5-HT2 receptor agonists and other opioids. The proposed studies will evaluate the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well-established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive-reinforcing (leading to misuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of chronic treatment on the development of tolerance to and physical dependence on opioids. If successful, these studies will provide proof-of-concept for this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic drug development.

There is an urgent need to prevent and reduce opioid use disorder (OUD) by reducing the need for opioid analgesia and preventing the escalation of opioid dosing in patients at greater risk of using more opioids following surgery. Brivoligide is a non-opioid drug candidate that can alter the course of postoperative pain for patients most likely to suffer increased pain and utilize more opioids following surgery. A single administration of brivoligide at the time of surgery can reduce acute postoperative pain in these patients by 30 percent to 40 percent beyond what can be achieved with the current standard of care for at least 28 days and reduce opioid utilization by 40 percent over a 3-month period following surgery. This project will support the research necessary to achieve regulatory approval of brivoligide with a broad indication, which will initially focus on the reduction of postoperative pain following mastectomy, a soft-tissue surgery model suitable to detect long-term pain and opioid reduction benefits. Brivoligide appears to be a very promising pharmacotherapy with the potential to greatly contribute to stemming the tide in the opioid crisis.

Deaths from opioid overdose are highly preventable with early detection and administration of naloxone, but overdose victims often die because they are alone or among untrained or impaired bystanders and thus do not receive timely resuscitation. There is an urgent, unmet need for a low-barrier, easily scalable solution that can identify opioid overdoses in real time and rapidly connect victims to naloxone therapy. This proposal seeks to commercialize an innovative overdose detection software product that can be downloaded on any commodity smartphone and can detect opioid- induced respiratory failure (i.e., overdose) and summon help. The software-only product, SecondChance, converts a smartphone into a short-range active sonar system capable of monitoring breathing and detecting overdose.

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.