A concept describes the purpose, scope, and objectives of a potential funding opportunity. Approved concepts are usually developed into Requests for Applications (RFAs), in which funds are set aside by the Institute to stimulate a specific program of research. Concepts are being posted to give interested researchers additional time to plan for application submissions. The NACDA conducts most, but not all, NIDA concept clearances. Concepts may also be cleared through other public venues. Concepts cleared through other public venues are marked with an asterisk (*).
Please send questions regarding specific concepts to the program contact listed in the description. Please also note that to avoid any conflicting information, once a concept has been finalized as a published RFA (or similar funding announcement), it is deleted from this early notification, concept clearance list.
- Virtual Reality Tools to Enhance Evidence Based Treatment of Substance Use Disorders
- Laboratories for Early Clinical Evaluation of Pharmacotherapies for Substance Use Disorders
- The Helping End Addiction Long-Term (HEAL)-ing Communities Study*
- National Drug Abuse Treatment Clinical Trials Network (CTN) Expansion to Address the Opioid Epidemic*
- The Justice & Community Opioid Innovation Network (JCOIN)*
- Responding to Opioid Use Disorders (OUD) in Tribal Communities in the Context of SAMHSA Tribal Funding
- Community Resource: Post-Mortem Brain Resources for Exploring HIV Compartments in Individuals with Opioid Use Disorders
- Loyalty and Reward Program to Increase Medication Assisted Treatment (MAT) Compliance
- Modeling HIV Neuropathology Using Microglia from Human iPS Cells and Cerebral Organoids
- Responding to the Opiate Crisis through Scalable, Data-Driven Justice-Behavioral Health Partnerships
- Respiratory Stimulants to Reverse Drug-Induced Respiratory Depression (RD)
- Pre-Exposure Prophylaxis for HIV Prevention and Treatment for Substance Using Populations
- Identifying Neural Mechanisms Linking Psychosocial Stress to Pain and Opioid Use Disorder
- Medications Development to Prevent and Treat Opioid Use Disorders and Overdose
Posted September 6, 2018
There are numerous existing evidence-based behavioral treatment approaches for substance use disorders. A significant proportion of patients who receive treatment using evidence-based behavioral therapies relapse, suggesting that additional adaptations are needed to enhance the effectiveness of these therapies. Technology driven approaches (e.g., cell phone based applications, text messaging interventions, ecological momentary assessment) to improving evidence-based treatments have shown some success.
Virtual reality (VR) is unique among other technological enhancements in that it can recreate some elements of the social situations and physical environments that typically trigger relapse, allowing patients to practice skills they will need when they encounter such situations in real life. The potential for VR to enhance treatment effects has been demonstrated in domains outside of substance use, such as comorbid depression, anxiety, posttraumatic stress disorder, obesity, and acute and chronic pain (e.g., Fodor LA et al., 2018, Tarrant J et al., 2018, Manzoni et al., 2015, and Pourmand A et al., 2018). In addition to the potential to increase the potency of interventions by allowing patients to practice skills in realistic virtual settings, VR also has the potential to extend access to treatment outside of clinical settings, and generate digital markers/digital phenotype tools for Clinical Research (Bourla A et all., 2018).
This initiative aims to support small businesses to develop VR-enhanced technologies that will:
- Support SUD treatments and recovery,
- Provide treatment alternatives for chronic pain,
- Serve as next generation Clinical Research Tools which leverage data from the VR experience and model SUD and comorbid mental illnesses disorders.
Numerous evidence-based substance abuse treatments may lend themselves to VR adaptation. Examples include, but not limited to:
- Cognitive Behavioral Therapy
- Contingency Management
- Motivational Interviewing/Motivational Enhancement Therapy
- Multisystemic Therapy
- Multidimensional Family Therapy
- The Matrix Model
- 12-Step Facilitation Therapy
- Behavioral Therapy
Irina Sazonova, M.S., Ph.D., Challenges and Prize Competitions, Educational Programs, Office of Translational Initiatives and Program Innovations, NIDA
Posted September 6, 2018
A significant challenge in the development of medications for Substance Use Disorders (SUDs) is the need for specialized laboratories that have the knowledge and expertise to timely and efficiently conduct FDA-defined Phase I and Phase II clinical trials. For example, Phase I clinical trials in addiction must evaluate the medical safety of compounds, that may involve the evaluation of safety of the interaction with a drug of abuse, or pharmacokinetic or pharmacodynamic studies. Such studies require an inpatient unit where subjects can feel comfortable and have adequate medical monitoring and other safety protection measures in place. They also require pharmacy support with a set of licenses and permits to allow the storage and administration of some substances, potentially including DEA scheduled drugs. These laboratories must have the ability to recruit participants with SUDs who are not motivated to receive treatment. Moreover, they must be able to conduct Good Clinical Practice (GCP) quality studies that satisfy the FDA requirements to accept the data for approval purposes.
Phase II studies mainly focus on the evaluation of the safety and early efficacy of medications. These studies can be conducted in outpatient settings in treatment-seeking populations with strict inclusion/exclusion criteria and specific treatment outcomes. The settings where Phase II studies are conducted must have the knowledge and expertise in the area of research, the ability to recruit study participants, and the clinical services necessary to attend to the needs of participating patients. Also, they must possess the necessary licenses and certificates to conduct these types of trials and the ability to follow GCP guidelines. The data collected from these studies must also satisfy the FDA quality requirements to support the approval of the compound.
Given the high level of specialization and strict regulatory requirements needed to conduct early clinical trials of medications for SUDs, it is critical to increase the availability of laboratories that can perform these types of studies. It is expected that each laboratory will be GCP-compliant, have access to an Institutional Review Board (IRB) to perform timely and efficient review and oversight, possess a track record of success in operational aspects of drug development, have successful clinical study initiation and recruitment, and the demonstrated ability to complete clinical studies with standards and timelines comparable to the pharmaceutical industry.
The purpose of this Funding Opportunity Announcement (FOA) is to accelerate the clinical development of medications to treat Substance Use Disorders (SUDs) by supporting laboratories with the expertise and resources to timely and efficiently conduct early (Phase I or Phase II) clinical trials of potential pharmacotherapies for SUDs.
Some examples of studies to be conducted in the laboratories may include:
- Early clinical studies with a potential medication candidate, such as First time in Humans (FIH), Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) or SAD-MAD combination, food effect
- Drug-Drug interaction (DDI) studies, including safety interaction studies of medications with drugs of abuse and other studies related to aspects of formulation development (e.g., bioavailability)
- Translational Phase 2A proof-of-mechanism (POM) studies. It is expected that neuroimaging and other technologies will be used where appropriate.
- Phase 2B dose-ranging and/or Early Signal of Efficacy (ESoE) type of trials
- Proof of Concept (POC) efficacy and safety clinical trials
Tanya Ramey, M.D. PhD, Medical Officer, Medical Clinical Branch, Division of Therapeutics and Medical Consequences (DTMC)
Posted June 13, 2018
Despite the availability of multiple effective evidence-based practices and programs, most Americans at risk for or with an opioid use disorder (OUD) do not receive effective prevention and treatment services, particularly in an integrated and coordinated manner. Simultaneously, opioid overdose rates continue to increase.
This initiative will support a new cooperative agreement multi-site national research effort to develop approaches for the systematic implementation and sustainability of effective interventions to address the opioid crisis in highly-impacted communities. Findings from this study will contribute to our understanding of how an integrated array of evidence-based prevention and treatment services can decrease rates of overdose deaths and events, the incidence of OUDs and HCV, and increase the number of individuals receiving medication-assisted treatment and retained in treatment beyond 6 months. In addition, the study will yield best practices for replication in other communities impacted by the opioid crisis including metrics for evaluating outcomes.
The HEALing Communities Study will address the following key questions:
- What is the individual and public health impact of implementing an evidence-based integrated OUD care delivery system in highly-impacted communities?
- What factors (organizational, community, policy-level) contribute to successfully implementing an integrated care delivery system?
- What analytic tools, resources, and strategies are most useful to help communities rapidly respond to the opioid crisis?
- What is the cost and cost effectiveness of designing and implementing a coordinated and integrated response in a highly-impacted area?
Redonna K. Chandler, Ph.D., Director, NIDA AIDS Research Program
National Drug Abuse Treatment Clinical Trials Network (CTN) Expansion to Address the Opioid Epidemic*
Posted June 13, 2018
NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN) was established in 1999 to bridge the gap between research and practice to improve addiction treatment. Through the collaborative partnership of scientists and treatment providers, the CTN seeks to address critical research questions with direct relevance to clinical practice and the needs of patients. Over the last two decades, the CTN’s research infrastructure and agenda have evolved to reflect the changing landscape of the SUD treatment community, transformation of health care systems, and emerging scientific advancements. In 2005 the CTN began to engage providers in general medical settings and healthcare systems, and with the 2015 grants solicitation and awards the Network began to develop a research portfolio encouraging the adoption of innovative bioinformatics approaches to improve the efficiency of SUD clinical research.
The CTN currently is comprised of 13 research Nodes, or primary performance sites, with numerous affiliated sites, and two coordinating centers. The CTN program is administered within NIDA through the Center for the Clinical Trials Network (CCTN). The ongoing opioid epidemic and overdose death crisis presents an urgent public health need to quickly expand the CTN to 1) increase the Network’s scientific and clinical trial capabilities, and 2) to better cover geographic regions most impacted by the opioid overdose epidemic. This expansion would enhance the CTN’s ability to use cutting-edge research designs, methods, and data resources, consistent with IOM recommendations. For example, the addition of Nodes with expertise in clinical data science and informatics would bolster the CTN’s capacity to conduct “learning health care system” studies embedded in clinical care. Additional Nodes located in geographic regions severely affected by the opioid epidemic would allow greater reach and impact of research across the country.
Through this targeted augmentation of the CTN research infrastructure, NIDA and the CCTN propose to build on the broad portfolio of research previously conducted in the CTN to 1) further investigate the use of mobile health technology and other digital tools to optimize OUD treatment, treatment success, and retention in care, 2) conduct implementation research studies to improve the speed and scope of the adoption of evidence-based practices, and 3) conduct studies to develop and test innovative care delivery models such as Bridge clinics, patient navigation models, primary care-pharmacy partnerships, and streamlined admission to treatment.
This initiative would build upon the existing NIDA CTN to support 3 – 4 additional Nodes that would enhance the Network’s capacity to nimbly respond to urgent public health needs and ultimately to reduce morbidity and mortality from opioid misuse and OUD. Successful Nodes will have core faculty with expertise in addiction medicine, large multi-site clinical trials, and bioinformatics; familiarity with state-level SUD treatment policies; and a demonstrated history of collaboration with health systems and/or research networks. Desirable features of additional Nodes include the following: 1) ability to engage patients in geographic hot spots of the opioid epidemic, 2) history of utilization of implementation science tools and constructs and capacity to conduct implementation research that would have significant direct public health impact, 3) ability to leverage advanced digital technology such as mobile health tools and electronic health record systems (EHR), and 4) ability to conduct research embedded in clinical care that utilizes pragmatic research designs, leverages existing clinical staff, and evaluates interventions or strategies that can be sustainably implemented in rural and other under-resourced yet highly impacted regions.
Ron Dobbins, M.B.A, Clinical Trials Program Specialist, Center for Clinical Trials Network
Posted June 13, 2018
Opioid addiction and opioid misuse consequences exist at the intersection of health and justice systems. Thus, the justice system represents a critical target in addressing the current opioid crisis. Illicit opioids, including fentanyl and heroin, accounted for more than 60% of opioid-related overdose deaths in 2016. More than 9 million people pass through the justice system each year and the average daily population of U.S. jails and prisons is 2.5 million. Most (70%) people who encounter the justice system have used drugs; 25% have used heroin—roughly 100 times the community-level rate of use. While medications for addiction treatment (MAT) increase connections to care and reduce mortality and recidivism, fewer than <1% of U.S. jails and prisons offer MAT. Recent data suggest that implementing MAT in jail and prison settings can dramatically decrease overdose deaths of justice-involved populations and even translate into substantial reduction in community-level mortality.
Collaboration between justice and public health systems is critical to an effective response to the opioid epidemic. Siloed approaches lead to fragmented, low quality care for patients, increased mortality, and increased costs to communities. A services cascade framework is a powerful and flexible tool that can help facilitate collaborations between justice systems and community-based organizations (Belenko et al., 2017). Flexible study designs are needed to systematically and rapidly evaluate the effects of existing and emergent innovations to enhance community capacity to effectively respond to the opioid crisis.
JCOIN will provide a nimble, coordinated infrastructure. Components and key activities that will be supported under JCOIN will include: rigorous multisite studies, national surveillance and survey activities, data infrastructure, training, rapid response trial mechanisms, and dissemination and implementation science. The overarching goal of JCOIN will be to facilitate effective justice-community partnerships that enhance outcomes for justice populations and the communities in which they reside and to rapidly translate these findings for broader dissemination.
Tisha Wiley, Ph.D., Assistant Director for Criminal Justice Research, Division of Epidemiology, Services, and Prevention Research
Responding to Opioid Use Disorders (OUD) in Tribal Communities in the Context of SAMHSA Tribal Funding
Posted May 15, 2018
American Indians and Alaska Natives (AI/AN) have been disproportionately affected by the opioid crisis, second to or equal to Whites in the rate of overdose deaths and diagnosis for OUD. AI/AN had the highest drug overdose death rates in 2015 and the largest percentage change increase in the number of deaths from 1995 to 2015. Despite this health burden, few studies of the prevention or treatment of OUD have been conducted with AI/AN.
Tribes and tribal organizations have both unique opportunities for and barriers to responding to the opioid epidemic. The status of tribes as sovereign nations uniquely positions them to use tribal policymaking in response to the opioid crisis. This provides an opportunity for research and practice partnerships to showcase how tribal responses, including those focused on prevention, treatment or multi-level, community wide responses, can address the risks for opioid use, improve treatment outcomes and reduce overdose deaths and addiction. Some unique barriers exist as well, particularly related to the implementation of medication assisted treatment (MAT), such as no published outcome studies of MAT nor studies indicating the availability of this treatment for AI/AN, the concern that using MAT is substituting one drug for another, the cultural incongruency of standard treatment approaches, distance to treatment, insufficient funding, and stigma. Many treatment programs do not reflect the AI/AN value for a holistic approach to recovery that includes bringing mental, emotional, physical and spiritual aspects of health into balance, nor do they incorporate traditional practices or other culturally appropriate strategies.
Recent funding to the Substance Abuse and Mental Health Services Administration (SAMHSA) addresses one barrier for AI/AN communities; insufficient funding for strategies to combat OUD. In their 2018 budget allocation, SAMHSA is required to provide $50,000,000 for Tribes and Tribal organization to respond to OUD, including prevention and treatment; an FOA is in development.
The goal of this FOA is to solicit applications from researchers partnering with AI/AN communities, tribes or tribal organizations to use community based participatory research approaches to develop and assess culturally appropriate interventions supported within the context of expanded SAMHSA funding. This research will help to identify the most efficacious strategies for preventing and/or treating OUD in tribal communities, where unique culture, structures for and access to health care, and beliefs about treatment all impact OUD outcomes. Specific to treatment, this research will help to identify and address barriers to appropriate treatment and hasten the availability of clinically appropriate MAT and other relevant strategies. Further, it will help to elucidate how cultural grounding or adaptation can improve treatment efficacy. Given that unique barriers to treatment for this population include distance, this research could test whether the use of long acting MAT (Sublocade, Vivitrol, Probuphine) helps in making MAT available to remote communities, helps reduce stigma, or otherwise improves treatment use and outcomes for AI/AN.
Community Resource: Post-Mortem Brain Resources for Exploring HIV Compartments in Individuals with Opioid Use Disorders
Posted May 15, 2018
Latent HIV infection can occur in a variety of cell types and tissues. The brain is one of these compartments, but the extent to which substance use impacts the establishment and maintenance of latent HIV infection is poorly understood. Post-mortem brains are needed to make valid comparisons for the effects that HIV has on the brain epigenome as well as determining how drugs affect HIV latent infections in the central nervous system. Thus, Control brains (HIV minus, with (100) Opioid+/HIV- and 100 Opioid +/HIV+ per year are proposed to be collected as part of this initiative. Emphasis will be placed on collecting post-mortem brains from infected and uninfected subjects who suffered from OUD.
The proposed research resource will help support research into:
- How do drugs of abuse affect the establishment and maintain latent HIV infection in different cell types and compartments of the central nervous system.
- How HIV infection together with drugs of abuse affects epigenetic changes such as methylation, chromatin modifications, eQTLs, and the 3D genome. The use of control tissue allows investigators to distinguish the effect of HIV infection from those produced by drugs of abuse.
Jonathan Pollock, Ph.D., Division of Neuroscience and Behavior
Posted February 6, 2018
In 2015, more than 2.6 million Americans were diagnosed with opioid use disorder (OUD) and 33,000 died of overdose involving one or more opioids, a death rate which has tripled since 2000. Not enough patients have access to the gold standard of treatment, medication assisted treatment (MAT) plus behavioral therapy, and thus, increasing negative consequences including relapse.
One possible solution to increase medication and therapy adherence is through contingency management, a practice where patients are given tangible rewards to reinforce positive behaviors such as abstinence. Studies conducted in both methadone and psychosocial treatment programs have demonstrated that incentive-based interventions are highly effective in increasing treatment retention and promoting abstinence from various drugs.
Despite its efficacy, CM studies are not widely disseminated. The primary reason for the hindered dissemination is due, in part, to cost and lack of clear regulatory and reimbursement strategies. However, as a result of the digital technology coming into fruition and the passage of the 21st Century Cures Act which clarified FDA’s regulation of medical software, this may change.
Two companies have recently received key FDA approval for breakthrough digital technologies. The first, received permission to market the first mobile medical application to help treat SUDs. The device delivers cognitive behavioral therapy to patients to teach the user skills that aid in the treatment of SUD and are intended to increase abstinence from substance abuse and increase retention in outpatient therapy programs. The second, a combination product, a drug with a digital ingestion tracking systems which records that the medication has been taken.
The approval of these technologies, coupled with the high cost of relapse, has created an opportunity for the development and commercialization of contingency management as a digital therapeutic which can be used to supplement current treatment or increase medication adherence.
To develop a digital therapeutic based on the principals of contingency management that acts as a combination product to increase medication adherence or supplements existing behavioral interventions to increase drug abstinence.
Will M. Aklin, Ph.D., Division of Therapeutics and Medical Consequences
Posted February 6, 2018
HIV-associated neurological disorders (HAND) persist in up to 50% of HIV-patients even when HIV replication is suppressed by cART. HIV does not infect neurons, but infects microglia and macrophages in the brain, causing HAND associated neuropathology. How microglia affect neurons and glia in human brains are not understood. Currently there are no effective approaches for live human brain studies or realistic HIV animal models for HIV neuropathology.
Recent technological advancements have allowed generating microglia and cerebral organoids from human iPSC lines. These microglia have been shown to be fully functional, secreting cytokines and phagocytosing neural debris, when introduced into cerebral organoids.
This initiative will support studies using human iPSC to generate cerebral organoids and microglia to study HIV neuropathology. This includes the following:
Establish iPSC lines from HIV-patients and HIV-free controls, and use these cells to generate cerebral organoids and microglial cells. Microglia can then be infected by HIV and introduced into the organoids.
Characterize and compare the morphology, neuronal composition, oligodendrocyte and astrocyte differentiation, synaptic density and other basic measures of neurodevelopment in HIV-latent, HIV-infected, and HIV-free organoids.
Study how HIV-infected microglia alter neuronal structure, physiology, and function in the brain.
Answer questions such as: How do substances of abuse impact these processes? Can genetic and genomic editing alleviate neuropathology in HAND?
Da-Yu Wu, Ph.D., Division of Neuroscience and Behavior
Responding to the Opiate Crisis through Scalable, Data-Driven Justice-Behavioral Health Partnerships
Posted February 6, 2018
Since 1990, NIDA has funded large initiatives focused on understanding substance use treatment in the criminal and juvenile justice systems (DATOS, CJ-DATS 1, CJ-DATS 2, JJ-TRIALS, STTR-Justice). NIDA’s current large-scale justice initiative, JJ-TRIALS, will end in 2018. These initiatives have each generated important insights into how to intervene to address substance use within justice settings. The CJ-DATS MAT protocol, for example, yielded a model for developing justice-behavioral health partnerships to connect individuals exiting secure settings to MAT. JJ-TRIALS focused on the juvenile justice system and provides a model for rigorous multi-site implementation science RCTs that offer practical, actionable insights into how to improve justice-behavioral health partnerships to reduce unmet needs among justice-involved youth. JJ-TRIALS adapted ideas from HIV services cascade, leading to the development of the behavioral health services cascade. This data-driven tool is used to facilitate interagency partnerships to ensure youth with substance use needs are referred and retained in appropriate services (Belenko et al., 2017). Importantly, this tool is flexible and can easily be further adapted to criminal justice and other settings where multiple systems must collaborate to meet the needs of patients.
This initiative will support a new cooperative research program that will result in exploratory and hypothesis-driven research projects that:
- Emphasize responding to the opioid crisis with comprehensive evidence-based services matched to patient needs. The overall goal is to facilitate justice-behavioral health partnerships that provide comprehensive evidence-based services to address opioid use in justice populations. These partnerships will enhance the capacity of the justice system to respond to the opioid crisis with comprehensive evidence-based services, including the full range of MAT as well as evidence-based behavioral interventions. This collaborative approach will help improve the capacity of systems to connect patients to the right service at the right time to reduce relapse, overdoses, and recidivism.
- Utilize an implementation science framework, with an emphasis on rigorous testing of scalable, practical implementation strategies. This initiative will build on the advances made by prior NIDA justice initiatives, in particular expanding the development of the behavioral health services cascade to provide a data-driven focus on interagency collaborations between justice systems and behavioral health providers using a data-driven decision making framework to drive organizational change goals (see Belenko et al., 2017). The target will be to identify and test implementation strategies that can be scaled and advance our understanding of how to speed the pipeline from science to service.
- Emphasize technology-facilitated data infrastructure and intervention tools. Recent technological innovations offer opportunities to enhance bidirectional data sharing, data-driven goal setting and decision making within organizations, and enhanced engagement with community-based justice populations. This initiative will require proposed studies to be designed to leverage existing and newly developed technology and health information platforms to facilitate and enhance the capacity of the justice system to partner with behavioral health systems. A recent NIDA-NIJ meeting identified several opportunities for technology to facilitate progress in these ways.
Tisha Wiley, Ph.D., Division of Epidemiology, Services, and Prevention Research
Posted February 6, 2018
The National Institute on Drug Abuse (NIDA) has an interest in reducing the impact of drug addiction on the health and well-being of the American people. At the current time, we are in a wave of mortalities based on drug-induced respiratory depression (RD). This disorder occurs when a high dose of an opioid or other sedating drug / combination, activates receptors in the brain stem, which serve to respiratory circuits. The effect is to weaken the respiratory drive to an extent that either the patient ceases to breathe, or the drive is insufficient to prevent aspiration of vomit into the lungs.
The current best pharmacological practice to counter drug-induced RD is to administer naloxone, an opioid receptor antagonist that occupies receptors, making them unavailable for opioids to activate. Until recently naloxone has proven to be an effective strategy, but today, inexpensive, high-potency opioids such as fentanyl and carfentanil are becoming commonplace in the illicit drug supply. The pharmacology and physiochemistry of fentanyl differs from morphine; it provides a very rapid onset of effect, and is both more potent and efficacious than morphine. Given that the end user of illicit opioids is frequently unaware of the exact composition of their drug purchase, these pharmacological differences are key drivers of the current wave of opioid overdoses and mortalities.
Naloxone is a competitive antagonist, it can only act to block vacant receptors and many synthetic opioids only slowly unbind from receptors. This means that to treat high potency opioid overdoses, naloxone must be provided at a high enough dose for a long period. Unfortunately, naloxone is eliminated rapidly from a patient’s circulation and so responders must remain observant and ready to repeatedly administer increasingly high doses in order to counter RD caused by synthetic opioids. In dependent opioid users, large doses of naloxone may unfortunately precipitate immediate withdrawal.
Given the assumption that economics will continue to drive the inclusion of (potentially increasingly) potent opioids in the illicit drug supply, NIDA wishes to facilitate the development of agents that can safely reverse RD without engaging opioid receptors. Pharmacologies have been demonstrated that can reverse opioid-induced RD by stimulating non-opioid sensitive components of the respiratory system. By facilitating the full exploitation and development of such agents, NIDA hopes to reduce morbidity and mortality associated opioid use, without regard to whether opioid receptors are occupied with potentially lethal concentrations of potent agonist.
To develop a lead compound and potential backup molecule (ideally from distinct structural classes) in a formulation that acts to reverse RD by mechanisms other than antagonizing the mu opioid receptor.
To demonstrate the efficacy of the lead compound in preclinical models of RD that include opioid-induced RD and / or RD induced by drugs or drug combinations that frequently cause life threatening RD in the real world. This can include alcohol, when in combination with other drugs such as benzodiazepines or opioids, or combinations of drugs that demonstrably cause significant risk of mortality in post-operative settings.
Project Activities and Expected Deliverables
The project may include medicinal chemistry to optimize the efficacy or other drug-like features of the lead compound, provided that a suitable assay system exists that both models real world situations adequately and provides sufficient through-put to allow for successful optimization.
The project may also include other studies that advance a molecule and at least one back up molecule with demonstrated efficacy, towards establishing the level of evidence of safety and efficacy required by FDA to allow clinical testing. Such studies might include preclinical efficacy and pharmacokinetic studies in a rodent and non-rodent species, manufacturing scale up chemistry, cGMP synthesis and formulation, toxicology and final formulation stability studies.
By the end of phase 1 sufficient data must exist to indicate that the medication can be administered via a route known to be safe and reliable in an unconscious individual.
The medication should reach efficacious concentrations at the site of action within a time period commensurate with the indication, i.e., to save the life of an RD patient discovered by a first responder shortly after RD has set in.
The persistence of the pharmacological action should exceed that of currently available alternatives, i.e., it should be able to reverse RD for more than four hours following a single administration.
The Phase I application must include:
- Go/no-go decision tree with quantitative, milestones
- Objective measures that demonstrate efficacy of the molecule against RD induced by several pharmacological mechanisms.
- Objective measures that demonstrate the mechanism of action (unless previously established) of pharmacological agent.
- Studies designed to address project-specific questions of feasibility.
- Detailed discussion of potential pitfalls, side effects and safety issues and how these concerns are to be mitigated.
Phase II Activities and Expected Deliverables
- Phase II involves execution and completion of studies on lead/backup molecule required to form a Drug Masterfile (DMF) sufficient to satisfy FDA IND requests for clinical testing.
- Development, submission and acceptance of the DMF by FDA CDER.
Aidan Hampson, Ph.D., Division of Therapeutics and Medical Consequences
Posted February 6, 2018
Antiretroviral treatment (ART) used prophylactically in the form of pre-exposure prophylaxis (PreP; e.g., emtricitabine and tenofovir disoproxil fumarate [Truvada®]) is recommended for populations at high risk for HIV acquisition,, including individuals who have injected drugs in the past 6 months and have shared needles or works or been in drug treatment in the past 6 months. The seminal trial to date on the efficacy of PreP among injecting populations is the Bangkok Tenofovir Study, in which there were 17 HIV infections among the 1,204 participants taking tenofovir, compared with 33 infections among the 1,207 participants taking placebo (49% reduction in risk of HIV acquisition among those receiving tenofovir). The sample was recruited from methadone clinics and no data were reported on drug use or injection behavior, and no drug testing was performed (Choopanya K. et al. 2013). Consequently, the actual efficacy of PreP for active injectors, adherent methadone users or even non-injectors who actively use opiates and other drugs is unknown.
NIDA has funded surprisingly little research on the several key question related to PreP use among substance using populations The primary goal of this RFA is to examine the role of PreP in substance use trajectories and or treatments, including:
- To what degree do substance use or HIV providers recommend or adopt PreP for substance using patients at risk for HIV (e.g., injection drug use)?
- To what degree does substance use affect access and adherence to PreP?
- How does drug use interact with PrEP efficacy, including injection as well as polydrug use with substances that independently affect immune function?
- Where does PreP fit within a comprehensive program for prevention of HIV acquisition?
This concept is squarely in line with high overarching HIV/AIDs priorities (NOT-15-137):
- Reducing Incidence of HIV/AIDS, including: developing and testing pre-exposure prophylaxis candidates and methods of delivery, especially those that mitigate adherence issues; and developing, testing, and implementing strategies to improve HIV testing and entry into prevention services.
- Next generation of HIV therapies with better safety and ease of use including: developing and testing HIV treatments that are less toxic, longer acting, have fewer side effects and complications, and easier to take and adhere to than current regimens. Additionally, implementation research to ensure initiation of treatment as soon as diagnosis has been made, retention and engagement in these services, and achievement and maintenance of optimal prevention and treatment responses.
Shoshana Y. Kahana, Ph.D., Health Scientist Administrator, Services Research Branch, Division of Epidemiology, Services and Prevention Research
Posted September 6, 2017
Psychosocial stress, defined as socioenvironmental demands that tax the adaptive capacity of the individual, is a major risk factor for opioid use disorders (OUDs). Psychosocial stress may impact OUD risk by altering cognitive and affective function and facilitating the development of affective disorders. Stressful environments have been associated with pronounced negative affect and affective disorders, and impairments in reasoning, memory, inhibitory and cognitive control. In addition to cognitive and affective outcomes, exposure to psychosocial stress has been shown to modulate pain perception and tolerance to opioid analgesics, which can also contribute to the potential for opioid abuse and addiction. For example, adverse childhood experiences such as verbal and sexual abuse, low family income, and early parental loss, have been associated with an increase in pain-related medical conditions during adulthood.
OUDs show high comorbidity with affective disorders such as major depression and anxiety. Further, opioid misuse rates among chronic pain patients are influenced by negative affect. Neurobiological changes in overlapping brain areas, circuits and neurochemistry have been implicated in chronic pain, depression, anxiety, and substance use disorders. Initial findings suggest that individuals with affective disorders exhibit blunted endogenous opioid function, which is associated with altered pain sensitivity and response to opioid medications. Furthermore, healthy individuals with lower endogenous opioid release are more likely to develop chronic pain and report more pain in laboratory assessments of pain, suggesting that natural variations in the endogenous opioid system produce individual differences in pain severity and processing. Collectively, these data suggest a complex multidimensional relationship between psychosocial stress, cognitive/affective processing, pain, and OUDs. However, important questions remain regarding the underlying mechanisms related to behavior, genetics, epigenetics, neural circuitry, and endogenous opioid function.
The goal of this initiative is to promote basic and clinical research directed at: (1) elucidating the neurobiological and behavioral mechanisms by which psychosocial stress alters pain sensitivity or cognitive/affective processes, biases opioid use, maintains opioid seeking and increases the risk of relapse; and (2) identifying the factors and the associated mechanisms of action underlying resilience or vulnerability to psychosocial stress-induced alterations in pain sensitivity or affective/cognitive functioning as it relates to OUD.
Posted February 15, 2017
Description: Given the current opioid use and overdose crisis in the country, the purpose of this Funding Opportunity Announcement is to support research that accelerates the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose. This project is part of the NIH initiative to establish a public-private partnership to address the opioid crisis via more effective and safe ways to prevent and treat opioid use disorders and overdose (https://www.nih.gov/opioid-crisis)
Application may include preclinical or clinical research studies that will have high impact and quickly yield the necessary results to advance closer to FDA approval medications that are safe and effective to prevent and treat OUDs and overdose.
The compounds to be evaluated can be small molecules or biologics. They can be tested in pre-clinical models and/or for the clinical manifestations of OUDs such as withdrawal, craving, relapse, or overdose. Applications may focus on the development of new chemical entities, new formulations of marketed medications available for other indications, or combinations of medications that hold promise for the treatment of OUDs and overdose.
Through this FOA, NIDA seeks to fast-track the discovery and development of medications to prevent and treat OUDs or opioid overdose and to advance them in the FDA's drug development approval pipeline.
Ivan Montoya, M.D., Division of Therapeutics and Medical Consequences