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.
- Preventing Opioid Use Disorder in Older Adolescents and Young Adults (ages 16–30)*
- The Trans-NIH baby Brain Cognitive Development (bBCD) Study*
- Renewal of the Adolescent Brain Cognitive Development (ABCD) Study*
- 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*
- The Justice & Community Opioid Innovation Network (JCOIN)*
- Community Resource: Post-Mortem Brain Resources for Exploring HIV Compartments in Individuals with Opioid Use Disorders
- 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
An estimated 11.4 million people misused opioids in 2017, of which 11.1 million misused prescription opioid analgesics. Opioid drugs, including opioid analgesics, heroin and illicit synthetics, accounted for more than 60% of overdoses in 2016. There is need to develop preventive strategies that can decrease the incidence and prevalence of opioid misuse and Opioid Use Disorder (OUD), particularly in at-risk populations.
Currently, evidence-based interventions exist to prevent substance use broadly, that predominantly target children and adolescents. However, there is a gap in the evidence for interventions and strategies to prevent non-medical use of opioids and OUD in the transition from adolescence to young adulthood.
The goal of this project is to develop, adapt and test interventions and strategies to prevent initiation of opioid misuse and development OUD in at-risk older adolescents and young adults (ages 16-30). Given the target population of older adolescents and young adults, research will likely take place in health care settings, justice settings and other systems and settings opportune for accessing and engaging at-risk older adolescents and young adults. This project aims to support research to develop strategies for identification, reach and engagement of at-risk older adolescents and young adults; development, adaptation and testing of interventions and strategies to prevent initiation and misuse of opioids and OUD; development and testing of strategies to facilitate implementation and sustainability of prevention interventions and strategies in health care, justice and other systems and settings opportune for engaging and providing interventions or services to at-risk older adolescents and young adults; and, conduct economic evaluations to quantify programmatic costs and cost-effectiveness of interventions and strategies developed and tested.
The ultimate goal of this project is to develop efficacious and effective interventions and strategies to prevent opioid misuse and OUD in older adolescents and young adults that will be adopted in health care systems, justice systems and other systems and settings.
Jacqueline Lloyd, PhD, Division of Epidemiology, Services and Prevention Research
Posted: September 26, 2018
There has been a dramatic increase in the number of babies who have been prenatally exposed to opioids due to the opioid crisis. Between 2004 and 2014, the number of infants born with neonatal opioid withdrawal syndrome (NOWS; also known as neonatal abstinence syndrome [NAS]) increased 433% from 1.5 to 8.0 per 1000 hospital births which translates into one neonate born with NOWS every 15 minutes. As this crisis continues to escalate, these numbers will also increase, and we do not know what the long-term implications of early exposure to opioids (or to medications used to treat opioid use disorder) will be. In addition, other drugs continue to be used during pregnancy and afterwards when many women are breastfeeding. The National Survey on Drug Use and Health indicates that in 2016, 6.3% of pregnant women used an illicit drug (Center for Behavioral Health Statistics and Quality, 2017), and many use more than one drug. A large and growing body of evidence indicates that early exposure to substances, including pre- or perinatally, is linked to greater risk for developing substance use disorders. Moreover, prenatal exposure is also associated with other behavioral problems, including ADHD, conduct disorder, anxiety, etc. However, a causal link is difficult to establish due to confounding factors such as socioeconomic, environmental, and genetic influences.
The goal of this project is to understand the long-term impacts of pre- and perinatal drug and adverse environmental (e.g., parental neglect, physical abuse) exposures on brain development and social/behavioral/academic achievement and how these in turn impact risk for substance use and mental illness. We propose to establish a large cohort (e.g., 7,500) of pregnant women from regions of the country significantly impacted by the opioid crisis and follow them and their newborns through childhood. The cohort will also include non-exposed children, which will establish normative brain and behavioral development trajectories for socioeconomically and environmentally matched children, to which altered trajectories can be compared. This prospective approach will allow us to investigate prodromal changes in brain and behavioral development resulting from early exposure to opioids, other substances, and associated adverse conditions that might predict emergence of substance use disorders and other mental illness.
Key research objectives include, but are not limited to:
- Understanding variability in individual developmental trajectories (e.g., brain, cognitive, emotional, social, academic) from birth through childhood.
- Understanding the impact of pre- and postnatal exposure to opioids, opioid treatment medications, cannabis, alcohol, tobacco, other prescription or illicit substances (alone or in combination) on developmental trajectories.
- Investigating the role of sex, genetic, epigenetic, social and other environmental factors on risk/resilience related to structural and functional brain development, social/behavioral/academic achievement, and future substance use and mental disorders.
Gaya J. Dowling, Ph.D., Director of the Adolescent Brain Cognitive Development (ABCD) Project
Posted: September 26, 2018
The ABCD study (ABCDStudy.org) is the largest long-term study of brain development and child health in the United States. It is structured as a cooperative agreement involving multiple NIH Institutes, 21 recruitment sites, a coordinating center, and a data analysis and imaging center. The consortium has been recruiting approximately 11,900 children ages 9-10, with plans to follow them through adolescence into early adulthood. A common protocol is used at all sites, involving biological, social, behavioral and neuroimaging measures. The primary goal is to create a diverse and well characterized cohort to understand how experiences in childhood interact with each other and a child’s changing biology to affect brain development and social, behavioral, mental and physical health outcomes. All data (with PII removed) will be shared widely with the research community through the NIMH Data Archive.
This initiative would renew the ABCD Consortium so that the cohort of children in this nationwide sample can be followed into young adulthood. The study was designed to address the following overarching research objectives, which are inherently interdependent and mutually informative:
- Describe individual developmental trajectories (e.g., brain, cognitive, emotional, academic), and the factors that can affect them.
- Develop national standards of healthy brain development.
- Investigate the roles and interaction of genes and the environment on development.
- Study how physical activity, sleep, screen time, sports injuries, and other experiences affect brain development.
- Examine the factors that influence the onset, course, and severity of mental illnesses.
- Understand the relationship between mental health and substance use.
- Study how use of different substances (caffeine, nicotine, alcohol, marijuana) affects developmental outcomes, and vice versa.
This initiative is supported by the Collaborative Research on Addiction at NIH (NIDA, NIAAA, NCI) and the following NIH Institutes and Centers (ICs), NICHD, NIMHD, NINDS, NHLBI, ORWH, OBSSR, and NCI on this initiative.
Bethany Deeds, Ph.D., Deputy Director of the Division of Epidemiology, Services, and Prevention Research
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
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
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
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