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National Advisory Council on Drug Abuse (NACDA) Approved Concepts

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.

Concept Index:

Renewal of the National Drug Abuse Treatment Clinical Trials Network (CTN)

Posted: May 16, 2019


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 technologies and scientific advancements.

The CTN currently is comprised of 13 Nodes, a data and statistical center and a clinical coordinating center. The CTN program is administered within NIDA through the Center for the Clinical Trials Network (CCTN). The award period for the 13 existing CTN Nodes ends May 31, 2020.

NIDA sees value in continuing to support the CTN research infrastructure to build on the broad portfolio of research previously conducted in the CTN and new CTN HEAL projects http://www.henanqingdian.com/drugs-abuse/opioids/nih-heal-initiative/clinical-trials-network-opioid-use-disorder-research-expansion-project. The network would support new Nodes as well as renewed support of existing Nodes. MPI collaborations across states to cover regions of the country are especially encouraged.


The proposed initiative seeks to continue to support CTN Nodes and NIDA’s clinical research network capacity to nimbly respond to urgent public health needs. This network of Nodes aims to support core faculty with extensive expertise in successfully leading multi-site clinical trials in SUD management and in bioinformatics; a demonstrated history of clinical or research collaboration with health systems and/or clinical research networks; and ability to conduct timely and tailored research with high impact to influence SUD treatment policies. Desirable features of participating Nodes include the following: 1) ability to engage diverse patients in areas highly impacted by substance use, 2) history of utilization of implementation science tools and constructs and capacity to conduct effectiveness and implementation research, 3) ability to leverage digital technologies and electronic platforms  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 general medical settings and specialty care settings.

Betty Tai, Ph.D., Center for the Clinical Trials Network

Grand Opportunity in Medications Development for Substance-Use Disorders

Posted: May 16, 2019


There are few medications approved by the FDA for the treatment Substance Use Disorders (SUDs) while the drug use problem keeps increasing. Therefore, the development of safe and effective medications for the treatment of SUDs is a public health priority. Medications development is expensive and there is little commitment from the pharmaceutical industry. There is a need to support large scale projects that can effectively accelerate the development of medications to treat SUDs with the goal of obtaining FDA approval. 


The goal of this FOA is to accelerate the development of safe and effective medications towards FDA approval. The project aims can range from the development of a new molecular entity to the expansion of an existing medication’s clinical indication(s). Each project should have a defined entry and exit point in the FDA’s medications development pathway. For this FOA, a significant commitment from NIDA is expected.

Ivan Montoya, MD., M.P.H., Division of Therapeutics and Medical Consequences (DTMC)

Strategic Alliances for Medications Development to Treat Substance Use Disorders

Posted: May 16, 2019


There are few medications approved by the FDA for the treatment of Substance Use Disorders (SUDs) while the drug use problem keeps increasing. Therefore, the development of safe and effective medications for the treatment of SUDs is a public health priority. Medications development is expensive and there is little commitment from the pharmaceutical industry. There is a need to support large scale projects that can effectively accelerate the development of medications to treat SUDs with the goal of obtaining FDA approval. Fostering collaborative ventures of NIDA with other entities such that each makes a significant commitment of resources to accelerate the development of safe and effective medications for SUDs towards FDA approval.


The goal is to support research that advances compounds towards FDA approval by leveraging NIDA funds with the strengths and resources of outside organizations such as for-profit and not-for-profit entities, academic institutions, pharmaceutical and biotechnology companies, private and public foundations, and small businesses. The project aims can range from the development of a new molecular entity to the expansion of an existing medication’s clinical indication(s). Each project should have a defined entry and exit point in the FDA’s medications development pathway

Ivan Montoya, MD., M.P.H., Division of Therapeutics and Medical Consequences (DTMC)

Step Up for OUD: Translational Stepladder Initiative

Posted: May 16, 2019


The lack of knowledge and understanding by academic researchers regarding how new technologies, including drugs, are brought to market and a lack of access to sufficient product development and commercialization expertise that are required to evaluate and to prepare the research discoveries for translation are among known barriers to effectively translating basic science discoveries from academia to patient benefit.  As a result, the outputs of publicly funded research are misaligned with requirements for privately financed further development, contributing to the Valley of Death creation. The proposed Initiative will nurture the validation and early development of pharmacological treatment approaches in the high priority opioid use disorder (OUD) space. To elevate the research projects to the levels of private sector expectations, NIDA will administer the Initiative as a cooperative agreement in a manner consistent with the business case development by providing (1) coordinated access to externally contracted expertise in areas required for early technology development, including scientific, regulatory, reimbursement, business, legal, and project management, and (2) research funding for the “critical path” studies specifically designed to reach the Value Inflection Point (VIP) (e.g. feasibility studies or proof-of-concept studies to accumulate, in rigorous and disciplined manner, enough promise to convince other parties to go to the next stage and enable the hand-off). NIDA team, comprised of experienced program officials and external consultants, will provide extensive assistance to the basic scientists in determining the VIP for each individual project with the goal to remove (business) risk at the lowest possible cost.


This Initiative strikes a balance between the NIDA commitment to fund basic science and to address urgent needs of patients with OUD. Novel and distinguishing attributes of the proposed Initiative include:

  • Focus on research conducted by the basic scientists, allowing basic scientists to contribute to translation but remain basic scientists;
  • Focus on a single indication, OUD, allowing efficient streamlining of the product development process and recruitment of exceptional external expertise in a highly targeted fashion;
  • Streamline product development processes allowing researchers to pursue not only target-based, but also novel phenotype -, network-, or brain circuit-based approaches;
  • Innovative grant making based on the most current managerial and innovation frameworks (e.g. Lean Product Development, Agile).

Elena Koustova, Ph.D., M.B.A. and Ramachandran Arudchandran, Ph.D., Office of Translational Initiatives and Program Innovations

Leveraging Big Data Science Approaches to Elucidate the Neurobiological Basis of Substance Use Disorder

Posted: February 15, 2019


The young field of big data science is providing computational tools, such as artificial intelligence and machine learning algorithms that can be used to mine data across levels of experimental analysis in innovative ways and extract new information to help elucidate the biological underpinning of substance use disorder. Additionally, combining large data sets from different sources can be used to answer research questions in a way that was not previously feasible. Computational approaches can be used to link changes in gene networks to neural systems and predict patterns of drug use and state changes that predispose to compulsive substance use or resilience to it. Drug addiction is a complex neuroadaptive process that begins with a molecular event that is amplified to cellular, circuit, and network changes that govern cognition and behavior, and changes in gene function produced by chronic drug administration may underlie the enduring behavior. Substantial data has been, and continues to be, generated by NIDA-funded studies regarding the effects of drugs of abuse at various levels of analysis, and the untapped power of data emerging from these studies lies in their mining, integration, and analysis.


This initiative will attract data and computational scientists to propose novel ways to integrate data from various levels to allow new types of analysis through big data science approaches. It is expected that with the development and application of novel computational, bioinformatics, statistical, and analytical approaches, previously inaccessible insights will reveal new aspects of addiction biology.  Some specific questions include:

  • How can neural data from the cellular level to circuits and behavior be integrated and mined using artificial intelligence/machine learning to help determine the pathways involved in drug addiction?
  • Are there novel data that can be integrated or novel ways of integrating existing data?
  • What predictions can be made about drug abuse, including treatment and prevention?

Roger Little, Ph.D. & Susan Wright, Ph.D. Division of Neuroscience and Behavior

The Rat Opioid Genome Project

Posted: February 15, 2019


The goal of the Rat Opioid Genome Project is to identify genetic variation underlying individual differences associated with vulnerability to the stages and sequela along the opioid use disorder (OUD) trajectory, ultimately resulting in addiction. Each of these vulnerabilities most likely has multiple causes, including genetic and environmental components. These studies will facilitate discovery of the genetic architecture (e.g. genes, gene networks and genetic pathways) underlying OUD.

A major challenge in preventing OUD is to identify the underlying genetic variation that contributes to various phenotypes across the OUD trajectory. Parsing out the genetic and environmental components associated with these stages requires an animal model. The rat provides a sound behavioral and genetically tractable model to uncover the genetic pathways that contribute to susceptibility or resilience to discrete stages along the OUD trajectory. This proposal capitalizes on two complementary rat resources: the Hybrid Rat Diversity Panel and outbred animal model systems. The Hybrid Rat Diversity Panel consists of 91 distinct inbred strains that display divergent phenotypes related to substance use disorders. Users can identify strains with divergent phenotypes and map the phenotypes. These genetically identical animals facilitate longitudinal and repeated studies within the same strains, as phenotype data from one study can be analyzed in subsequent experiments. Outbred animals mimic human studies and any one cohort contains the genetic diversity of the starting population. Outbred animal studies facilitate quantitative trait locus (QTL) discovery. These complementary approaches facilitate gene discovery, with the Hybrid Rat Diversity Panel providing a strong understanding of how genetic variation influences phenotypes and behaviors underlying OUD and the outbred animals fostering gene discovery.


This project will provide a foundation for identification of genetic variants associated with vulnerability to specific stages along the trajectory of OUD and build a strong basis for cross-species comparisons of the genes and gene networks associated with OUD. It is designed to test hypotheses generated by human genetic studies and identify new genes involved in OUD using rat models. It will provide molecular targets for future therapeutics and interventions, as well as help tease out the molecular endophenotypes associated at early stages of OUD that can stratify an individual’s risk for OUD following initial use of opioids. This stratification can be used to inform human studies and cluster individuals with OUD based on predisposing genetic factors. This initiative takes a systematic approach from phenotype/behavior to genes to identify causal variants underlying the different stages of OUD and lead to the development of new therapies to identify at-risk individuals to halt opioid use at different stages along the trajectory.

Potential Research Questions: What are the genetic components of various stages across the OUD trajectory (e.g. tolerance, dependence, addiction) or adverse effects (e.g. respiratory depression, hyperalgesia)?

  • Are there different genetic components associated with the different stages? Can they be used to stratify different risk at the end stages of disease? Do these different genetic underpinnings represent distinct genetic and neural networks?
  • Are there sex differences in these behaviors and phenotypes?
  • What genes do single cell and tissue transcriptome studies implicate? What role do other factors (e.g. chromatin, genetic background, Gene x Gene, Gene x Drug, Gene x Environment) play in OUD?

Amy Lossie, Ph.D. Division of Neuroscience and Behavior

Assessing Effects of Cannabinoids on HIV-associated Neuroinflammation

Posted: February 15, 2019


Acute cannabis administration is proposed to alleviate HIV-associated immune and neurological complications, although concerns remain about the aversive effects and impact of prolonged cannabis administration.  The potential beneficial actions of cannabis towards HIV-associated disease is based on positive observations of anti-oxidative, anti-excitotoxic, and anti-inflammatory properties in the study of models for several other neurodegenerative diseases.  However, existing data about the protective effect of cannabis is largely observational without causal evidence.  We have limited knowledge about dynamic changes along with the time course and pattern of administration, or with the status of the endocannabinoid (endoCB) system at treatment.  The therapeutic potential/benefit of cannabis on HIV pathogenesis has not been systematically investigated.  Questions remain about the integrity of the endoCB system during HIV pathogenesis or under substance use disorders to inform how the preconditions may impact the therapeutic potential of cannabis.  Further, a longitudinal design is necessary to determine the limits of cannabis for this treatment purpose. 


This initiative supports research that will elucidate the roles or limits of using cannabis to mitigate HIV associated neuroinflammation.  It will be carried out with preclinical and clinical neuroAIDS models, to understand the interrelationships among cannabis, biomarkers of endoCB and neuroinflammation, and chronic neuroimmune complications.

Yu (Woody) Lin, Ph.D. Division of Neuroscience and Behavior

Targeting Inflammasomes in Drug Abuse and HIV

Posted: February 15, 2019


Neuroinflammation triggered by brain trauma, neurodegenerative diseases or other neurotoxicant-induced central nervous system (CNS) disorders including human immunodeficiency virus type-1 (HIV-1) infection initiates CNS innate immune responses.  HIV-1 penetrates the blood brain barrier, infects macrophages and microglial cells, and promotes a cascade of inflammatory responses including the formation of inflammasomes.

Inflammasomes are a complex of high molecular weight proteins within the cytosol of stimulated cells that mediate the activation of inflammatory cascades. In response to insults, Nod-like receptors (NLRs) recruit adaptor proteins and caspase-1 to assemble inflammasomes and process the release of pro-inflammatory cytokines IL-1b, IL-18 and IL-33. The NLRP3 inflammasomes are the most well-characterized that comprises NLRP3, apoptosis-associated speck-like (ASC) adapter protein, and the downstream effector protease procasepase-1.

Recent evidence suggests that chronic drug exposure, i.e., cocaine, methamphetamine and morphine, can induce inflammasome activation primarily mediated by NLRP3 within microglia. Additionally, emerging data suggest that HIV-1 infection can also prime inflammasome activation. Drug abuse, especially in association with HIV-1 infection, induces reactive oxygen species (ROS) production, impairs blood brain barrier integrity, and promotes monocyte transmigration. These upstream events exert synergistic effects that prime oligomerization and activation of inflammasome and release of pro-inflammatory cytokine IL-1b. Persistent inflammatory signaling pathways involved inflammasome formation and activation may lead to progressive loss of the functional capacity of the immune system. This could contribute to the pathogenesis that underlies HIV-associated neurocognitive disorders (HAND).


The scientific objective of this research is to delineate the role of inflammasomes in neuropathology produced by chronic drug exposure and HIV infection. Understanding the involvement of inflammasome in the immune activation may help identify molecular markers and CNS immune cells associated with HIV-1 infection or disease progression among substance abuse populations, as well as identify novel therapies to target inflammasome activation or suppression to treat neuroinflammation and immune dysregulation aroused in these processes.

Anne Tsai, Ph.D. Division of Neuroscience and Behavior

Advancing the Study of Recovery Support Services for Those Treated with Medications for Opioid Use Disorder 

Posted: February 15, 2019


Numerous studies are examining how to improve access to effective treatment for individuals with opioid use disorder.  Few studies have rigorously examined recovery support services (RSS) that may aid stabilization and ongoing remission and recovery.  RSS include peer-based recovery support services, recovery community centers, education-based recovery support services, recovery housing, and clinical models of continuing care. These services have often been developed by individuals in recovery, suggesting needs that are insufficiently met elsewhere, and are disseminating rapidly. However, according to a recent expert panel meeting, systematic literature review, and review of federally-funded projects, substantial research gaps exist. States and other payers have begun to pay for these services to address the needs of those affected by the opioid crisis but need evidence to continue their investment.  At the same time, many of the available services are or are perceived to be unsupportive of individuals continuing on OUD medications.  Given that the recovery support services research field is relatively small, but the demand for these services is growing, now is an opportune time to rapidly strengthen the scientific base of research in this area.


To support activities that would lead to rapid, collaborative development and dissemination of scientific resources needed to develop meaningful, actionable research in this field.  Participants might include not only researchers, but other relevant stakeholders such as people in recovery, providers, payers, state personnel or others who would make use of the findings. Development of common, agreed upon scientific resources and methods and preliminary data that could be used to support R01-level research, are examples of the type of work that might be pursued under this initiative.  Absent a specific initiative, it is unlikely that these resources would be developed, missing an opportunity to advance methods and increase the efficiency of the research process when it is needed most. Because of the foundational yet timely nature of this work, participation from several other institutes and agencies with an interest in recovery will be pursued.

Sarah Q. Duffy, Ph.D. Division of Epidemiology, Services, and Prevention Research

Clinical Outcome Assessments for Clinical Trials of Substance Use Disorders as FDA-qualified Drug Development Tools

Posted: February 15, 2019


Development of novel Clinical Outcome Assessments (COAs) for Substance Use Disorders (SUDs), and most importantly for Opioid Use Disorder (OUD), is urgently needed to accelerate innovative clinical drug development and deal effectively with the Opioid Crisis. Existing COAs may not be fully reflective of what is truly important to patients from their point of view. The Opioid Crisis prompted a recent, April 2018, FDA-lead Patient Focused Drug Development (PFDD) OUD meeting where the regulators had an opportunity to hear directly from patients regarding their experiences, describe the main effects of OUD that are affecting their daily lives, and identify the most important symptoms that need to be effectively treated. Based on the outcome of this meeting new COAs will emerge, as well as a renewed focus on SUDs symptoms seen as key by the sufferers.

An expanded portfolio of COAs in addictions will be enriched with novel and/or additional improved clinical assessments. Furthermore, novel COAs will be especially significant if they go through the rigorous FDA Drug Development Tools (DDT) qualification process. The Center for Drug Evaluation and Research (CDER) reviews submitted data for a new DDT and qualifies it as such within specific Context of Use (COU). Qualified DDTs could be used as validated and reliable instruments for human laboratory early clinical trials and for phase 3 confirmatory studies with a high level of confidence.

A COA can be a Clinician-reported Outcome (ClinRO) that is based on a report from a trained healthcare professional and observation of patient’s health condition; or a Patient-Reported Outcome (PRO), where a report comes from a patient about the status of their health without additional interpretation by a clinician or anyone else; or a Performance Outcome (PerfO), where a patient is administered a standardized task and their performance is evaluated by a trained individual, or is independently completed; or an Observer-Reported Outcome (ObsRO) that is based on a report of observable signs, events or behaviors, related to a patients’ health condition by someone other than a patient or a healthcare profession (e.g., a family member).

A qualified COA should be: a) a measure that produces a score; b) a reliable assessment for the targeted construct; c) include defined methods and instructions for administration and well-documented methods for scoring, analysis and interpretation of the results in the targeted patient population; d) include a standard format for data collection. A COA is expected to be used across early and late drug development studies and related research.


This funding opportunity will serve to support the development of novel COAs and the optimization of existing COAs, including: psychometric scales, tasks and/or measures for any of SUDs, and/or as a measure/task for an RDoC construct that reflects functional aspects of behavioral, cognitive and affective processes of addiction. This announcement encourages submissions that will plan for and result in novel or improved psychometric scales, tasks and measures that demonstrate good validity, robust measurement properties and could be qualified as DDTs for a defined COU.

Tanya Ramey, M.D., Ph.D. Division of Therapeutics and Medical Consequences  

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

Respiratory Stimulants to Reverse Drug-Induced Respiratory Depression (RD)

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

Identifying Neural Mechanisms Linking Psychosocial Stress to Pain and Opioid Use Disorder

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.

Vani Pariyadath, Ph.D. and Shelley Su, Ph.D., Division of Neuroscience and Behavior

This page was last updated May 2019