Improving Treatments for Opioid Misuse and Addiction
Approximately than 2 million Americans have opioid use disorder (OUD), and milions more misuse opioids, using them for durations, doses, or reasons other than those for which they were prescribed.5 This has resulted in an alarming increase in opioid addiction and overdose deaths.6 Most people with OUD do not receive appropriate treatment due to the limited number of effective therapies, and few options for managing withdrawal and craving — critical to support long-term recovery — exist. Preventive and therapeutic interventions aligned with patient and provider needs are necessary, as are effective implementation strategies for evidence-based approaches. In addition, better treatments and long-term evaluation are necessary for the thousands of infants born every year with NAS/NOWS.
A series of highly focused studies will expedite the development of therapies to treat OUD and reverse overdose. Clinical trials will test innovative ways to identify and treat newborns exposed to opioids and track their long-term development. Implementation studies will test the integration of promising prevention strategies and evidence-based treatment for OUD in multiple settings, including primary and emergency care, the criminal justice system, and other community settings, and in communities highly affected by the opioid crisis.
Expand Therapeutic Options for Opioid Addiction, Overdose Prevention, and Reversal
Expanded treatment options for OUD are needed to promote long-term recovery in more patients. Methadone, buprenorphine, and naltrexone are approved by the U.S. Food and Drug Administration (FDA) to treat OUD, but treatment uptake, response, and adherence are not optimal.7,8 Naltrexone is approved by the FDA to prevent opioid use relapse in people with no physical dependence on opioids, but initiation is difficult and adherence to treatment is low. Naloxone can effectively reverse opioid overdose, but because of its relatively short half-life compared to synthetic opioids, such as fentanyl and its analogues, multiple doses can be required to reverse respiratory arrest. Naloxone effectiveness also declines when opioids are combined with other drugs (e.g., alcohol, benzodiazepines). The NIH HEAL Initiative will accelerate the development of novel medications and devices to treat all aspects of the opioid addiction cycle, including progression to chronic use, withdrawal symptoms, craving, relapse, and overdose.
Area of Opportunity #1: New formulations of existing medications to improve treatment compliance, prevent relapse, and reduce risk of misuse: NIH will develop new treatment strategies for OUD, including longer-acting formulations of existing addiction treatment medications, such as buprenorphine and naltrexone, to promote adherence to treatment while preventing medication misuse.
Area of Opportunity #2: Stronger, longer-duration formulations to counteract opioid overdose: NIH will invest in the development of stronger, longer-acting formulations of opioid antagonists, including formulations of naloxone and novel compounds, to reverse overdose caused by opioids and combinations of drugs including opioids.
Area of Opportunity #3: Interventions against respiratory depression: NIH will develop new classes of compounds and devices to counter respiratory depression induced by opioids alone or in combination with other substances, such as agonists to the serotonin 1A receptor/5-HT 1A and AMPAkines.11
Area of Opportunity #4: Novel medications, immunotherapies, and devices to treat withdrawal, craving, progression, and relapse:
- Drug repurposing: New therapeutic approaches to treat OUD may result from repurposing medications already approved for other indications, such as lorcaserin, which has FDA approval for controlling appetite, for use in reducing opioid seeking;12 and evaluating medications already in use internationally but not in the United States.
- Development of novel immunotherapies: NIH will support coordinated studies to develop anti-opioid vaccines that induce high-affinity antibodies that bind target opioids to reduce their euphoric effects and protect against overdose without interfering with OUD treatments, overdose rescue drugs, physiological pain control, or alternate pharmacological approaches to pain management.13
- Reduce drug craving in people with OUD: To reduce drug craving in people with OUD, NIH will assess a novel therapeutic agent targeting the brain’s reward pathway. Studies will test the safety, efficacy, and underlying mechanisms of craving reduction as a strategy to prevent opioid misuse, dependence, and relapse and improve outcomes for people with OUD. Discovery and validation of novel biological targets, such as dopamine D3 receptor antagonists, will also seek to prevent compulsive drug taking.
Area of Opportunity #5: New medication targets for the treatment of OUD: In addition, NIH will pursue promising candidates for new addiction treatments through focused medication development efforts. Meritorious preclinical target identification and validation efforts will reveal new mechanisms of action for OUD treatment.
Enhance Treatments for Infants with NAS/NOWS
From 2004 to 2014, the incidence of NAS/NOWS increased fivefold among infants covered by Medicaid in 46 states. In communities severely affected by the opioid crisis, as many as 10 percent of newborns are affected by NOWS.14 Finding the best approaches to address the medical and social needs of these children — from the newborn period to adolescence — is critical for the future health of our country.
Area of Opportunity #1: Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW): NIH will expand ACT NOW,15 a series of pilot studies to assess NOWS prevalence and variation in current approaches to clinical management of infants with NOWS, to develop common protocols for conducting large-scale studies across the country. In this next phase, ACT NOW will conduct clinical trials to determine best clinical practices, including assessment of both drug-free treatment approaches and currently used medications. The goal of these trials is to find innovative ways to identify and treat newborns exposed to opioids, thus reducing the impact of NOWS and improving both short- and long-term developmental outcomes in children.
Area of Opportunity #2: Cognitive development of infants exposed to opioids: A large and growing body of evidence indicates that early exposure to substances, including prenatally or perinatally, is linked to greater risk for developing substance use disorders. To begin to disentangle the effects of early substance exposure from confounding factors, such as socioeconomic, environmental, and genetic influences, NIH will establish a large cohort of pregnant women from regions of the country significantly affected by the opioid crisis and follow them and their children for at least 10 years. Among the data to be collected are pregnancy/fetal measures; infant and early childhood structural and functional brain imaging; anthropometrics; medical history; family history; biospecimens; and social, emotional, and cognitive development. The cohort will also include socioeconomically and environmentally matched children who were not exposed to opioids. Understanding changes in brain and behavioral development resulting from early exposure to opioids will inform precision prevention for substance use disorders and mental illness.
Develop New or Improved Prevention and Treatment Strategies for Addiction
Area of Opportunity #1: Preventing at-risk adolescents from developing OUD as they transition into adulthood: Through the NIH HEAL Initiative, NIH will develop and test strategies to prevent opioid misuse and addiction in at-risk older adolescents and young adults (ages 16-30), a group at highest risk for opioid initiation, misuse, OUD, and overdose fatality. NIH will study this high-risk group in a variety of health care settings, such as primary care, emergency departments, urgent care clinics, infectious disease clinics, school-based and community college health centers, workplaces, and justice settings, building on successful research on models to prevent alcohol consumption among adolescents and young adults. This study aims to generate effective prevention strategies targeted to geographic areas most affected by the opioid crisis.
Area of Opportunity #2: Understanding sleep dysfunction in OUD and recovery: Sleep problems are linked with opioid addiction, contribute to the severity of opioid withdrawal, and factor into the efficacy of medication-based treatment for OUD. NIH will employ an array of genomic, molecular, pharmacological, and clinical approaches that are appropriate to elucidate sleep and circadian factors relevant to addiction and to determine how these factors influence one another. This research will open new avenues to improve therapeutic strategies, OUD prevention, and treatment approaches.
Area of Opportunity #3: Management of subsyndromal and low-severity OUD: OUD begins with opioid misuse, below the threshold OUD, or for which the use of existing medications for OUD is not indicated. This project will study subsyndromal OUD (i.e., opioid misuse that does not meet any criteria for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) OUD diagnosis) and/or low-severity OUD (OUD that meets only one or two DSM-5 diagnostic criteria). Historically, such low-severity opioid misuse, especially in the context of co-occurring pain and psychiatric disorders, has been poorly identified in clinical settings. The NIH HEAL Initiative will recruit individuals with subsyndromal and low-severity OUD in general medical settings, such as primary or integrated care settings, to define, identify, and intervene in the management of opioid misuse.
Area of Opportunity #4: Determining the optimal length of medication treatment for opioid addiction: Longer duration of medication treatment for opioid addiction is associated with better patient outcomes, and the risk of relapse greatly increases after medication is discontinued. However, there are no studies that have evaluated what the optimal length of time is for treatment to successfully promote long-term recovery. NIH will conduct a randomized controlled clinical trial of two FDA-approved medications to treat opioid addiction: methadone and buprenorphine. These studies will help define the optimal duration of medication-based treatment for OUD, taking into account various patient populations and treatment settings.
Area of Opportunity #5: Optimizing collaborative care for patients with OUD and common mental disorders: Collaborative care programs provide patients with treatment teams that include primary care providers, care managers, and behavioral health specialty consultants. Although collaborative care is effective for the treatment of mood and anxiety disorders, its effectiveness has not been demonstrated for OUD and other substance use disorders. NIH will test the adaptation, effectiveness, adoption, scalability, and sustainability of collaborative care for individuals with OUD and co-occurring mental health conditions using integrated treatment models in primary care settings. Patients with OUD and a mental health condition will be identified in primary care as well as following emergency care for nonfatal overdose and intentional self-harm. This study will demonstrate how collaborative care may (1) decrease opioid use, (2) sustain OUD recovery over time, (3) improve symptoms and functional impairments associated with mental health conditions, and (4) reduce risk for and death by accidental overdose or suicide.
Optimize Effective Treatment Strategies for Opioid Addiction
Despite the availability of multiple effective evidence-based treatments and programs, most Americans at risk for or with an OUD do not receive these services.16 At the same time, opioid overdose rates continue to increase.17 To better understand how the integration of promising and evidence-based strategies and treatments might decrease OUD, overdose events, and deaths, NIH will deploy a suite of implementation science efforts to test the integration of evidence-based interventions in an array of settings.
Area of Opportunity #1: Enhanced National Institute on Drug Abuse (NIDA) National Drug Abuse Treatment Clinical Trials Network (CTN) for opioid research: NIH will expand the size and scope of research conducted by the National Drug Abuse Treatment CTN to address emergent needs presented by the opioid crisis. The CTN is a cooperative of NIDA, academic researchers, and community providers to develop, validate, refine, and translate into practice new treatment options for patients with substance use disorders.18,19 By incorporating new research sites and investigators into existing research nodes and centers, the CTN will integrate new opioid-related research questions into studies currently underway, expedite new studies in general medical and other settings, and enhance clinical and research training opportunities.
Area of Opportunity #2: Opioid innovation in the criminal justice system: Improving the quality of OUD treatment within the justice system will be critical to address the opioid crisis.20 The NIDA Justice Community Opioid Intervention Network (JCOIN) will study quality care for opioid misuse and OUD in justice populations by facilitating partnerships between local and state justice systems and community-based treatment providers. JCOIN will include (1) a national survey of addiction treatment delivery services within the justice system; (2) studies on the effectiveness and adoption of new medications, prevention and treatment interventions, and technologies; and (3) novel uses of existing data sources. Together, these studies will generate real-world evidence to address the unique needs of individuals with OUD in justice settings.
Area of Opportunity #3: Behavioral research to improve medication-based treatment for OUD: To understand the effectiveness of combining behavioral interventions with medication-based treatment for OUD, NIH will study whether select behavioral interventions — such as mindfulness meditation, cognitive behavioral therapy, or multidisciplinary rehabilitation — improve adherence to medication-based treatment, improve medication-based treatment outcomes, and reduce relapse rates in individuals seeking treatment for OUD. NIH will work with the Substance Abuse and Mental Health Services Administration (SAMHSA) to carry out this research in tandem with SAMHSA State Targeted Response to the Opioid Crisis awards made to address the opioid crisis. This study will include large-scale effectiveness trials for behavioral interventions as part of medication-based treatment and integrate behavioral interventions into ongoing studies that focus on improving medication-based treatment access and delivery.
Area of Opportunity #4: The HEALing Communities Study: The HEALing Communities Study will test integration of prevention, overdose treatment, and medication-based treatment in select communities hard hit by the opioid crisis in a coordinated array of settings: primary care; emergency departments; specialty care, including prenatal care, infectious disease, and behavioral health; the criminal justice system; and other community settings. NIH will encourage collaboration with health care and justice systems, fire and police departments, and state and local governments in both rural and urban areas highly affected by the opioid crisis. Findings will establish best practices for integrating prevention and treatment strategies that can be replicated by communities nationwide.
Enhancing Pain Management
Opioid medications are prescribed for many of the 50 million Americans with chronic pain to manage their pain, yet there is limited evidence to suggest that long-term use of opioids is effective for patients with chronic pain.21 New, safer treatment options for pain management are needed to improve quality of life and reduce the number of people exposed to the risks of opioids. Toward this goal, NIH will take a multipronged approach to support research across the development spectrum. This encompasses efforts to understand the biological underpinnings of chronic pain; accelerate the discovery, preclinical development, and testing of non-addictive alternatives to opioids; and use multipronged approaches to understand and treat specific pain conditions, comparative effectiveness research, and tailored approaches to acute and chronic pain conditions, as well as pragmatic and implementation studies for the management of pain focused on patient outcomes and real-world results.
Understanding the Biological Underpinnings of Chronic Pain
Chronic pain is complex, diverse, and difficult to manage, and current treatments, such as opioids, are not effective for many individuals.22 Chronic pain often begins with an acute pain event. While acute pain usually goes away as an injury heals, in some cases the pain from an injury, surgery, or disease process persists long beyond healing of the initial event — sometimes for years or even a lifetime.23 Changes to the body and brain that occur during the development of chronic pain are poorly understood. Understanding the biopsychosocial mechanisms that drive these changes could provide a means to reduce chronic pain through better management of acute pain.
Area of Opportunity #1: The Acute to Chronic Pain Signatures Program: To understand the biopsychosocial characteristics of people who are susceptible to making the transition from acute to chronic pain, Acute to Chronic Pain Signatures will collect data from (1) patients who have acute pain associated with a surgical procedure and (2) patients who suffered from an acute musculoskeletal trauma. Neuroimaging, -omics, sensory testing, and psychosocial assessments collected for several months after the acute pain event will form a comprehensive data set to help predict which patients will recover and which patients will develop long-lasting chronic pain. The ultimate goal for this research is to develop a signature to predict who is at risk for and who is resilient to development of chronic pain and to guide precision acute pain management approaches to prevent the occurrence of lasting pain, thereby reducing reliance on opioids.
Accelerate the Discovery and Preclinical Development of Non-addictive Treatments for Pain
More effective medications for pain are needed, but previous analgesic development efforts have been hampered by poorly predictive animal models, changes in biopharmaceutical industry focus, and perceived regulatory and reimbursement concerns.24 Through a suite of targeted research efforts, NIH will accelerate the discovery and preclinical development of new medications and devices to treat pain.
Area of Opportunity #1: Discover and validate novel targets for safe and effective pain treatment: NIH will support multisite validation studies and multidisciplinary tools to reveal novel targets for the treatment of pain, encompassing all levels of the pain-processing pathway from a basic biology perspective. This research will increase opportunities to commercialize small molecules, natural products, biologics, and devices that engage targets for the treatment of pain.
Area of Opportunity #2: Engineering preclinical testing platforms to identify and profile non-addictive therapeutics for pain and addiction:
- Animal models for pain: NIH will support the development of animal models that more closely reflect a variety of human pain conditions to test potential non-addictive treatments (small molecules, biologics, natural products, or devices) for acute and chronic pain management. By reducing the upfront economic burden for preclinical screening, the program will incentivize the discovery and testing of non-addictive therapies and generate rigorous, high-quality data that can advance potential treatments in the clinical pipeline for acute pain and chronic pain conditions.
- Human cell-based screening platforms to accelerate development of novel drugs to treat pain, addiction, and overdose: NIH will (1) develop human-based screening platforms that more closely approximate human physiology of pain and addiction than currently available cellular and animal platforms, (2) use these platforms to identify pharmacological probes or leads for testing new therapies, and (3) accelerate studies of novel small-molecule and biologic drug candidates for testing in humans.
Area of Opportunity #3: Translating discoveries into effective devices for pain treatment: Foundational activities in the NIH Stimulating Peripheral Activity to Relieve Conditions (SPARC) and Brain Research through Advancing Innovative Neurotechnologies© (BRAIN) initiatives are rapidly expanding our understanding of the human neurological system; high-resolution maps of the anatomy and physiology of spinal and peripheral pathways offer insight on pathways of pain signaling. Leveraging these insights will enhance targeting and reduce the invasiveness of devices to bridge the translational pipeline from mechanism to therapy. By supporting target identification, late-stage translational therapeutic and diagnostic device development, verification and validation activities, and early clinical studies, NIH will advance device-based treatments for people without effective ways to manage their pain.
Advance New Non-addictive Treatments for Pain Through the Clinical Trial Pipeline
While there is a clear need for novel pharmacological options for the treatment of pain, perceived regulatory and business factors have caused a number of biopharmaceutical companies to deprioritize several promising pain treatment programs. These NIH research efforts, described below, to be carried out in collaboration with biopharmaceutical groups and device companies, are designed to incentivize and accelerate the development of new, non-addictive pain treatments. All activities in partnership with the biopharmaceutical groups will be supported fully with government funds, and the NIH will retain all decision-making authority.
Area of Opportunity #1: Discovery and validation of biomarkers and endpoints for pain: the NIH HEAL Initiative will support biomarker discovery and rigorous validation to accelerate high-quality therapeutic development and move clinical research toward Phase 2 trials and beyond. Promising biomarkers from retrospective analyses of existing biospecimens, small proof-of-concept studies, and larger prospective clinical studies will be selected and studied in conjunction with the research in the Early Phase Pain Investigation Network (EPPIC-Net) or other existing clinical trials. Successful development of biomarkers will help to stratify patient populations and predict responses to therapies being tested.
Area of Opportunity #2: Testing of novel assets in an early-phase pain clinical trial network: In partnership with biopharmaceutical companies, the FDA and the Foundation for the NIH (FNIH), NIH will collect and evaluate pharmacological assets contributed by academia and by biopharmaceutical and medical device companies for their potential use as non-addictive treatments for pain and addiction. These may be novel agents or assets deprioritized for reasons other than safety, and could be redeveloped or repurposed. Assets judged to be of high potential will be tested in EPPIC-Net or further developed through NIH preclinical development programs.
Trials through EPPIC-Net will also serve to validate specific biomarkers in a multisite setting and accommodate novel trial designs. Studies will focus on specific well-phenotyped pain conditions with a high unmet medical need. The network will include a clinical coordinating center and specialized clinical site hubs able to recruit participants with specific pain conditions as well as a data coordinating center that will serve EPPIC-Net, and meet needs for data and biosample sharing across the partnership and other NIH HEAL Initiative programs. Through its standing infrastructure, the network will reduce study start-up times, incentivize testing, and derisk the challenges of Phase 2 clinical trials to accelerate the approval of effective, non-addictive therapies for treating pain and addiction.
Area of Opportunity #3: NIH Back Pain Consortium (BACPAC): In conjunction with EPPIC-Net, NIH will conduct studies to better understand the mechanisms of common pain conditions, such as chronic low back pain; improve patient phenotyping; develop improved diagnostic and treatment tools; and identify, prioritize, and test mechanistically based therapies. Back pain is one of the most common pain conditions worldwide and is a major contributor to the prescription and use of opioids in America. The biological and psychosocial bases of chronic low back pain, however, are not well understood. The mechanisms that cause back pain are complex and are linked to structural, dynamic, cellular, and molecular abnormalities interacting in an environment influenced by mechanical, biological, and biopsychosocial factors that result in pain, decreased physical function, and emotional and social distress. Discoveries made through BACPAC will serve as the basis for predictive algorithms to design, test, and tailor novel non-addictive precision treatments and for development of therapies that provide an integrated, multimodal approach to manage chronic low back pain effectively. Ultimately, these studies aim to reduce the need for opioid use among millions of Americans.
Establish the Best Pain Management Strategies for Acute and Chronic Pain Conditions
Area of Opportunity #1: Pain Management Effectiveness Research Network (ERN) for Clinical Trials: Evidence for optimal pain management in many clinical situations is often insufficient. The NIH HEAL Initiative Pain Management ERN will provide infrastructure to conduct Phase 3 clinical trials designed to evaluate the effectiveness of pharmacologic and nonpharmacologic therapies for a broad array of acute and chronic pain conditions. The research supported through the Pain Management ERN will build evidence that strengthens current practice-based guidelines for management of a variety of pain conditions. Collectively, the findings will (1) strengthen and inform current guidelines for pharmacologic and nonpharmacologic treatments for pain, (2) manage acute and chronic pain in patients from diverse communities, (3) provide patients and practitioners with a suite of effective strategies to alleviate pain that will reduce reliance on opioids, and 4) improve the quality of life for patients and their families.
Area of Opportunity #2: Integrated approach to pain and opioid use in patients undergoing hemodialysis: To improve pain care and reduce opioid use in patient populations for which high amounts of opioids are typically prescribed for pain, such as patients undergoing hemodialysis, NIH will develop and test multimodal, non-opioid treatment approaches that are tailored to the individual patient. The studies will include evaluation of novel agents to relieve pain in conjunction with behavioral interventions, such as cognitive behavioral therapy, designed to align with a patient’s biopsychosocial characteristics. Analysis of comorbid illnesses, such as diabetes and mental health disorders, and social determinants of health, including socioeconomic status, social isolation, social support, and racial discrimination, along with information in electronic health records will identify risk factors for pain and opioid use in patients undergoing hemodialysis. Ultimately, the study will measure the effects of these interventions on pain severity, patient satisfaction with care, quality of life, hospitalization rate, and mortality.
Area of Opportunity #3: Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM): Through the initiative, NIH will support clinical research to integrate evidence-based interventions for pain into health care systems. Studies will be embedded in real-world settings to determine the effectiveness of multiple interventions across pain conditions. Methods and infrastructure for this research were developed through the NIH Health Care Systems Research Collaboratory initiative, which embeds pragmatic clinical research into health care systems. This approach accelerates dissemination and implementation of effective interventions that directly impact pain care for patients and provides evidence to inform best practices for pain management for clinicians, patients, and health care policy.