HEAL Initiative Research Plan

Introduction

The public health crisis of opioid misuse and addiction in America is rapidly evolving. More than 42,000 Americans died of opioid overdose in 2016,1 and over 2 million Americans live with addiction to opioids. Moreover, more than 25 million Americans live with daily chronic pain2, and lack effective and safe non-opioid options for pain management.3 These staggering numbers are likely underestimates, and still fail to capture the full extent of the damage of the opioid crisis, which reaches across every domain of family and community life —from lost productivity and economic opportunity, to intergenerational and childhood trauma, to extreme strain on community resources, including first responders, emergency rooms, hospitals, and treatment centers. With the support of the President and the U.S. Department of Health and Human Services (HHS), the National Institutes of Health (NIH) launched HEAL, Helping to End Addiction Long-term, to provide scientific solutions to the national opioid crisis and offer new hope for individuals, families, and communities affected by this devastating crisis.

“With our partners, the NIH will take an ‘all hands on deck’ approach to developing and delivering the scientific tools that will help end this crisis and prevent it from reemerging in the future.”

Drs. Nora Volkow and Francis Collins, New England Journal of Medicine, 2017

NIH has identified a set of research priorities reflecting urgent unmet needs across the lifespan, areas of promising scientific opportunity, and concrete strategies capable of providing rapid and durable solutions to the opioid crisis:

Improve Treatments for Opioid Misuse and Addiction:

  • Expand therapeutic options for opioid addiction, overdose prevention and reversal
  • Enhance treatments for infants born with Neonatal Abstinence Syndrome (NAS)/Neonatal opioid withdrawal syndrome (NOWs)
  • Optimize effective treatment strategies for opioid addiction

Enhance Pain Management:

  • Understand the biological underpinnings of chronic pain
  • Accelerate the discovery and pre-clinical development of non-addictive pain treatments
  • Advance new non-addictive pain treatments through the clinical pipeline

Thanks to a generous appropriation of $500 million in the Fiscal Year 2018 Consolidated Appropriations Act, NIH has the resources needed to jumpstart an ambitious and targeted research plan focused on tackling unmet needs of those with opioid addiction and chronic pain. The Act provides that for both the National Institute on Drug Abuse (NIDA) and the National Institute of Neurological Disorders and Stroke (NINDS).

Language from the FY 2018 Consolidated Appropriations Act: “$250,000,000 [for each Institute] shall be available until September 30, 2019 for research related to opioid addiction, development of opioid alternatives, pain management, and addiction treatment.” “The NIH Director may transfer funds specifically appropriated for opioid addiction, opioid alternatives, pain management, and addiction treatment to other Institutes and Centers of the NIH.”

Design Progress

Recognizing that the opioid crisis touches us all, NIH engaged in a yearlong consultation with patients, advocates, academic experts, private sector leaders, and federal partners to identify the greatest needs and areas of opportunity. NIH deliberations were also informed by existing efforts, including recommendations from the President’s Commission on Combating Drug Addiction and the Opioid Crisis the National Pain Strategy and the Federal Pain Research Strategy. Opportunities identified through these consultations ultimately serve as the foundation for the major research priorities outlined for the HEAL Initiative. Following stakeholder consultations, leadership across the NIH —spanning discipline and disease areas — identified promising research projects for HEAL that aligned with the identified research priorities. The HEAL research plan for FY2018 is described below. Importantly, these new and expanded efforts will augment ongoing NIH investments in pain and opioid addiction research and provide a framework for future strategic research investments.

Research Opportunities

Improve Treatments for Opioid Misuse and Addiction

More than 2 million Americans have an opioid use disorder (OUD), and millions more misuse opioids, using them for durations, in amounts, or for reasons other than prescribed.4 This has resulted in an alarming increase in opioid addiction and overdose deaths.5 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, which is critical to support long-term recovery. Preventative 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 high-impact studies will expedite the development of therapies to treat OUD and prevent and reverse overdose. Focused clinical trials will test innovative ways to identify and treat newborns exposed to opioids. Implementation studies will test the integration of promising prevention strategies and evidence-based treatment for OUD into multiple settings, including primary and emergency care, the criminal justice system, and other community systems and settings, and in the context of demonstration projects 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.6,7Naltrexone is approved by the FDA to prevent opioid use relapse in people with no physical dependence on opioids, but initiation is difficult and, therefore, adherence to treatment is low.8 Naloxone can effectively reverse opioid overdose, but because of its relatively short half-life compared to synthetic opioids (fentanyl and its analogues), multiple doses can be required to reverse respiratory arrest, and its effectiveness declines when opioids are combined with other drugs (alcohol, benzodiazepines).9 HEAL 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, such as creating 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 longer-lasting naloxone formulations 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 invest in research to 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).10

Area of Opportunity #4: Novel medications, immunotherapies, and devices to treat withdrawal, craving, progression, and relapse:

a) Focused OUD medications development: New therapeutic approaches to treat OUD may result from repurposing already-approved medications such as lorcaserin, FDA-approved for controlling appetite, to reduce opioid seeking;11 evaluating medications already in use internationally but not in the United States; and discovery and validation of novel biological targets such as dopamine D3 receptor antagonists to prevent compulsive drug taking).12

b) Development of novel immunotherapies for OUD: A vaccine to induce antibody-mediated opioid neutralization would provide an important safety net for patients in recovery from OUD. Antibodies to opioids in the bloodstream could prevent opioids from entering the brain, thereby preventing both euphoria and dangerous respiratory-depression.13 A coordinated, multi-disciplinary consortium will pair investigators with expertise in opioid metabolism, biological transport, and mechanisms of action with vaccine development programs and resources. NIH will also accelerate the progress of ongoing efforts to develop vaccines directed at heroin and other opioids.

c) Reduce drug craving and harm in people with OUD: To reduce drug craving in people with OUD, NIH will assess novel therapeutic agents targeting the brain 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 the morbidity and mortality of people with OUD.

Area of Opportunity #5: New medication targets for the treatment of OUD: NIH will pursue promising candidates for new addiction treatments in addition through focused medication development efforts. Meritorious preclinical target identification and validation efforts will reveal new mechanisms of action for OUD treatments.

Enhance Treatments for Infants with Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome

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% 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, and develop common protocols for conducting large-scale studies across the country, particularly in areas hardest hit by the opioid epidemic. In this next phase, ACT NOW will conduct clinical trials to determine best clinical practices, including assessment of 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.

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 evidence-based prevention and treatment 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 NIDA 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 venture 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 The CTN has already generated important findings on the effectiveness and safety of medication treatments for OUD, the utility of behavioral interventions for OUD management, and the use of medication-assisted treatment (MAT).19 By incorporating new research sites and investigators into existing research nodes and centers, the CTN will incorporate OUD-related research questions into studies currently underway, expedite new studies of OUD treatment in general medical and other settings, and enhance clinical and research training opportunities.

Area of Opportunity #2: Justice Community Opioid Innovation Network (JCOIN)

Improving the quality of OUD treatment within the justice system will be critical to address the opioid crisis.20 Through the NIDA JCOIN, NIH will establish a network of research investigators to rapidly conduct studies on quality care for opioid misuse and OUD in justice populations by facilitating partnerships between local and state justice systems and community-based treatment providers. Specifically, this will include (1) implementing a national survey of addiction treatment delivery services within the justice system; (2) conducting studies on the effectiveness and adoption of new medications, prevention and treatment interventions, and technologies in justice system settings; and (3) leveraging existing data sources and developing innovative research methods to address the opioid crisis.

Area of Opportunity #3: HEALing Communities Study

The HEALing Communities Study will support a multi-site, national research effort to develop approaches for the implementation of effective interventions for opioid misuse, OUD, and opioid overdose. The study, still in development, will test integration of prevention, overdose treatment, and MAT 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. Awards will be competitive, and NIH will encourage applications from researchers with linkages to healthcare and justice systems, fire and police departments, and state and local governments in both rural and urban areas highly affected by the opioid crisis. Success of implementation strategies will be measured along sequential stages, including prevention, screening and detection of opioid misuse and OUD, linkage to care, medication initiation, and long-term treatment retention and abstinence. This study will be developed in close collaboration with the Substance Abuse and Mental Health Services Administration and other federal partners to avoid duplication and leverage complementary ongoing efforts. Findings will establish best practices for integrating evidence-based strategies in highly-affected communities that can be replicated nationwide.

Enhance Pain Management

Many of the 25 million Americans with daily chronic pain are prescribed opioid medications to manage their pain, yet there is little evidence to suggest that long-term use of opioids is effective for patients with chronic pain.21 New treatment options for pain are needed to reduce the number of people exposed to the risks of opioids. Toward this goal, NIH will support research to understand the biological underpinnings of chronic pain, and in collaboration with private sector partners, develop a data sharing collaborative, identify new biomarkers for pain, and create a clinical trials network for testing new pain therapies.

Understand the Biological Underpinnings of Chronic Pain

Chronic pain is complex and difficult to manage. 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. The processes that drive these changes could provide a means to prevent the transition through better management of acute pain. Understanding the biological mechanisms underlying the transition from acute to chronic pain are necessary to effectively manage and prevent its occurrence.

Area of Opportunity #1: The Acute to Chronic Pain Signatures Program: To understand the biological characteristics of people who are susceptible to transition from acute to chronic pain, Acute to Chronic Pain Signatures will collect data from: (1) surgical 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 predict which people might be at risk for developing 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 Pre-Clinical Development of Non-Addictive Treatments for Pain

Previous drug development efforts have been hampered by overreliance on 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 medication and device treatments for pain.

Area of Opportunity #1: Discover and validate novel targets for safe and effective pain treatment: NIH will support discovery projects to reveal novel targets for small molecules, biologics, natural products, and devices for the treatment of pain. These targets will encompass all levels of the pain processing pathway from a basic biology perspective. Multidisciplinary tools and multi-site validation will validate pain targets. This research will increase opportunities to commercialize small molecules, biologics, and neuromodulation devices that engage targets for the treatment of pain.

Area of Opportunity #2: Engineer preclinical testing platforms to identify and profile non-addictive therapeutics for pain and addiction

a) Animal models for pain — NIH will support the development of animal models that more closely mimic a variety of human pain conditions to test potential non-addictive treatments (small molecules, biologics, natural products, or devices) for acute and chronic pain. By reducing the upfront economic burden for preclinical screening, the program will incentivize the discovery of non-addicting therapies, and generate rigorous, high quality data within a pipeline of novel non-opioid and non-addictive therapies. These potential therapies can be further developed and tested for the treatment of acute and chronic pain syndromes.

b) Human cell-based screening platforms and 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.

Advance New Non-Addictive Treatments for Pain through the Clinical Pipeline

Public-Private Partnerships:

While there is a clear need for novel pharmacological options for the treatment of pain, perceived regulatory and business factors have caused biopharmaceutical companies to deprioritize several promising pain treatment programs. NIH will initiate a series of research efforts, to be carried out in collaboration with biopharmaceutical groups to incentivize and accelerate the development of new non-addictive pain medications. All partnership activities will be supported fully with government funds, and the NIH will retain all decision-making authority.

Area of Opportunity #1: Partnership: Data and asset sharing

In partnership with biopharmaceutical companies, FDA, and the Foundation for the NIH (FNIH), NIH will collect and evaluate pharmacological assets contributed by academia, biopharmaceutical, and device companies for their potential as non-addictive treatment of 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 further developed and tested in NIH preclinical development programs and Clinical Trials Network for pain (please see below). NIH also will work with private-sector partners to develop a program for sharing relevant clinical, preclinical, and pharmacokinetic data to share knowledge about the reasons for success or failure of past pain therapy development programs.

Area of Opportunity #2: Partnership: biomarkers

In collaboration with industry experts, NIH will support biomarker discovery and rigorous validation to accelerate high-quality neurotherapeutic and pain clinical research toward Phase II 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 planned clinical trials network (CTN) for pain. Successful development of biomarkers will help define patient populations and responses to therapies being tested.

Area of Opportunity #3: Partnership: clinical trial network

The clinical trial network will focus primarily on Phase II trials with assets from companies through partnerships established as part of HEAL, but will be open to viable assets from academia and other sources. The network also will validate specific biomarkers in a multi-site setting and accommodate novel trial designs, and will focus on specific well-phenotyped pain conditions with a high unmet medical need. Organized in a “hub and spoke” model, the network design will promote effective training and consistency among clinical sites and streamlined selection and approval of protocols. The network will include a clinical coordinating center, data coordinating center, and hubs identified as “centers of excellence” able to recruit participants with specific pain conditions. Through its standing infrastructure, the clinical trial network will reduce start-up times, incentivize testing, and de-risk the challenges of Phase II clinical trials to accelerate the approval of effective, non-addictive therapies for treating pain.

Proposed Fiscal Year 2018 Budget for HEAL

Improve Treatments for Opioid Misuse and Addiction FY18 in M (tentative)
Focused Medications Development to Treat OUD and Prevent/Reverse Overdose 70.25
Development of Novel Immunotherapies for OUD 5
Reduction of Drug Craving and Harm in People with OUD 1
Advancing Clinical Trials for Neonatal Opioid Withdrawal (ACT NOW) 10
Enhanced NIDA Clinical Trials Network for Opioid Research 29
Justice Community Opioid Innovation Network 5.75
HEALing Communities Study** 96.25
Enhance Pain Management  
Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment 20
Human Cell-Based Screening Models to Identify and Profile Non-Addictive Therapeutics for Pain 20.1
Preclinical Animal Models to Identify and Profile Non-Addictive Therapeutics for Pain 2.95
Data and Asset Sharing for New Pain Therapies 2.1
Biomarkers for New Pain Therapies 1.2
Clinical Trials Network for New Pain Therapies 1.8
Consortia Management 0.15
Supplements 10
TOTAL ‘18 265.55
Carryover 234.45
TOTAL 500

*Subject to change
**Still under development

Future Directions and Integrated Efforts

The current plan reflects an initial investment to jumpstart the FY 2018 plans for HEAL. Further investments, both for remaining FY 2018 funds and for anticipated FY 2019 investments, are currently in an active planning stage. Additional resources will be directed toward gaps in current plans, including prevention research, precision medicine for pain and addiction, and non-pharmacological and integrated models of pain management.

Collaborations and Governance

A trans-NIH initiative representing an “all hands on deck” effort, HEAL will forge collaborations between research programs across NIH, HHS, and with the private sector. The NIH Pain Consortium, which includes 25 NIH Institutes, Centers, and Offices, will coordinate HEAL efforts to develop safe, non-addictive pain medications and other strategies for pain management. In addition, specific HEAL projects will maintain standing oversight structures to promote effective collaborations:

  • Partnership Consortia: To ensure a steady and strong communication process between the public and private sector groups in a HEAL partnership, NIH plans to establish a consortium of NIH, FDA, and academic leaders to provide input to NIH on the overall progress of the partnership. All funding decisions will be made based on objective review of data and assets by NIH Institute Directors in the relevant area of research, with guidance from the appropriate NIH Institute Advisory Councils.
  • HEALing Communities: NIH will partner with the Substance Abuse and Mental Health Services Administration (SAMHSA) Centers for Disease Control and Prevention (CDC), Health Resources and Services Administration (HRSA), Agency for Healthcare Research and Quality (AHRQ), FDA, Centers for Medicare & Medicaid Services (CMS), and Department of Justice (DOJ), under the leadership of the Assistant Secretary for Health, to execute the initiative through the creation of an interagency coordinating committee. In addition, a steering committee of grantee institutions and federal partners will be created to ensure rapid and efficient progress of the initiative toward its goals.

Deliverables and Timeline

In the short term (within 3-5 years), HEAL research investments are expected to deliver:

  • Implementation strategies demonstrated to significantly increase initiation of MAT and retention in treatment beyond 6 months, and decrease rates of opioid addiction and overdose death.
  • Biological signatures to predict which patients are at risk for developing chronic pain, guiding precision medicine approaches to prevent chronic pain and thereby reducing reliance on opioids.
  • A comprehensive data set for the research community to reveal factors that predict transition or resilience to chronic pain.
  • A clinical trials network poised for the rapid testing of new pain therapies.
  • New evidence-based approaches to improving care for infants with NOWs.

In the longer-term (over 5 years), HEAL will deliver:

Pharmaceutical programs leading to 15 Investigational New Drugs (INDs), with the goal of 5 New Drug Applications (NDAs) submitted to the FDA for:

  • Overdose reversal agents.
  • More flexible and new medications for the treatment of OUD.
  • New interventions against respiratory depression to stop overdose death.
  • Novel medications to treat withdrawal, craving, and relapse.
  • Increased options for small molecules, biologics, and neuromodulation devices that engage targets for the treatment of pain.
  • Rigorous, high quality data and pain models to support a pipeline of novel non-opioid and non-addictive therapies that can be further developed and tested for the treatment of acute and chronic pain syndromes.

References

[1] Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999–2016. NCHS Data Brief, no 294. Hyattsville, MD: National Center for Health Statistics. 2017/ CDC. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2016. Available at http://wonder.cdc.gov

[2] Center for Behavioral Health Statistics and Quality. (2017). 2016 National Survey on Drug Use and Health: Detailed Tables. Substance Abuse and Mental Health Services Administration, Rockville, MD.

[3] Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. Journal of Pain. 2015;16(8):769-780.

[4] Center for Behavioral Health Statistics and Quality. (2017). 2016 National Survey on Drug Use and Health: Detailed Tables. Substance Abuse and Mental Health Services Administration, Rockville, MD.

[5] Jones CM, Einstein EB, Compton WM. Changes in synthetic opioid involvement in drug overdose deaths in the United States, 2010-2016. JAMA.2018;319(7):1819-1821.

[6] Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med. 2014 May 29;370(22):2063-6.

[7] Bart G. Maintenance Medication for Opiate Addiction: The Foundation of Recovery. Journal of addictive diseases. 2012;31(3):207-225.

[8] Sigmon SC, Bisaga A, Nunes EV, O’Connor PG, Kosten T, Woody G. Opioid Detoxification and Naltrexone Induction Strategies: Recommendations for Clinical Practice. The American journal of drug and alcohol abuse. 2012;38(3):187-199..

[9] Rzasa Lynn R, Galinkin J. Naloxone dosage for opioid reversal: current evidence and clinical implications. Therapeutic Advances in Drug Safety. 2018;9(1):63-88.

[10] Van der Schier R, Roozekrans M, van Velzen M, Dahan A, Niesters M. Opioid-induced respiratory depression: reversal by non-opioid drugs. F1000Prime Reports. 2014;6:79.

[11] Neelakantan H, Holliday ED, Fox RG, Stutz SJ, Comer SD, Haney M, Anastasio NC, Moeller FG, Cunningham KA. Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats. ACS Chem Neurosci. 2017 May 17;8(5):1065-1073.

[12] Eon V, Giuvelis D, Ananthan S, Bilsky E. Efficacy of dopamine D3 receptor antagonist SR 21502 in reducing opioid tolerance and dependence. FASEB J 2015;29:Suppl 6:415-415.

[13] Hwang CS, Janda KD. A Vision for Vaccines: Combating the Opioid Epidemic. Biochemistry. 2017 Oct 24;56(42):5625-5627.

[14] Winkelman, T. N. A., et al. (2018). Incidence and Costs of Neonatal Abstinence Syndrome Among Infants With Medicaid: 2004-2014. PEDIATRICS. Mar 2018, e20173520.

[15] https://www.nichd.nih.gov/news/releases/100217-ACTNOW

[16] Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med. 2014 May 29;370(22):2063-6.

[17] Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999–2016. NCHS Data Brief, no 294. Hyattsville, MD: National Center for Health Statistics. 2017/ CDC. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2016. Available at http://wonder.cdc.gov

[18] https://www.drugabuse.gov/about-nida/organization/cctn/ctn

[19] http://ctndisseminationlibrary.org/

[20] Brinkley-Rubinstein L, Zaller N, Martino S, Cloud DH, McCauley E, Heise A, Seal D. Criminal justice continuum for opioid users at risk of overdose. Addictive Behaviors. 2018. [epub ahead of print]

[21] Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49.

[22] Morrone LA, Scuteri D, Rombolà L, Mizoguchi H, Bagetta G. Opioids Resistance in Chronic Pain Management. Current Neuropharmacology. 2017;15(3):444-456.

[23] Mifflin KA, Kerr BJ. The transition from acute to chronic pain: understanding how different biological systems interact. Can J Anaesth. 2014 Feb;61(2):112-22.

[24] Yekkirala AS, Roberson DP, Bean BP, Woolf CJ. Breaking barriers to novel analgesic drug development. Nature reviews Drug discovery. 2017;16(8):545-564. doi:10.1038/nrd.2017.87.

This page last reviewed on June 12, 2018