Clinical Trials Network | NIDA

The National Drug Abuse Treatment Clinical Trials Network (CTN) provides an enterprise in which NIDA, treatment researchers, and community-based service providers work toward new treatment options in community-level clinical practice.

Mission

CTN is a means by which medical and specialty treatment providers, treatment researchers, participating patients, and the National Institute on Drug Abuse cooperatively develop, validate, refine, and deliver new treatment options to patients. This unique partnership enables the following:

  • Conducting studies of behavioral, pharmacological, and integrated behavioral and pharmacological treatment interventions of therapeutic effect in rigorous, multisite clinical trials to determine effectiveness across a broad range of community-based treatment settings and diversified patient populations; and
  • Ensuring the transfer of research results to physicians, clinicians, providers, and patients.

CTN Organization Framework 

The Clinical Trials Network (CTN) framework consists of sixteen nodes, a Clinical Coordinating Center, and a Data and Statistics Center. This framework links a variety of treatment providers and patient populations throughout the country. This allows the CTN to provide a broad and powerful infrastructure for rapid, multi-site testing of promising science-based therapies and the subsequent delivery of these treatments to patients in a variety of treatment settings.

History

Over the past several years, research programs within the NIDA have produced dramatic advances in understanding drug abuse and addiction. This has led to the development of an array of new treatments and therapies to help patients with drug abuse problems. However, the efficacy of new treatments for drug addiction has been demonstrated primarily in specialized research settings, with somewhat restricted patient populations. In order to fulfill their promise, advances achieved in drug abuse research centers must reach patients in the community-based settings where most treatment is provided. To enhance the delivery of scientifically based treatments to drug abuse patients, NIDA has established the National Drug Abuse Treatment Clinical Trials Network (CTN).

CTN as a Platform

The CTN, with its engagement of diverse populations, is also designed to provide a platform for other studies, which would be funded under separate research grants. Three important ways to use the CTN are: to conduct ancillary studies in connection with CTN protocols; to utilize CTN Node facilities as a platform for investigations; and for nodes to serve as home bases for NIH Training Centers and individual researchers who have NIH fellowships or career development awards.

CTN Highlights

Emergency department (ED) clinicians are in a unique position to interact with people struggling with opioid addiction. Some ED clinicians will see the same patients in their emergency clinics multiple times, often after administering life saving naloxone to reverse an overdose. NIDA has funded research into the initiation of medications for opioid use disorder for addiction to opioids right there in the emergency setting, in collaboration with emergency department specialists at Yale University. The resources below were developed by emergency medicine and addiction medicine researchers. The views and opinions expressed in these resources are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies.

Why the Emergency Department (ED)?

That is Where the Patients Are! The opioid epidemic is strongly impacting EDs, with 2018 data from the CDC indicating that there has been a 30% increase in visits for opioid overdose from July 2016 – September 20171. Addiction is a chronic, relapsing disease, and a strongly stigmatized one. It is NOT a moral failing. People who present to the ED for other chronic disease like diabetes and asthma are stabilized with medications and handed off for outpatient care. Individuals with opioid use disorder (OUD) do best with a similar treatment plan.

What is the Evidence?

A 2015 study (JAMA) found that twice as many patients were in OUD treatment at 30 days (~80%) with ED-initiated buprenorphine & a brief negotiation interview (BNI) compared with referral only or a BNI + facilitated referral and used less illicit opioids in the last 7 days.2

What Do I Need to Know About Buprenorphine?

It is NOT simply replacing one drug for another. Buprenorphine treatment decreases withdrawal and craving. Patients who receive buprenorphine are less likely to overdose, die, use illicit opioids, or spread HCV or HIV and have fewer injection drug use complications and contacts with the criminal justice system.3

Since 2002, ED physicians have been able to administer buprenorphine in the ED for opioid withdrawal. Within 30-45 minutes patients will be much more comfortable. MDs, PAs, and APRNs can prescribe buprenorphine with referral to ongoing treatment. (A DATA waiver (X-waiver) is no longer needed to prescribe buprenorphine. Visit SAMHSA's website for more information about the removal of the DATA waiver requirement.

Buprenorphine is a partial agonist at the mu opioid receptor, where it has a very high affinity but low intrinsic activity. Its high affinity means it will out-compete and displace full opioid agonists. It is administered when the patient exhibits withdrawal symptoms (COWS > 8). Its low intrinsic activity results in less euphoria and lower diversion potential.

Motivating Patients

Development of the videos provided below was funded by a partnership between Yale University and Aetna; however, all content and clinical recommendations were developed by clinicians with expertise in emergency department settings, with grant funding from NIDA and contract support from NIDA’s Clinical Trials Network. This information has been provided as a courtesy on the NIDAMED Web portal, and does not constitute official clinical guidelines or standards. The views and opinions expressed in these resources are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies.
 

Tools and Assessments

Provider Resources

Heroes in Practice

Emergency physicians around the country have partnered with state entities to develop a spectrum of innovative strategies. These strategies entail increasing access to care, identifying those at high risk for overdose, safe prescribing, offering access to naloxone, sharing data among agencies, and decreasing stigma by recognizing not only that words matter, but accurate words matter. Some of these heroes are highlighted in the videos below describing what they are doing to combat the opioid epidemic. These resources were developed by emergency medicine and addiction medicine researchers. The views and opinions expressed in these resources are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies.

The CTN Dissemination Initiative aims to reduce the gap that exists between the publication of research on treatment of substance use disorders and implementation in clinical practice. It incorporates collaboration among clinicians, researchers, and experienced trainers to develop user-friendly tools and products to facilitate the adoption of research-based interventions into clinical settings. Explore this page for more information about the different components of the CTN Dissemination Initiative.

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Meeting Summary

In response to the rapid escalation in the detection of xylazine in the unregulated drug supply, in April 2023, the White House designated fentanyl contaminated with xylazine an "emerging threat". The National Institute on Drug Abuse (NIDA) Center for the Clinical Trials Network (CCTN) convened health care professionals and federal partners to review current practices in xylazine-related testing, treatment, and wound care to inform evolving best-practices in the field. This convening focused on the most critical areas of concern with the goal of rapidly identifying current practices and a xylazine-opioid research agenda.

Welcome and Opening Remarks

The meeting is opened by NIDA Director Nora Volkow, M.D., with welcoming remarks from CCTN Director Betty Tai, Ph.D., and CCTN Associate Director, Kristen Huntley, Ph.D. The two meeting co-chairs—Jeanmarie Perrone, M.D., University of Pennsylvania, and Rachel Haroz, M.D., Cooper Medical School of Rowan University—who helped shape the agenda and identify experts on the topic, also provided introductory remarks.

Session 1: Pharmacology and Clinical Manifestations of Withdrawal and Overdose

Presenters focus on current knowledge of xylazine’s pharmacology, clinical outcomes of xylazine-exposed patients who present in the emergency department (ED), and the signs and symptoms of xylazine withdrawal—as well as their treatment.

  • Xylazine Pharmacology
    Joseph D’Orazio, M.D., Temple University School of Medicine and Giacomo Gianotti, D.V.M., D.V.Sc., DACVAA, University of Pennsylvania School of Veterinary Medicine
    Dr. D’Orazio explains how xylazine decreases sympathetic nervous system outflow, causes sedation, and produces other physiological effects. When fentanyl and xylazine are combined, naloxone should be provided per the usual protocol when an opioid overdose is suspected.
  • Xylazine Withdrawal, Opioid Withdrawal, and Medication Induction
    Matthew Salzman, M.D., Cooper Medical School of Rowan University
    Dr. Salzman describes his clinical experience managing withdrawal and notes the challenge of not knowing the relative concentrations of fentanyl and xylazine in the drugs patients have taken. The complete xylazine withdrawal syndrome is not clear, and some patients report that that their xylazine withdrawal is not adequately treated.
  • Opioid Overdoses Involving Xylazine in Emergency Department Patients: A Multicenter Study
    Jennifer Love, M.D., Icahn School of Medicine at Mount Sinai
    Dr. Love discusses a multicenter cohort study to investigate the effects of xylazine on the clinical outcomes of ED patients with a suspected opioid overdose. Results indicated that after adjusting for relevant characteristics, patients positive for xylazine had lower odds of cardiac arrest and coma within 4 hours compared to those with only opioids. 
  • Manifestations of Xylazine and Fentanyl Withdrawal in a Hospital Cohort
    Maggie Lowenstein, M.D., M.S.H.P., and Ashish Thakrar, M.D., University of Pennsylvania Perelman School of Medicine
    Dr. Lowenstein reviews a study on xylazine withdrawal, commenting that symptoms (e.g., anxiety, restlessness, and discomfort) varied greatly and that most patients had good outcomes with treatment. Dr. Thakrar discusses a study in Philadelphia, which estimated that the duration of xylazine in urine samples was less than 24-48 hours.

Session 2: Xylazine Wounds 

Little is understood about xylazine wounds (generally seen on the arms and legs) or satellite wounds (i.e., distinct injuries not at an injection site). Presenters describe how care is being provided for patients in the community—as individuals with open wounds are often turned away from inpatient drug treatment centers and shelters—and surgical management over the long term.

  • Hands On: Care Provided in the Community
    Stephanie Klipp, R.N., CARN, CAAP, CRS, Courage Medicine
    Ms. Klipp explains that in Philadelphia, most xylazine-exposed individuals are unhoused and have difficulty accessing regular wound treatment and keeping the necessary self-care supplies. In addition to describing wound treatment, Ms. Klipp points out the need for updated hospital protocols, low-barrier wound care, training on this topic, stigma reduction, and substance use treatment.
  • Surgical: Managing Complex Wounds Long-Term
    Lisa Rae, M.D., Temple Burn Center
    Xylazine wounds are necrotizing soft tissue wounds that feature a unique pattern not seen with heroin-related wounds. Dr. Rae notes that her approach is moving away from aggressive excision (typically the first-line treatment), outlines key clinical and research questions, discusses the unique characteristics of satellite wounds, and reviews harm reduction strategies to reduce operative interventions and help avoid amputation.

Session 3: Testing 

Commercial testing of the illicit drug supply has increased significantly, which raises many questions. Speakers discuss how patients view the usefulness of xylazine tests, a state-wide program that checks the illicit drug supply, and a research collaborative for drug testing with rapid sharing of results.

  • Patient Perspectives and Utility of Xylazine Test Strips
    Megan K. Reed, Ph.D., M.P.H., Department of Emergency Medicine, Thomas Jefferson University
    Dr. Reed discusses the results of two qualitative research studies with people who use drugs, focusing on (1) practices related to fentanyl test strips on non-heroin drugs and (2) responses to xylazine. She explains study participants’ concerns about fatal overdose, desire for test strips, dislike of the sensations associated with xylazine exposure, and experiences of withdrawal.
  • State-wide Drug Testing in Rhode Island: Xylazine
    Rachel Wightman, M.D., Alpert Medical School of Brown University and Rhode Island Department of Health
    Dr. Wightman reviews Rhode Island’s drug testing program which rapidly disseminates results to inform harm reduction efforts. She notes that xylazine is always detected in the presence of fentanyl. She stresses the need for research on xylazine’s pharmacokinetics, the development of an integrated testing infrastructure, and qualitative information to interpret and contextualize the results of quantitative testing. 
  • Xylazine Testing for Harm Reduction and Clinical Care
    Edward R. Sisco, Ph.D., National Institute of Standards and Technology
    Dr. Sisco explains NIST’s work with Johns Hopkins to evaluate xylazine test strips. The Rapid Drug Analysis and Research program tests samples for drugs within 24 to 48 hours and sends results back within 5 minutes. Dr. Sisco reviews the program’s process, results to date, and future work. 

Roundtable Discussion and Wrap Up

Drs. Perrone, Haroz, and Thakrar lead a discussion in which participants generate several high-priority research questions in the areas of (1) pharmacology and clinical manifestations of withdrawal and overdose, (2) xylazine wounds, and (3) testing. Aidan Hampson, Ph.D., describes NIDA’s Notice of Special Interest (NOSI), Xylazine: Understanding its Use and the Consequences (NOT-DA-24-009). The purpose of the NOSI is to encourage research on the prevalence and consequences of xylazine use, as well as its treatment—including overdose alone or in combination with other drugs.

Closing Remarks

Drs. Volkow and Perrone thank participants for a rich discussion and Dr. Huntley expresses gratitude to the meeting co-chairs for their work, especially the identification of experts on this topic.

The National Institutes of Health (NIH) encourages the development and use of common data elements (CDE) for clinical research, patient registries, and other human subject research in order to improve data quality and opportunities for comparison and combination of data from multiple studies and with electronic health records.

The Common Data Elements portal provides a single source for National Institute on Drug Abuse Clinical Trials Network-recommended CDEs of Substance Use Disorders for use in clinical trials and electronic health records. 

 

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