DETROIT – A team led by Wayne State University School of Medicine researcher Mark Greenwald, Ph.D., will use a four-year, $2,279,723 competitively renewed grant from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health to explore whether the opioid addiction treatment medication buprenorphine can decrease the magnitude and/or duration of responses to stressors faced by recovering addicts.

The results of the study could reveal a new therapeutic feature of the drug, possibly helping drug-abstinent individuals avoid relapse.

Greenwald is a professor and associate chair of research in Wayne State’s Department of Psychiatry and Behavioral Neurosciences. He also directs the department’s Substance Abuse Research Division.

“Biobehavioral Studies of Opioid Seeking: Effect of Buprenorphine/Naloxone Dose on Experimental Stress Reactivity and Opioid Abstinence” is the third phase of a project initially funded by the NIDA in 2003.

“We first developed and validated our experimental methods, then made changes over the course of the project to tackle more challenging questions,” Greenwald said. “We want to address the terrible epidemic of opioid abuse, overdose and deaths that our society is witnessing.”

Opioids such as hydrocodone, oxycodone, morphine, codeine and heroin relieve pain by activating pain receptors in the brain; however, they also have high abuse potential.

“Stress is a major contributor to all drug addictions and other behavioral health problems, so improving our understanding of the neurochemistry of stress and its effects on behavior have broader significance,” Greenwald said. “Research on stress and addiction is a major growth area, but much of it has been done with laboratory animals. It’s also important to recognize that although our research participants are generally healthy – because we screen them to exclude those with medical and psychiatric problems – in the real world, opioid abusers often have co-occurring psychiatric problems that reflect extraordinary challenges of stress and poverty.”

To promote the generalizability and clinical relevance of their findings, the researchers expanded study recruitment in this current cycle to all individuals with opioid use disorder, including those with prescription opioid use problems. More than 28,000 Americans died of an opioid-induced drug overdose in 2014, the most recent year for which data are available. About four people a day overdose from opioids in Michigan.

“Without exaggeration, the current opioid epidemic is unprecedented. Regrettably, we see reports of opioid overdoses and deaths nearly every day in the media. The White House,  Congress, Drug Enforcement Administration, Food and Drug Administration, Centers for Disease Control and Prevention, and the NIDA are all focused on this complex problem,” Greenwald said. “This project is one piece of that challenging puzzle. Our longer-term objectives are to identify new therapies, for example, adjunctive medications, that attenuate stress reactivity. These could cut across all addictions and behavioral health problems to have a tremendous impact.”

Greenwald serves on the Wayne State University Task Force for Prescription Drug and Opioid Abuse, which last month proposed curriculum changes that would better prepare health professions students to work with persons who have substance abuse disorders, including more treatment education and tools to address increased challenges in prescribing controlled substances.

“I’m interested in addressing problems that addiction treatment professionals face: What knowledge and tools can we bring to bear when a patient presents with a chronic, relapsing history of drug use? Most of my studies have focused on opioid addiction, and this grant project has specifically examined multiple determinants of opioid addiction,” he said.

From 2011 to 2015, the project team examined the effects of stress exposure on those seeking opioids.

“We were first to translate an animal model into the human laboratory setting using a pharmacological stressor to investigate its effects on drug seeking,” he said. “This stressor involves administering controlled doses of two drugs that can co-activate the brain’s noradrenergic and glucocorticoid systems – yohimbine and hydrocortisone.”

The stressor can increase subjective and physiological markers of stress such as blood pressure, cortisol and anxiety, which are related to increased drug seeking, Greenwald explained.

In the current cycle, the researchers will manipulate the buprenorphine dose across different weeks for each participant to determine whether the medication can dose-dependently blunt the effects of the stressor. They will also investigate whether stress responses during the initial part of the study predict subsequent relapse as they reduce the buprenorphine dose and for up to three months afterward.

Naloxone overdose protection kits will be provided to enrolled participants.

“I'm also excited to have added collaborations with two investigators who will significantly expand our array of biomarkers. The first is to measure chronic stress using cortisol levels in hair samples. The second is to measure indices of inflammation in blood samples. These will be quite innovative,” he said.

The grant award number is DA015462.

About Wayne State University

Wayne State University is one of the nation’s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit research.wayne.edu.