In 2015, the number of opioids prescribed was enough for every American to be medicated for three weeks, according to the Centers for Disease Control and Prevention (CDC).
Opioids decrease pain perception, but they can also cause respiratory depression, hormonal imbalance, bone thinning and addiction, even when taken as prescribed. The CDC reports that more than 200,000 people died in the U.S. from 1999 to 2016 from opioid-related overdoses with more than 63,000 deaths in 2016 alone.
It’s a sobering statistic that is giving medical professionals pause and has communities attempting to respond.
But despite the widespread availability of prescription painkillers, an underlying truth remains: America is a country struggling with pain. Studies show that Americans report more pain than other countries, and we also perceive pain differently.
“Pain threads through most disease entities that are seen in an acute-care hospital, emergency rooms or on an outpatient basis,” says Robert Hurley, MD, PhD, professor of anesthesiology and public health for Wake Forest School of Medicine and executive director of the Pain Shared Service Line for Wake Forest Baptist Health. “Pain is the No. 1 reason for a patient coming to the ED and the No. 1 reason for coming for a clinical visit.”
With the opioid crisis sweeping the country, researchers at the School of Medicine created the Center for Research on Substance Use and Addiction two years ago.
Michael Nader, PhD, a professor of physiology and pharmacology, is co-director of the Center along with Mark Wolfson, PhD, professor of social sciences and health policy.
The Center funds translational research pilot awards for competitive studies focusing on preclinical models, population research and clinical-translational research. Established for School of Medicine researchers, the Center encourages multi-departmental and collaborative projects.
Nader studies how drugs affect the brain while Wolfson researches the role of public policy as it relates to drug use and abuse.
“As you can see, we have very diverse backgrounds,” Nader says. “That’s one of the hallmarks of our Center. The goal is to get basic scientists, clinicians and population-based researchers in the same room to talk about a common problem, and there are a lot of people at this institution who are interested in substance abuse research.”
“Yes, there are,” Wolfson adds, noting that the Center already has 66 members from more than 14 departments.
“That’s really the main focus of the Center,” Nader says.
Given the scope of the opioid epidemic in the United States, a lot of the Center’s energy focuses on finding solutions to the crisis. Center members are working on a variety of opioid studies including the effectiveness of organized community strategies, peer-support programs, pain-management alternatives and experimental analgesics.
One approach to dealing with the opioid epidemic is to reduce the supply in households by implementing organized disposal efforts such as drop boxes or take-back events.
“But we’re a little skeptical of how well they work,” admits Wolfson. “There’s a reservoir in people’s medicine’s cabinets that can be stolen, used by adolescents or misused in any number of ways.”
Working jointly with the University of Kentucky, Wolfson’s research focuses on whether improved messaging and more visible campaigns can increase community participation in organized disposal programs.
Wolfson also works with the N.C. Department of Health & Human Services to study the effectiveness of substance abuse prevention priorities such as media campaigns and physician training for responsible prescribing.
“We’re studying whether or not these programs work,” Wolfson says. “We’re also interested in whether state laws that place limits on opioid prescriptions actually result lower rates of misuse, or if they end up having unintended consequences such as people turning to illicit opioids such as heroin.”
Preventing & Treating Addiction
Appropriate prescribing is also an interest of Hurley. Through his work with the Pain Shared Service Line, he collaborates with physicians and clinicians across the institution to try and practice in a more similar fashion related to pain.
And the reality is that pain can often be adequately managed without opioid prescriptions by using state-of-the-art protocols when treating pain.
“There are many different ways to provide excellent pain care that do not involve an opioid,” Hurley says.
NSAIDs, Tylenol and other treatments can be far more effective in managing pain.
“In many studies, Toradol [an NSAID], for example, has been shown to be much more effective than morphine in similar dosages,” Hurley notes.
Treating non-cancer-related chronic pain often requires discussions with patients that opioids, because of their addictive nature, can have a negative impact and may not provide any longer-term pain relief.
“My major goal here is to provide the highest quality pain care for our patients while reducing harm,” Hurley says.
Hurley’s work focuses on three realms—clinical, research and education. “I do team-based collaborative research primarily focused on pain, pain care and pain education. So, it involves the treatment of patients, but it also involves research on improving our educational modalities and approaches for physicians, clinicians and medical students,” Hurley says.
One of Hurley’s current research projects came out of a grant he received for being named a Robert Wood Johnson Clinical Scholar, a prestigious program that selects only 29 scholars a year. Scholars use their clinical expertise and research methods to help find solutions to problems facing the U.S. health care system.
The research project, PROMPT: Prevention of Opioid Misuse Through Peer Training is a study led by Syed Ahmed, MD, DrPH at the Medical College of Wisconsin.
“It’s an interesting project because it revolves around a large problem that is very hard to address,” Hurley says. “It’s the veteran population, but veterans with opioid-related problems who do not trust the VA system or any health care provider.”
However, they do trust other veterans who have recovered opioid addiction, and so the project addresses opioid misuse through a peer counseling network within Dryhootch, a nonprofit that provides mentoring services from veterans to veterans.
The goal is to prevent opioid misuse and deaths by training mentors on a specialized opioid curriculum, Hurley says.
“If this approach is deemed effective, it can be expanded to other communities.”
Researchers are also studying how people respond to pain differently.
“People having pain is normal,” but patterns of recovery greatly differ,” says Meredith Adams, MD, assistant professor of anesthesiology for the School of Medicine. Adams is the first anesthesiologist career development awardee funded by the NIH National Institute of Biomedical Imaging and Bioengineering. She is using novel pain informatics methods to solve the opioid crisis.
“Even healthy people experience pain,” Adams notes. “Let’s say an Olympic athlete is immobile for two weeks, when he or she starts moving again, there will be pain, and that’s expected.”
Adams also says that opioids can also give patients a heightened sensitivity to pain. “It’s called opioid-induced hyperalgesia,” says Adams.
She characterizes the opioid epidemic as a “crisis of hope.”
“A lot of the communities that are most impacted by the crisis are also economically depressed,” Adams says. “Opiates are good at treating physical pain to a certain extent, but they also treat emotional pain.”
Adams treats patients for acute and chronic pain. She also teaches and works with a multidisciplinary team at the Medical Center, but the majority of her NIH-funded work focuses on identifying opioid treatment response phenotypes in low back pain.
“I’m studying who does well on opioid medications and who doesn’t,” Adams says.
The research involves building infrastructure to do big data analytics in patient health records.
“When you go to the doctor and say, ‘I was feeling better when I did this’ or ‘It hurt when I did that,” there isn’t an easy way to extract that information for analysis,” Adams says. “I am applying computer science methods called machine learning and natural language processing, which are ways of having a computer analyze that text data.
Adams agrees that big data alone isn’t going to solve the crisis, but she’s laying a foundation to see where patterns emerge and to have a better understanding of how populations respond.
“I’m building the infrastructure for future studies—whether it’s genomic or predictive modeling,” Adams says.
Adams is hopeful that with a better understanding how populations respond, we can work toward preventing addiction.
“The goal is to prevent people from going down the addiction pathway and find better ways to treat pain.”
A Promising Approach
An opioid without addiction potential? It would be an enormous discovery. However, one researcher at the School of Medicine took a major step toward that reality with a study recently published in Science Translational Medicine.
Mei-Chuan (Holden) Ko, PhD, professor of physiology and pharmacology, says that AT-121, a chemical compound discovered by Nurulain Zaveri, PhD, of Astraea Therapeutics, was found to be safe and non-addictive in nonhuman primates.
“We know that the nonhuman primate’s responses to opioids, in terms of potency and side effects, are very similar to humans,” Ko says.
Opioids are very effective at treating pain because of the activation of the mu opioid receptor. However, this receptor activation can also induce serious side effects. The study tested how the compound worked on the mu opioid receptor and the nociceptin receptor, which enhances analgesia and blocks abuse side effects. Drugs such as fentanyl and oxycodone work only on the mu opioid receptor. AT-121 works on both receptors.
“AT-121 doesn’t elicit any side effects typically associated with opioids like respiratory depression, abuse potential and physical dependence,” Ko says.
The compound is also more potent. Researchers revealed that AT-121 has the same level of pain relief, but at a 100 times lower dose than morphine.
It’s an incredible breakthrough, but Ko cautions that drug discovery is a long process. Next steps include more safety and toxicity trials before applying for FDA approval.
“It definitely has a long road to go,” Ko says. “But as scientists, we’re excited because the drug shows such a promising profile.”
While AT-121 shows promise, the reality is that truly confronting the pain crisis—and by extension, the opioid epidemic—means investing in a range of programs and continuing rigorous research to combat the crisis. Researchers at the Center for Research on Substance Use and Addiction are taking steps to do just that and are already seeing the fruits of their labors.
“Our Center is in its infancy,” says Nader. “But it has already been very successful.”