The Quest for Safer Painkillers

In Brief:

A popular online simulation game called “Will You Press The Button?” poses two scenarios to the player and asks the title question. One scenario offers amazing possibilities like having all the riches you could spend, being immune to disease, or becoming the greatest artist in the world. However, every positive scenario is coupled with a negative one that would bring devastating consequences to you or others. The game is an exaggerated simulation of weighing the pros and cons of a situation, knowing that with every good scenario comes an equally bad one.

This game got me thinking about the real-life opioid crisis our world is facing right now. Unfortunately, opioid addiction from the overuse of opioids for pain management has grown into a global health epidemic. In 2016, more than 60,000 people died from opioid overdoses in the United States alone, and that number is climbing. Imagine being in the situation of having to “press the button” to decide to take opioids to manage your pain, knowing there’s a risk of breathing problems that keep oxygen from getting to your brain and can be fatal. Plus, there’s the ever-looming threat of addiction with continued use. Thankfully, scientists are in an ongoing quest to develop safer opioids that are effective painkillers without dangerous side effects.

One researcher, Dr. Tao Che at the University of North Carolina, believes he is on the right track to creating a safer opioid. The painkiller he is working to design will allow users to experience the positive, painkilling effects of the opioid without facing serious negative side effects.

Researchers are seeking ways to switch on pain relief while switching off side effects
Researchers are seeking ways to switch on pain relief while switching off side effects.

First, a bit of background. Opiate molecules work by binding to protein molecules known as receptors on cell surfaces. This binding triggers one or more chemical reactions, or pathways, inside the cell. Many scientists believe that these chemical reactions result in different effects in the body. For example, one pathway might be responsible for pain relief, whereas another pathway might result in serious side effects.

Dr. Che’s research is based on the hypothesis that it is possible to develop a new type of opioid molecule that would only trigger the pathways resulting in pain relief, while avoiding pathways that suppress breathing or cause other negative side effects. Laboratory experiments in mice have confirmed that when scientists shut down a negative-reaction pathway (something not yet possible to do in humans), they were able to boost pain relief and reduce side effects. This experiment confirms the hypothesis that different pathways cause different results in the body. Dr. Che is working to develop a new opioid molecule that manages to trigger only the pathway that causes pain relief.

Other researchers have come up with alternate solutions. For example, Dr. Christoph Stein, a professor at the Charité in Berlin, is developing a new painkilling compound that focuses its effect on injured tissue, rather than affecting the entire body. Specifically, he is developing a compound that activates the opioid receptors in low pH conditions. Since injured tissue has a lower pH environment, the painkiller would only target injury sites. Dr. Stein’s next steps will be to further refine this compound, although getting enough funding is a significant challenge.

Both Dr. Che and Dr. Stein share the goal of providing safer painkillers that deliver the benefits without the devastating side effects of opioids. Unlike the online simulation game, patients may never again be faced with having to make the real-life difficult decision of taking the good—pain relief— with the bad—death from side effects triggered by overdose. With ongoing research, the goal of developing safer opioids may be reached in the not too distant future.


Dr. Tao Che is a postdoctoral research assistant at the University of North Carolina at Chapel Hill. After receiving his Ph.D. at Case Western Reserve University, he has focused on researching the structure and function of the kappa opioid receptor.

Dr. Christoph Stein is a professor and the medical director of the Department of Anesthesiology and Operative Intensive Care Medicine at Charité in Berlin. He is internationally recognized in the field of opioid pharmacology, molecular mechanisms, and pain treatment.

Works Cited:

  1. Che, Tao, et al. “Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.” Cell, vol. 172, no. 1, 2018, pp. 55-67.
  2. Spahn, V., et al. “A nontoxic painkiller designed by modeling of pathological receptor conformations.” Science, vol. 355, no. 6328, pp. 966-969.
  3. Rood, Jenny. “The Quest for Safer Opioid Drugs.” The Scientist, 1 Jan. 2018,
  4. Stein, Christoph. Personal interview by the author. 16 Jul. 2018.
  5. Che, Tao. Personal interview by the author. 11 Jul. 2018

Image Credits:
Feature and Story Image: Graphics by Staff Illustrator: Selena Liu

Chief Editor: Akila Saravanan
Creative Team Manager: Lucia Tian
Team Editor: Sophie Zhang
Team Graphic Designer: Selena Liu

This article was written by Victoria Ho. As always, before leaving a response to this article please view our Rules of Conduct. Thanks! -cSw Editorial Staff