While opioids like fentanyl and oxycodone are among the most powerful painkillers known to modern medicine, they are also extremely addictive and therefore, increasingly hard to get – even for those suffering from severe pain. A new finding may offer hope to pain patients in the form of powerful painkillers that lack the most hard-to-handle side effects of current options.

In seeking to block pain, pharmacologists long ago figured out that compounds that work on the opioid receptors on nerve cells work the best. However, as the current opioid crisis illustrates, these drugs are highly addictive. Our nerves have two types of opioid receptors and the most addictive drugs target the mu receptors. Seeking to find alternatives to these medications, scientists focused on the other receptors, known as kappa. But drugs that work on these pathways come with their own side effects, most notably, hallucinations.

Still, because addiction isn’t an issue, working with the kappa receptors has held promise. Now, researchers at the Washington University School of Medicine (WashU Medicine) and the University of Health Sciences & Pharmacy in St. Louis, have figured out that there is more than one type of kappa receptor. More importantly, they discovered that while they can all offer some pain relief, they don’t all cause hallucinations.

The key lies in a group of signaling compounds known as G proteins. When encountered by the kappa opioid receptors, these proteins activate different pathways. With further testing, the research team believes that they will be able to sort out which pathways provide relief from pain without triggering hallucinations. Once that puzzle is sorted out, it is theoretically possible to create painkillers that would work as well as the best opioids, without carrying along their harmful side effects.

“All of these proteins are similar to one another, but the specific protein subtypes that bind to the kappa receptor determine which pathways will be activated,” said principal investigator Tao Che, an assistant professor of anesthesiology at WashU Medicine. “We have found that the hallucinogenic drugs can preferentially activate one specific G protein but not other, related G proteins, suggesting that beneficial effects such as pain relief can be separated from side effects such as hallucinations. So we expect it will be possible to find therapeutics that activate the kappa receptor to kill pain without also activating the specific pathway that causes hallucinations.”

The current finding joins other research that is seeking to replace opioids with safer options. A 2018 study, for example, found success with a non-addictive painkiller in non-human primates, while a more recent effort discovered that three older antibiotics were effective in combating neuropathic pain in mice. There may even be hope that using a compound in tarantula venom could one day lead to non-addictive painkillers. Considering that over 70,000 deaths from opioids other than methadone were reported across the United States alone in 2021, any compound that can bring relief to patients without causing addiction or other serious mental health effects would be a welcome addition to the current state of pain management.

The research has been published in the journal, Nature.

Source: Washington University School of Medicine in St. Louis