Scientists have just taken a step closer to developing a high-strength painkiller that is not as addictive as opioids.
Opioids are sometimes prescribed to patients for use as pain relief in the short term. But they come with serious side effects and risks, including addictions, and subsequently death from overdose, as highlighted in the hit Netflix series Painkiller.
Overdoses involving opioids—including prescription opioids, heroin, and synthetic opioids like fentanyl—killed more than 80,000 people in the U.S. in 2021, and nearly 88 percent of those deaths involved synthetic opioids.
For this reason, scientists are searching for effective, less addictive, alternatives to treat pain.
New research published in the journal Neuron from the University of Chicago, suggests scientists may have taken a step towards finding one. While they have not developed any new drugs, they are looking into new pathways of administering drugs to lessen the risk of addiction seen with opioids.
In mice, they identified an alternative signaling pathway in the brain that alleviates pain. This was the case even in animals that have a tolerance to the powerful drugs. When taken through this pathway, pain relief did not result in withdrawals. It also did not trigger reward systems in the brain—opioids can cause this system to be flooded with an excess of dopamine, which the brain associated with the addictive substance. This means that there is a smaller risk of addiction through this pathway.
"Deaths due to opioid overdose, particularly synthetic opioid drugs such as fentanyl have been rising dramatically for nearly ten years," Daniel McGehee, Ph.D., professor of anesthesia and critical care at UChicago and senior author of the new study, told Newsweek. "Changes to prescribing of opioids, availability of naloxone to treat individuals who are experiencing overdose, and improved public education are all helping—but the death toll continues to rise."
"Identifying non-opioid drugs that relieve pain will help limit availability of these drugs, as they offer alternatives to replace or reduce opioid use in the clinic. Along with overdose and addiction issues, there are other complications and side effects of opioids, including tolerance, where the pain relieving properties diminish with repeated use, hypersensitivity to pain when patients stop taking the drug, constipation, and other peripheral side effects. Pain relief without those side effects would certainly be valuable in the clinic."
The pathway, called the ventrolateral periaqueductal gray, serves as an "important crossroads of systems that control pain," the study reports.
Scientists already know that stimulation to this region with certain drugs can help pain. However until now, non opioid circuits that alter pain in this area have not been well-studied.
"We found that pain relief through this circuit was not associated with withdrawal effects commonly associated with opioids," first author of the study Dr. Shivang Sullere, a previous graduate student in the Committee on Neurobiology at UChicago, now a postdoctoral scholar at the Harvard Medical School, told Newsweek.
Sullere said that through this circuit, opioids can still be administered at less than the maximum dose, but their addictive side effects will be limited.
The neurotransmitter acetylcholine is involved in these circuits. When this neurotransmitter is targeted, it can change pain responses. McGehee and Sullere assessed acetylcholine and how it is released under different forms of pain.
This assessment produced several surprises.
Acetylcholine receptors usually generate more activity in the nervous system. But when a drug was injected that targeted this receptor in mice, it relieved pain for several hours, the study reported.
"That was a huge and extremely unexpected outcome," McGehee said in a press release. "Persistent inhibition [of pain] was not on our radar at all."
The researchers also tested several ways of repeated stimulation of the pathway, and exposure to a drug that targets the acetylcholine receptor.
"[We] did not see evidence of tolerance to the pain-relieving effects. And as the title of our study indicates, this analgesic effect remained even after development of tolerance to opioids. It was truly exciting to learn that this method for relieving pain does not have many of the side effects associated with opioid analgesic drugs," McGehee told Newsweek.
The bad news remains that there is no pain killer found that is quite as effective at relieving pain as opioids.
But this research represents a promising way forward in developing alternatives.
"We are exploring the mechanisms underlying the change in acetylcholine release in this brain area during painful experiences. We want to find other ways to recruit or activate this system for relieving pain—and that will keep us busy for the next few years," McGehee said.
Do you have a tip on a science story that Newsweek should be covering? Do you have a question about opioids? Let us know via science@newsweek.com.
Uncommon Knowledge
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