Chinese researchers raise hopes of developing less addictive painkillers
- Scientists have uncovered clues that could help develop opioids that have fewer dangerous side effects compared with drugs such as fentanyl
- Chronic pain is a serious medical problem at a time when the US is in the grip of an opioid crisis that has resulted in hundreds of thousands of deaths
Chinese researchers hope they are a step closer to developing powerful painkillers that reduce the risk of patients becoming addicted after new research helped show the mechanisms by which opioids such as morphine and fentanyl relieve pain.
Chronic pain is a major problem in modern medicine, with more than 50 million American adults suffering, according to a report by the Centres for Disease Control and Prevention from 2020. In China, an estimated 300 million people suffer from chronic pain and the number keeps growing, according to research from Tsinghua University from the same year.
The use of opioids dates back thousands of years and they are effective in treating acute and chronic pain.
But opioids can also cause serious side effects, including addiction and breathing difficulties that can prove fatal if patients overdose.
Don’t blame China for US opioid crisis, says ambassador
Currently the United States is grappling with an opioid crisis that has seen deaths from drug overdoses quintuple since 1999.
According to the CDC, more than 564,000 people died from overdoses caused by both prescription and illicit opioids between 1999 and 2020.
This means there is an urgent need to develop new and less-addictive opioid analgesics.
But until the latest study, published in Cell earlier this month, scientists were not sure how they worked – something that limited their ability to develop new treatments.
“One of the long-standing questions in this field is which signalling pathways are responsible for the analgesic and adverse effects of opioids,” Zhuang Youwen, lead author of the study from the Shanghai Institute of Materia Medica, said on Monday.
“Pain has become the third major health problem in our society following cancer and cardiovascular diseases … and there is strong demand for the development of potent and safe analgesics,” Zhang Xu, a neuroscientist with the Chinese Academy of Sciences, added in a statement on the institute’s website.
Opioids work by latching onto a protein in the brain known as the mu opioid receptor and triggering two neural pathways known as the G protein and beta-arrestin.
08:14
Hooked on heroin: A Chinese town's battle with trafficking and addiction
Previous research has suggested that the analgesic effect may be the result of G protein signalling, while adverse effects such as addiction and respiratory problems might be caused by beta-arrestin signalling.
Even though this proposal has been challenged by recent studies, scientists have been working to decrease beta-arrestin signalling activities to reduce side effects, according to the authors of the new study.
One drug, called oliceridine, or TRV130, was approved by the US Food and Drug Administration in 2020 for the treatment of moderate to severe pain.
How opioid addicts get drugs from an online black market
Studies in rodents indicate the drug still has side effects but they are less severe than those of morphine and fentanyl, though the mechanisms by which they operate remain unknown.
The new study found how fentanyl and morphine interacted with the mu opioid receptor and provided a molecular basis for the different potency levels of the two drugs. The researchers also compared them with other drugs, finding that they have much higher beta-arrestin signalling activities compared with TRV130 and two others.
12:56
Fighting fentanyl: the drug from China destroying American lives
Based on these findings, the authors designed two compounds that showed little to no beta-arrestin signalling activity, while the G protein signalling activity was about the same as that of fentanyl.
Zhuang said it was not yet clear if the drop in beta-arrestin signalling would reduce adverse side effects, but added: “That is what we will continue to do. We want to find compounds that are potent and have low adverse effects.”
