Scientists discover what could be a 'perfect' painkiller without side effects

New drug discovered by team including Nobel Prize-winning chemist shows 'promise' as a replacement for opium-based drugs like morphine – although it has only been tested in mice so far

The opium poppy has been the source of the most powerful painkiller known to science for thousands of years (Noorullah Shirzada/AFP/Getty Images)

Scientists believe they may have found a new form of painkiller that works just as well as morphine but lacks its potentially lethal side effect and is not addictive.

A team that included Nobel Prize-winning chemist Professor Brian Kobilka, of Stanford University in the US discovered the drug called PZM21 after evaluating some three million different compounds.

Morphine, derived from the opium poppy, works by acting on a receptor in the brain that reduces pains, but it also affects a different receptor that can lead to fatal breathing problems in the event of an overdose.

But PZM21, which so far has only been tested on mice, appears to act on the first receptor to about the same level as morphine without significantly changing the second one.

It also caused less constipation than opiate drugs, a factor that limits how much of the drug can be given.

And it is believed the new drug dulls the feeling of pain in the brain because it appears to have little effect on reflex responses linked to the spinal cord.

Writing in the journal Nature, the researchers said PZM21 had a “potent, selective and efficacious” effect on the brain receptor involved in the sensation of pain.

The drug could be an answer to a problem that dates back more than 100 years – how to alleviate pain without danger side effects.

“Opiate addiction, compounded by the potentially lethal side effects of opiates such as respiratory depression, has driven optimization campaigns for safer and more effective analgesics since the 19th century,” the researchers wrote.

“Although the natural products morphine and codeine, and the semi-synthetic drug heroin, are more reliably effective analgesics than raw opium, they retain its liabilities.

“Despite the introduction of potent synthetic opioid agonists like methadone and fentanyl ... developing analgesics without the drawbacks of classic opioids has remained an elusive goal.”

In the mice studies, PZM21 did not appear to affect their breathing and the painkilling effect of PZM21 lasted for up to three hours, “substantially longer” than the maximum dose of morphine.

The “constipating effect” was also “substantially less than morphine” and the mice did not show signs of addiction.

It is thought morphine addiction is a result of the activation of the brain’s dopamine reward circuits. When this happens in mice, they tend to run about a lot.

But the researchers wrote that PZM21 had “no apparent effect on locomotion”.

Professor Kobilka described it as a “promising drug candidate” that had been identified using computer screening, chemistry, extensive testing and “intuition”.

Significant further research will be needed to show that the new drug is both safe and effective on humans before it could actually be prescribed or used in hospitals.

Commenting on the paper in Nature, Professor Brigitte Kieffer, of McGill University in Canada, wrote that opium had been used “medicinally and recreationally for more than 4,000 years because of its remarkable pain-relieving and euphoria-inducing properties”.

But it had been a “long road” towards finding a replacement without its downsides.

The new paper, she said, described “a step towards this perfect drug”.

“Are we getting closer to the ideal pain-reliever? PZM21 is a leading member of a nascent club of pain-effective [drugs] that seem to have reduced risk for abuse,” Dr Kieffer said.

“These are not exactly opioids, and structure-based discovery approaches should increase their number and enhance the chances of a successful drug reaching the market at last.”

Dr Anthony Davenport, of Cambridge Univeristy, an expert in cardiovascular pharmacology who was not involved in the study, said the paper was “very exciting”.

He said Professor Kobilka had won the Nobel Prize for his work on how brain receptors are affected by certain drugs.

“The concept has the potential to revolutionize pharmacology and has been elegantly exploited with the discovery of PZM21,” Dr Davenport said.

“The authors show PZM21 selectively activates the [specific brain] pathway to give the desired analgesia in animal models.”

However, he added it was “not clear how easily PZM21 or related analogues would translate into the clinic with further studies needed on toxicology and metabolism”.