Perfect painkiller? Safe alternative to opiates may have been found

The Independent has claimed: “Scientists discover what could be a ‘perfect’ painkiller without side effects”.

Opiate-based painkillers such as morphine are extremely effective in relieving pain. The problem is that they are also addictive if taken on a medium- to long-term basis. Also morphine, if taken at high dosage, can cause potentially fatal breathing difficulties (respiratory depression).

New research suggests that a newly-identified compound, PZM21, could be more effective at longer-lasting pain relief than morphine, without any of the attendant drawbacks.

The compound caused less activation of the brain’s reward system compared to morphine, indicating that it may be less addictive. And when tested in mice it also resulted in less respiratory depression and constipation than morphine.

However, this was an early-stage laboratory study in mice. We don’t know that this provides the whole answer, and findings would need to be replicated in humans.

It is also important to stress that when taking painkillers, more doesn’t mean better. It can be extremely dangerous to take more than your recommended dose. This applies not only to prescription painkillers, but over-the-counter products such as paracetamol.

Where did the story come from?

The study was carried out by researchers from Stanford University School of Medicine, the University of California, UNC Chapel Hill Medical School all in the US and the Friedrich-Alexander-Universitat Erlangen-Nurnberg and the Paracelsus Medical University in Germany. It was funded by the US National Institutes of Health grants.

The study was published in the peer-reviewed medical journal Nature.

There may be a conflict of interest as several of the authors have filed a provisional patent on PZM21 and related molecules. Several are also consultants and co-founders of Epiodyne, a company seeking to develop new analgesics. Though these sort of links with industry, when it comes to researching drugs, are nothing out of the ordinary.

The UK media’s reporting was generally accurate; with the Independent acknowledging the limitations of the drug as it “shows ‘promise’ as a replacement for opium-based drugs such as morphine – although it has only been tested in mice so far”.

What kind of research was this?

This was an animal study which aimed to identify a new compound that could act as a more effective painkiller than morphine.

Morphine is an alkaloid from the opium poppy that is used to treat pain. Although the natural products morphine, codeine, and the semi-synthetic drug heroin, are more reliably effective at providing pain relief than raw opium, they have potentially lethal side effects. These include respiratory depression and constipation. Current opioid painkillers also have the negative side effect of being addictive.

Animal studies are often used in early stages of research to see how biological mechanisms may work in humans. However, humans are not identical to animals and there are many stages of development from animal-based studies to developing treatments for humans.

What did the research involve?

This was complex laboratory research which measured the painkilling properties of a new compound called PZM21 on mice. This compound is thought to work further down the painkilling pathway than morphine, so it was hoped that it would have fewer undesirable side effects.

The researchers compared PZM21 with morphine, another compound called TRV130 and placebo. They looked at the strength of pain relief, how long it lasted and whether it acted on the addiction centres in the brain. They also measured any effect on the breathing rate and constipation.

What were the basic results?

Pain relief from PZM21 lasted longer than morphine. The effectiveness and length of pain relief was assessed by seeing how well (or not) the mice tolerated exposure to heat.

It was found to last up to 180 minutes in mice. It was 40% effective at this time point compared to 5% for morphine. At 120 minutes, PZM21 was still able to exert 60% pain relief compared to 15% for morphine.

PZM21 caused less activation of reward pathways compared to morphine. This was assessed by studying how the mice moved. Rodents that are “high” tend to run round at great speed (which is known as an acute hyperlocomotive response).

PZM21 did not reduce the breathing rate compared to placebo. The rate during the injection for all of the mice was high at around 400 breaths per minute (normal is around 80 to 230). Morphine caused it to reduce to around 150 breaths per minute, while PZM21 and placebo reduced it to around 250 breaths per minute.

PZM21 caused less constipation than morphine.

How did the researchers interpret the results?

The researchers concluded that “the structure-based approach led to a compound with novel properties; it was structurally distinct compared to previously explored opioid ligands, with not only substantial signalling bias but also with unexpected opioid receptor selectivity.

“These features have contributed to favourable biological effects, with long-lasting analgesia coupled to apparent elimination of respiratory depression, specificity for central over reflex analgesia, lack of locomotor potentiation and conditioned place preference, and hence a reduced potential for opioid-induced reinforcement for PZM21 and molecules like it.”

Conclusion

This experimental study identified a new compound, PZM21, and investigated its effectiveness and safety in mice compared to morphine and TRV130. This research hopes to aid the development of an effective alternative to morphine that has none of the drawbacks, such as respiratory depression, constipation and addiction.

The researchers’ experiments in mice found that PZM21 was more effective as a longer-lasting painkiller than morphine and that, at equal painkilling doses, had hardly any effect on respiratory depression, unlike morphine. They also found that compared to morphine, the constipating effect was reduced and the compound did not activate the dopaminergic reward system, a mediator of addiction.

This research helps take us one step closer to developing effective painkillers that are without the potentially lethal side effects of morphine. But this was an early stage experiment in mice. We don’t know that this drug will provide the answer and findings will need to be confirmed in human studies.

While these findings may drive future drug research, it is unclear how long this process may take. 

Links To The Headlines

Scientists discover what could be a ‘perfect’ painkiller without side effects. The Independent, August 17 2016

An end to morphine? New drug could provide safer painkiller alternative amid opioid epidemic. Mail Online, August 17 2016

AN END TO MORPHINE? Boffins develop ‘promising’ new painkiller that is safer than morphine. The Sun, August 17 2016

Links To Science

Manglik A, Lin H, Aryal DK, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature. Published online August 16 2016