How closely is oxycodone related to morphine

New pain relievers work better than opioids

Hope for pain sufferers: Researchers may have discovered a potent alternative to popular opioid pain relievers. The new active ingredient inhibits pain in rhesus monkeys 100 times more effectively than morphine, but it is neither dependent nor does it cause respiratory paralysis or other side effects typical of opioids, as the scientists report in the journal “Science Translational Medicine”. If this effect can be transferred to humans, it could help pain patients worldwide.

Whether in the back, head or joints: Millions of people worldwide suffer from chronic pain. Many of them are only helped by opioids - derivatives of opium that block pain stimuli by docking on so-called mu-opioid receptors in the spinal cord and brain. The problem: Opioids are addictive and their effect is weakened after a while due to a habituation effect. In addition, opioids in higher doses have a breathing-paralyzing effect and may even strengthen the pain memory instead of erasing it, as has been hoped in the meantime.

Search for the perfect attachment partner

Scientists around the world are therefore looking for pain relievers that are as effective as the common opioids, but do not have their side effects and potential for addiction. Such a drug could now have been discovered by Huiping Ding of the Wake Forest School of Medicine in the USA and his team. For their study, they specifically looked for molecules that not only bind to the mu-opioid receptor, but also to another opioid docking point, the nociceptin receptor.

"Molecules that dock on the nociceptin receptor increase the pain-relieving effect of the mu receptor at the level of the spinal cord and brain," the researchers explain. “But they do not cause respiratory paralysis and dependencies on other active substances.” On the computer, they tested numerous molecules to determine how well they bound to the nociceptin receptors and optimized the best candidates through chemical modification.

AT-121 has already proven to be highly effective and well tolerated in rhesus monkeys. © Jakub Ha &

100 times more potent than morphine

The scientists found what they were looking for with AT-121: This molecule docked with high efficiency on the mu and nociceptin receptors and activated the corresponding signal chains even at a low dose. Ding and his colleagues then used rhesus monkeys to test how well this remedy works against pain in the living organism. They received various doses of AT-121 injected under the skin and then completed pain tests. The researchers also examined the side effects of the agent.

The result: Even a very small dose of AT-121 inhibited the monkeys' pain just as effectively as a classic opioid. "The analysis of the dose-response curve showed that this effect was 199 times more potent than morphine," the researchers report. Already 0.01 milligrams per gram of body weight blocked the pain stimuli - with morphine, one gram per kilogram is required for this.

No potential for addiction to be determined

But what about the drug's addictive potential? In return, the rhesus monkeys were given switches with which they could administer doses of the opioids cocaine, remifentanyl or oxycodone or AT-121 to themselves. As expected, the opioids led to the typical addiction reinforcement after just a few days: the monkeys administered more and more of them and suffered withdrawal symptoms when they were forced to stop, as the researchers report.

Not so with AT-121: The rhesus monkeys did not press the switch for a new dose of this agent more often than in the control experiments with saline solution. Withdrawal symptoms did not occur either. Another experiment also showed that even at a ten times higher dose of AT-121, neither respiratory paralysis nor cardiovascular complications occurred. "The animals also showed no drowsiness or impaired motor skills," report Ding and his colleagues.

Also effective in humans?

According to the researchers, AT-121 and similar active substances could be a promising alternative to the classic opioids. "According to our study, AT-121 is not only well tolerated and not addictive, it is also very effective against pain," says Ding's colleague Mei-Chuan Ko. Instead, it even seems to be able to remove an existing dependence on oxycodone or other opioid pain relievers.

A similarly good effect in humans is quite likely, emphasize the researchers. As primates, rhesus monkeys are already closely related to us humans. "The fact that these results were obtained with non-human primates is of great importance," explains Ko. "It shows that compounds like AT-121 have the potential to work effectively in humans as an alternative to common opioid pain relievers."

In fact, other research teams have already found active ingredients that have been successful in mice, for example. However, the step from mouse to human fails far more often. Whether the AT-121 actually works for us and is safe must now be clarified further. (Science Translational Medicine, 2018; doi: 10.1126 / scitranslmed.aar3483)

(Wake Forest Baptist Medical Center, Aug 31, 2018 - NPO)

August 31, 2018