Chronic pain: New compound may replace opioids

Researchers tested an alternative to opioids in a mouse model of chronic pain and found it to be safe, effective, and possess none of the side effects of opioids.

A person is said to have chronic pain when they feel pain every day for 3 months.

Opioids such as morphine and fentanyl are routinely prescribed to treat the "major public health problem" that is chronic pain, but over-prescription of opioids has also led to a public health crisis.

Opioids activate reward centers in the brain, which makes them highly addictive. In the U.S., over 2 million people have developed "substance use disorders" as a result of being prescribed opioid pain relievers.

Additionally, in the long-term, opioids may not even be useful for treating chronic pain, because the body becomes tolerant to the drugs. Also, opioids can make the body even more sensitive to pain, and some studies have shown that they can raise the risk of chronic pain in the long run.

In this context, the need for creating safer alternatives to opioids is dire. New research brings some much-needed hope, as a modified form of a botulinum toxin is proved to be safe and effective for treating chronic pain in rodents.

Maria Maiarù, who is a research associate in the Cell & Developmental Biology department at the University College London (UCL) in the United Kingdom, is the lead author of the paper.

The findings have now been published in the journal Science Translational Medicine.

Creating a pain-silencing 'warhead'
 
Maiarù and her colleagues broke down a botulinum molecule and reconstructed it using an opioid called dermorphin.

By doing so, they created a compound that they call derm-bot, which they used to switch off the pain signals that spinal cord neurons send to the brain.

First, dermorphin binds to the opioid receptors on the neurons' surface. Then, this gives the derm-bot compound access inside the cell, where botulinum blocks the release of the neurotransmitter that carries the pain signal to the brain.

Co-corresponding study author Prof. Bazbek Davletov — of the Department of Biomedical Science at the University of Sheffield, also in the U.K. — says, "We needed to find the best pain targeting molecular parts to direct the botulinum silencing 'warhead' to the pain-controlling system in the spine."

"For this, we developed a molecular Lego system which allows us to link the botulinum 'warhead' to a navigation molecule, in this case, the strong opioid called dermorphin, allowing the creation of [...] long-lasting painkillers without the side effects of opioids."

Compound could revolutionize treatment

To test the effects and behavior of the compound in a mouse model of inflammation and chronic pain, the researchers treated 200 mice with one shot of either derm-bot, sp-bot — which is a differently modified botulinum molecule — or with one injection of morphine.

The behavior of all the rodents was tracked for 5 years. During this time, the rodents' responses to pain, as well as the location and binding properties of the two botulinum-based compounds, were examined.

"We were impressed to see that one tiny injection was enough to stop chronic pain caused by inflammation and nerve damage for at least a month," says Maiarù.

"Both sp-bot and derm-bot have a long-lasting effect in both [the] inflammatory and neuropathic pain model, successfully silencing neurons without cell death," she continues.

"Furthermore," says Maiarù, "a single injection of derm-bot reduced mechanical hypersensitivity to the same extent as morphine. We hope to take our investigations forward with the aim of translating this into the clinic."

The drug "avoids the adverse events of tolerance and addiction often associated with repeated opioid drug use," explains co-corresponding study author UCL professor Steve Hunt.