Scientists are scrambling to find painkillers that can ease suffering without the addictive potential of opioids. One potential solution, a new study out Wednesday in Science Translational Medicine suggests, might involve creating modified versions of the common wrinkle treatment botox, otherwise known as botulinum toxin.
Botox is produced by its namesake Clostridium botulinum, a soil-loving bacteria that only can grow in oxygen-free environments. It’s a potent neurotoxin that can paralyse the entire body, causing people to die from respiratory failure. People can get sick from botulinum toxin found inside sealed cans contaminated with the bacteria, a disease called botulism. But certain types of the toxin (there are eight in total) can also be used in low doses to block nerve signals for months at a time, including those responsible for communicating with muscles.
For decades, botox injections have been used as a muscle relaxant, allowing people to temporarily get rid of facial wrinkles. Increasingly, it’s also been used for conditions like muscle spasms, chronic migraines, and neck pain.
Even when botox is used to treat pain, though, it does so by blocking the nerves responsible for controlling muscles, not the nerves that transmit pain signals to the brain. Opioids, on the other hand, are uncannily good at interacting with the nerves responsible for pain conduction, but their effects only last for a few hours at most and come with all sorts of unwanted side effects.
The researchers behind this current study, mostly based at the University of Sheffield, say they’ve found a way to create a hybrid that combines the best of both types of drug.
“We invented a molecular Lego system, named protein stapling, which allows us to put together various molecules by simple mixing,” senior author Bazbek Davletov, chair of the department of biomedical science at the University of Sheffield, told Gizmodo via email.
They switched out aspects of the botox molecule with that of dermorphin, an opioid 40 times more potent than morphine that was first discovered in tree frogs. Dermorphin has mostly been used in animals, including, most infamously, as a performance enhancer for racehorses. “In our engineering process, we replaced the botulinum part responsible for binding to muscle-controlling neurons with peptides which bind only to pain-conducting nerves,” Davletov said.
In experiments with mice over a five-year-span, the team’s creation, dubbed Derm-BOT, seemed to reduce pain sensitivity to the same degree as morphine, for up to 23 days. And there was no sign of either addiction or toxicity in the mice’s brains. Because only tiny doses of botox are needed to block nerves for three to four months, Davletov said, the treatment is also less likely to provoke an immune response that would hamper its painkilling effects.
The team also paired botox with another toxin, substance P-saporin. Substance P-saporin is used to treat cancer pain in dogs in low doses, but even in those doses, it can kill off nerve cells, making it too risky an option for people. Their hybrid version, called SP-BOT, also seemed to block chronic inflammatory and nerve pain in mice, without any cell death. Neither Derm-BOT nor SP-BOT appeared to interfere with regular pain sensation.
“The most promising aspect of our new approach is that we can prolong the opioid pain relief effect for many months with a single injection of our new bio-pharmaceuticals,” Davletov said. “This could benefit chronic pain sufferers in many ways and also avoid the terrible consequences of continuous use of opioids.”
The authors admit that many opioid alternatives have similarly shown promise in animals, only to fail in clinical trials in people. But given the desperate need for better painkillers, they believe their experimental treatments are worth pursuing further.
“We now need to produce the Derm-BOT drug under conditions required for human grade bio-pharmaceuticals,” Davletov said. “Then we can move towards clinical trials.”
Because of how expensive that process can be, the team is currently looking for partners with “experience in pharmaceutical translation,” he added. [Science Translational Medicine]