Alternative to opioids found in trio of old antibiotics

New research led by scientists from UT Southwestern suggests a novel combination of three old antibiotics may be repurposed into an alternative to opiates for a particular kind of nerve pain.

The new research was inspired by the ongoing opioid epidemic in the United States. Enas Kandil, associate professor of anesthesiology and pain management at UT Southwestern, joined forces with a number of colleagues to try and find alternative pain killing drugs. Instead of developing an entirely new drug, a process that can take decades of work and billions of dollars, the researchers set out to find pre-approved drugs with undiscovered effects.

Previous research from neuroscientist Mark Henkemeyer had discovered a specific protein, called EphB1, plays a major role in the onset of nerve pain. This protein sits on the surface of nerve cells and Henkemeyer’s prior work had revealed when mice are engineered with no EphB1 they seem to not feel neuropathic pain at all.

The new research set out to investigate whether any pre-approved drug could effectively inhibit EphB1 activity. A large library of FDA-approved medicines was scanned, with the researchers looking at different drug molecules to see if any had the capacity to bind to EphB1.

Three old antibiotics unexpectedly fit the bill. Demeclocycline, chlortetracycline, and minocycline – all members of a family of antibiotics called tetracyclines.

Subsequent in vitro testing confirmed the drugs did effectively bond with, and inhibit, EphB1 activity. But did that action translate into a nerve painkiller?

The antibiotics were then tested on trio of mouse models designed to investigate neuropathic pain. Combining the three antibiotics into a single injection resulted in significant reductions to the animals' pain responses. Each antibiotic was somewhat effective alone, but the triple combination was most effective at the lowest doses.

Examining tissue from the animals revealed EphB1 proteins had effectively been inactivated by the novel antibiotic formulation. This indicates that blocking EphB1 with these antibiotics can eliminate neuropathic pain, at least in animal tests.

Kandil says the next stage of research will be investigating whether this antibiotic-induced mechanism occurs in humans. It is always difficult to predict how effectively animal studies translate across to humans, but Kandil is confident these antibiotics, used for half a century with a proven safety profile, could potentially be an effective neuropathic pain reliever.

"Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic," says Kandil. "This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

The new study is published in the journal PNAS.

Source: UT Southwestern