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Alternative to opioids found in trio of old antibiotics

Alternative to opioids found i...
A combination of three old antibiotics has been found to block nerve pain in mice
A combination of three old antibiotics has been found to block nerve pain in mice
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This illustration shows the atomic level resolution of the tetracycline antibiotic bound to the EphB1 receptor.
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This illustration shows the atomic level resolution of the tetracycline antibiotic bound to the EphB1 receptor.
A combination of three old antibiotics has been found to block nerve pain in mice
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A combination of three old antibiotics has been found to block nerve pain in mice

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.

This illustration shows the atomic level resolution of the tetracycline antibiotic bound to the EphB1 receptor.
This illustration shows the atomic level resolution of the tetracycline antibiotic bound to the EphB1 receptor.

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

7 comments
TomWatson
EphB-1 - Stamp it out! This may be promising for my back issue, but no Buzz, Dammit!!
see3d
The danger is unintended side-effects. How would long-term use disrupt the beneficial bacteria in the gut?
Jinpa
A significant problem with using antibiotics is that it pretty much wrecks the microbiome. So unless convincing studies are done which show that such problems do not occur, this may be a cure worse than other treatments, or the disease or condition that the combination described is intended to treat. First, do no harm.
Kevin Ritchey
I used minocycline for years and found no pain reduction after suffering from a large cell sacral tumor removal. Certainly not as prescribed.
Karmudjun
The trio "at low doses" may indeed knock EphB-1 out - or end up causing nerve cells to up regulate EphB-1 receptors, as one guesses might happen with long term use (like the minocycline comment below) and wouldn't that limit effectiveness of the triad? Not to mention the close to 10% side effect of tendon rupture with tetracyclines, a threat that limits my recommendation for prescribing at standard doses. More study in human subjects please!

Very nice write up Rich, we do need non-addictive methods of managing neuropathic pain. Some of the most difficult pain syndromes to treat. Keep bringing on the studies!
Dan
Same ole story day. Try this, you're cured get out of my office you drug seeking addict. Stop torturing animals to give people something, without really giving them anything at all. Documented pain patients with all of the proof of need have gone through the same thing for years, before finally getting the opioids that do some good. Walking around like a zombie in pain so they can give you anything except what really works. If it gets any easier to be a pain doctor. They won't even have to show up at work to refer you to pain causing physical therapy, or call you a lair. Desperate people will have "no choice again" for their future health with this new experiment, and the doctor's just want the money and the next so-called drug seeker with proof of need, waiting for any relief.
Karmudjun
@Dan, as a physician who treated patients in pain as a calling, I feel sorry for you. Your view of our medical profession and almost all of your comment is cynical at best. I fear you haven’t had good experiences with physicians.

Pain medicine is difficult, it is not a walk in the park. A pain practice does deal in opiates to dull the sensation of pain when alternatives don’t help. Opiates leave patients constipated, can even leave them sleep apneaic or hypoxic. Some of us think the personality changes induced are not a safe trade-off either.

I had several patients walking around like zombies because we found only opiates could dull their pain. So what in your opinion ‘really works’? That ‘magic bullet’ is one I’d like to know even though I’m no longer treating patients.

Lastly, desperate people DO have choices, the choices they make with or without medical advice are not coerced. And doctor shopping occurs way too frequently among those ‘desperate’ people.