Could a pufferfish toxin be a safe alternative to opioids?

Scientists at Boston Children’s Hospital have developed a new method for delivering a pufferfish toxin as a painkiller. (George Parrilla/Wikimedia Commons)

A tiny bite of ill-prepared pufferfish could kill a person because of a potent, naturally occurring neurotoxin called tetrodotoxin (TTX). Despite those lethal risks on the dinner table, scientists have been exploring TTX’s use in pain management. And now, researchers at Boston Children’s Hospital have developed a novel way to deliver TTX as a painkiller, and they have turned up some positive results from rat studies.

TTX’s poisonous effect lies in its ability to block voltage-dependent sodium ion channels in motor nerves, causing symptoms such as numbness and paralysis serious enough to cause death. But the sodium channels also serve as conduits for pain signals to the central nervous system, so inhibiting them could theoretically offer pain relief.

The Boston Children’s team, led by Daniel Kohane, has made an extended-release version of TTX by attaching it to a polymer backbone. The new regimen is designed to release the drug in small, safe doses, the researchers explained in a recent study published in the journal Nature Communications.

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Kohane’s team has previously used near-infrared light and ultrasound to control the release of the nerve-blocking drug, triggering on-demand relief of pain. This time around, rather than packing TTX into small liposomes as they did before, the researchers bound it to the polymer. The body’s own hydrolysis—the natural breaking down of a compound by water—slowly degrades the bond and releases TTX.

Kohane’s fellows, Chao Zhao and Andong Liu, tried different drug loads and polymer formulations to prolong the potential nerve-blocking effect with the least toxicity, according to a statement.

To further increase its safety, they added a chemical penetration enhancer that makes the nerve tissue more penetrable, therefore allowing smaller amounts of TTX to achieve the same effect.

“A lesson we learned is that with our previous delivery systems, the drug can leak out too quickly, leading to systemic toxicity,” Kohane said in a statement. “In this system, we gave an amount of tetrodotoxin intravenously that would be enough to kill a rat several times over if given in the unbound state, and the animals didn’t even seem to notice it.”

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When injected in rats, the TTX-based regimen blocked the targeted nerves for up to three days with little toxicity and no apparent sign of tissue injury, the team said.

Converting the toxic TTX into an analgesic has been tried before. Canadian company Wex Pharmaceuticals has even tested a TTX therapy in a phase 3 trial on cancer patients with chemotherapy-related pain. Though results from that study weren’t strong enough to support the therapy’s official use, it did demonstrate “a clinically important analgesic signal,” investigators of that study said.

Developing safer painkillers has become an urgent task lately as opioid abuse continues its rampage through the U.S. University of North Carolina scientists recently made a drug that could selectively bind to the kappa opioid receptor, which they argued could reduce the addictive effects of activating too many receptors like common opioids do. A team at Indiana University previously reported promising mouse results for a positive allosteric modulator compound that could amplify the brain’s ability to produce pain-relieving chemicals.

Kohane and colleagues also hope their new approach could make TTX a better alternative to opioids. In theory, the nerve blocking effect in humans could even last longer than it does in rodents, as TTX can be administered more safely to people, according to Kohane.

“We could think about very long durations of nerve block for patients with cancer pain, for example,” he said in a statement. “Certainly for days, and maybe for weeks.”

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