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Critter Chemistry

March 16, 2004

Painkilling Puffers

A powerful neurotoxin from puffer fish could provide some cancer patients with non-opioid pain relief

Victoria Gilman

DEFENSIVE In addition to toxic skin, puffer fish are best known for their ability to inflate like a balloon when threatened.

Many sushi lovers look forward to the uniquely exquisite pain caused by a mouthful of wasabi. The potent green paste, which can cause tingling tongues and teary eyes, is part of the enjoyment of the experience. But sushi gourmets also know that if fugu is on the menu, a potentially more potent delicacy is in the offering.

Fugu, the sushi-specific term for puffer fish, is described as the Russian roulette of restaurant fare. That's because the puffer's organs are laced with tetrodotoxin (TTX), a nonprotein sodium channel blocker that causes respiratory paralysis. Amounts as small as a milligram can kill an adult in four to six hours, and there is no known antidote. In Japan, sushi chefs who prepare fugu must be trained and licensed, as the slightest slip of a knife could contaminate toxin-free areas of the fish.

Despite its frightening reputation, fugu remains a popular treat in many Asian nations. Now the puffer's toxin is entering the spotlight in the West, no longer as a killer, but as a potential pain reliever. In early January, International Wex Technologies, a small bioscience firm based in Vancouver, announced that it has been cleared to embark on Phase IIb/III clinical trials for Tectin, a purified form of TTX that has already shown promising results in treating severe cancer pain. The drug is proving to be more powerful than morphine without the side effect of physical dependence.

As a poison, TTX works by blocking voltage-gated sodium channels on nerve membranes. The molecule binds to a peptide complex at the mouth of the channel, where it remains for several seconds. Without sodium cations entering the nerve, the action potential of the membrane is halted and signals are no longer transmitted. Symptoms of TTX poisoning can start as early as 15 minutes after ingestion, progressing from tingling or burning of the lips and tongue to nausea and vomiting, abdominal pain, speech difficulties, paralysis, and seizures.


TTX accumulates in the skin and internal organs of many of the 150 species of puffer fish, where it is produced by symbiotic marine bacteria. The fish has evolved with a mutated version of the sodium channel receptor that makes it immune to the toxin, giving the bacteria a home and granting slow-swimming puffers wide protection from predation. A variety of other marine animals also store TTX as a defense mechanism, as do certain frogs, newts, and salamanders. Some of these creatures, like the Australian blue-ringed octopus, use it actively to disable prey.

TTX has been used in Asia for years as a folk medicine to treat pain from migraines and menstrual cramps. To develop the toxin as a drug safe enough for commercial markets, Wex created proprietary technology to extract and purify TTX from the waste products of puffer fish killed for consumption, such as the yellowfin puffer (Fugu xanthopterus). "It basically comes out as a single compound," says Donna Shum, Wex's chief operating officer. "In the health industry, you don't want any unknowns."

In the Phase II trials for Tectin, patients were administered microgram amounts of the drug via intermuscular injection twice a day for four days. The amount of each dose is so small it can't be seen with the naked eye--a Wex spokesperson estimates that an 8-oz glass of water would equal 5 million doses of Tectin.

The 22 patients who participated in the clinical trial all suffered from severe pain related to cancer and its treatments, and none had experienced pain relief from any established analgesic. At the end of the study, 17 patients reported full or partial pain reduction, some for as long as two weeks after their final dose.

"The drug probably has promise for a select group of people suffering from cancer pain," says C. Richard Chapman, professor of anesthesiology and director of the Pain Research Center at the University of Utah. The mechanisms that cause pain can vary enormously, he says, and TTX is probably acting only on tissue injury signals transmitted within peripheral nerves. Despite its risks, morphine has held its place as a common pain management drug because it has a more general effect. "Morphine acts primarily at the spinal cord and also at higher levels in the nervous system," Chapman explains.

Chapman also points out that TTX falls into a category of drugs called anticonvulsants that are already in use in pain management. "The important question is whether this drug is adding anything new. It may be that TTX acts more selectively, in which case it could be a winner," he says. Until more extensive data are available, Chapman recommends that those involved temper their enthusiasm. "TTX needs to show a distinct advantage over other anticonvulsants to be marketable," he says.

Wex has now begun plans for the Phase III trials, which will involve randomized, double-blind, placebo-controlled tests in up to 400 participants in medical centers across Canada. Wex is also changing its delivery method from intermuscular to subcutaneous injection. If Wex can produce meaningful results from the TTX trials and publish in recognized journals, Chapman thinks the pain management community in the U.S. will pay attention.

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