With the opioid crisis in the spotlight, scientists are searching for new ways to tackle pain. One group has turned its attention to a lethal toxin that occurs naturally in some marine creatures. The latest study in rats provides encouraging results.

Opioids are a range of drugs that act on opioid receptors to quickly relieve pain. Although they are effective and safe when people use them correctly, they are highly addictive.

According to the Centers for Disease Control and Prevention (CDC), in the United States in 2017, two-thirds of drug overdose deaths involved an opioid. In the same year, 47,000 people died due to opioid overdoses, and prescription opioids played a role in 36% of these deaths. According to the National Institute on Drug Abuse, in 2017, 1.7 million people in the United States had "substance use disorders related to prescription opioid pain relievers." These statistics underline the urgent need for a nonaddictive but still effective replacement for opioids.

Dr. Daniel Kohane, PhD, recently led a study by a group of researchers from Boston Children's Hospital in Massachusetts who believe that they might have found the solution in a lethal, ocean-derived toxin. The scientists published their most recent findings in the journal Nature Communications.

Tetrodotoxin on trial

Several different sea creatures, including pufferfish and blue-ringed octopuses, contain tetrodotoxin. This toxin blocks sodium channels, preventing nerves from carrying impulses. Following ingestion, it can cause symptoms that include headaches, vomiting, and a tingling sensation in the tongue and lips. If a person consumes enough of it, it can lead to respiratory arrest and death.

Tetrodotoxin is roughly 1,200 times more toxic than cyanide, which, perhaps, makes it an unlikely candidate to treat acute pain. Dr. Kohane has been interested in the therapeutic potential of this toxic compound for some time. Medical News Today recently asked him why tetrodotoxin interested him, and he said, "Tetrodotoxin and compounds like it are very potent local anesthetics. Also, unlike conventional local anesthetics, they don't cause seizures, cardiac arrhythmias, and tissue (nerve and muscle) injury."

Dr. Kohane had already demonstrated in an earlier study that tetrodotoxin produces anesthesia. The problem, however, is the chemical's potent toxicity. In small amounts, pain relief is significant, but in higher quantities, it is lethal. Dr. Kohane has attempted to limit the compound's toxicity while maintaining its potent analgesia.

For instance, in a previous study, his team packaged tetrodotoxin within a lipid membrane. On the surface of the membrane, they added molecules called sonosensitizers that are sensitive to sound. Then, they implanted the tiny sacs under the skin of rats. Next, using ultrasound, they triggered the toxin's release in small doses, relieving pain and minimizing toxicity.

In another study, Dr. Kohane and his team combined two nerve-blocking agents: tetrodotoxin and capsaicin (the chemical that gives chili peppers their punch). They found that the two compounds enhanced each other's effect, blocking nerve conduction more than the sum of using the two drugs separately.

Removing a toxin's teeth

Despite his earlier work, as it stands, tetrodotoxin's toxicity limits its use in humans. "A lesson we learned is that with our previous delivery systems, the drug can leak out too quickly, leading to systemic toxicity," says Dr. Kohane.

Dr. Kohane, however, is persistent. In his most recent study in an animal model, he and his team fused tetrodotoxin to a polymer backbone. The body can only break down the bonds that hold the backbone to the drug gradually, releasing the toxin slowly.

"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."

—Lead author Dr. Daniel Kohane, PhD

With his colleagues, Chao Zhao, PhD, and Andong Liu, PhD, Dr. Kohane trialed a range of polymers to achieve the longest-lasting nerve block with minimal levels of toxicity. As Zhao explains, "We can modulate the polymer composition to control the release rate."

Chemical safety measure

To improve safety further, the scientists added a third character in the form of a chemical that enhanced the permeability of nerve tissue. This allowed the toxin to enter the nerves more easily, and, therefore, the researchers could reduce the dose of tetrodotoxin.

As Dr. Kohane explains "With the enhancer, drug concentrations that are ineffective become effective, without increasing systemic toxicity. Each bit of drug you put in packs the most punch possible."

With this concoction of polymer, toxin, and permeability enhancer, a single injection near the sciatic nerve of rats blocked the nerve for 3 days. Importantly, there were no apparent signs of tissue damage or toxicity.

These are still early days, and it is likely to be a long time before tetrodotoxin will take the reins from opioids, but the wheels of research are turning. Dr. Kohane told MNT that some groups are trialing tetrodotoxin in humans.

He explained that "similar compounds, such as neosaxitoxin, have been used in humans for infiltration anesthesia [...] but are still undergoing clinical trials." When we asked him about the main stumbling blocks, he replied, "The usual: time, money, regulatory processes."

Because 130 people, on average, die from opioid overdoses every day in the United States, medical researchers need to follow every line of investigation to its conclusion. Dr. Kohane told MNT that he has "a lot" of follow-up work planned, so the future looks bright for this unusually potent toxin.