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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 U.S. had “substance use disorders related to prescription opioid pain relievers”. The statistics above underline the urgent need for a nonaddictive but still effective replacement for opioids.
Dr. Kohane, however, is persistent. In his most recent study in an animal model, he and his team fused tetrodotoxin to a polymer backbone.
Dr. Daniel Kohane, Ph.D., 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.
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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.
The statistics above underline the urgent need for a nonaddictive but still effective replacement for opioids.
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.”
With his colleagues, Chao Zhao, Ph.D., and Andong Liu, Ph.D., 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.”