It may seem counterintuitive, but scientists are investigating a potent neurotoxin found in pufferfish known as tetrodotoxin to relieve lingering, hard-to-treat pain in the skin known as chronic subcutaneous pain.
“The main challenge is [controlling] its toxicity,” explained Chao Zhao at the University of Alabama. This is because even a small dose of a couple of milligrams can be lethal. But Zhao and his team have come up with a solution in the form of a marker pen.
“Our pen is designed to control the dose with great precision, ensuring that only a tiny, safe amount reaches the skin,” he said. “This way, we can take advantage of tetrodotoxin’s strong pain-relieving effects while minimizing risks.”
Though still proof-of-concept, the team are confident that their “simplified approach to a difficult problem” will lay the foundation for more studies, and, if found safe and effective, this research could be extended to human trials.
Pen precision
The idea of using marker pen to safely deliver tetrodotoxin came to Zhao giving a lecture, during which he was writing on a whiteboard.
“A marker pen stores water-based ink in a sponge core and delivers a consistent amount through capillary action,” explained Zhao. “If we replace the ink with an aqueous tetrodotoxin solution, the pen could continuously release a precise, controlled amount of tetrodotoxin — potentially at the nanogram level, far below the toxic threshold.”
Tetrodotoxin works by blocking electrical signaling along nerves with a potency estimated to be 1,000 times that of standard local anesthetics, and 3,000 times stronger than morphine for pain relief.
But this is a double-edged sword because while potent, it is also extremely toxic.
The problem is that current therapies including topical creams and anesthetic injections, only work well for moderate pain but do not help severe long-term pain. This is because they are not powerful enough, their effects are short lived or the way they work does not treat the root of the problem.
Zhao explained that unlike conventional pain medications that broadly act on pain pathways, such as opioids, tetrodotoxin specifically blocks the channels that allow transmission of pain.
“By silencing these channels, tetrodotoxin can effectively prevent the continuous and excessive firing of sensory neurons that drive postherpetic neuralgia pain,” he said. “In 2020, my father developed postherpetic neuralgia [after a bout of shingles]. He tried almost all commercially available creams and patches to relieve the pain. Witnessing his suffering inspired me to develop a more potent and effective method to treat postherpetic neuralgia and other severe skin pain conditions.”
Zhao says that, in addition to its superior potency, tetrodotoxin has several advantages over commonly used anesthetics such as bupivacaine and lidocaine. For example, it does not cause muscle cell breakdown or permanent nerve damage, nor does it cross the blood–brain barrier, reducing the risk of addiction. Unlike conventional local anesthetics, it also does not affect cardiac cells or normal heart function.
Risk and reward
To create their pens, Zhao and his team filled commercially available felt tip marker pens with a very small dose of tetrodotoxin mixed with other compounds to improve skin permeability.
In animal studies, the team found that just 900 nanograms of tetrodotoxin caused complete relief from pain for 4 hours, and reduced pain for approximately 11 hours. Importantly, there was no toxicity observed or damage to muscles or nerves.
This isn’t the first time tetrodotoxin has been explored, in fact, human trials in cancer patients demonstrated pain relief but also found side effects. Concerns about safety including toxicity, the drug delivery system, and logistical challenges of storage and transportation have hindered its progression as a pain killer in clinical practice.
Getting the delivery system right is essential if therapeutics are to be developed. Considering the high risk, the team say they would take safety precautions to minimize toxicity to humans. For example, if the pen was damaged and tetrodotoxin leaked out.
“To prevent any risk of human poisoning from environmental exposure to tetrodotoxin, the amount of tetrodotoxin in each marker pen will be kept below the minimum oral dose known to cause acute toxicity in humans. This amount is considered safe for practical use, as it is significantly lower than both the lethal dose and the dose that causes noticeable symptoms in human,” explained Zhao.
The team say because their application is topical, a much lower dose is generally needed in these cases, compared to what was tested in previous trials, where it was given as injections and therefore increasing the risk of the toxin entering the bloodstream.
Further preclinical studies will determine whether tetrodotoxin, delivered via the marker pen system, can successfully translate into a safe and effective treatment for patients.
Reference: Cai, Y, et al., Tetrodotoxin Delivery Pen Safely Uses Potent Natural Neurotoxin to Manage Severe Cutaneous Pain, Advanced Healthcare Materials (2025)s. DOI: 10.1002/adhm.202401549
