Drugs developed from biological toxins are new additions to the therapeutic armamentarium for pain control. One example is purified Botulinum toxin Type A (Botox), which binds to the presynaptic nerve terminal to prevent the release of acetylcholine and thereby prevents neurotransmission. This extremely potent bacterial toxin is currently being used for the treatment of myofascial pain, various spasmodic neuromuscular disorders, and for cosmetic procedures. Another example is Ziconotide, an N-type calcium channel blocker, which could soon be approved by the FDA for intrathecal treatment of neuropathic pain through the SynchroMed implantable drug infusion system. This new drug is a conopeptide that was developed through research on marine cone shell conotoxin.

Mappa Pufferfish   Photograph by Carlos Villoch © 2001 by Image Quest 3-D Read our copyright notice	Solander's Sharpnose Puffer (Canthigaster solandri) Photograph by Carlos Villoch © 2001 by Image Quest 3-D Read our copyright notice

 

Perhaps the most fascinating new potential drug is derived from highly purified blowfish toxin (Tetrodotoxin), a complex non-protein toxin extracted from the blowfish. Many colorful species of this spiny, balloon-like "puffer fish" are known to exist and they vary widely in the amount of toxin present. The blowfish is known as "fugu" in Japanese, and the word is believed to be derived from "fukube", meaning a round-bellied type of vase. The ancient Chinese and Japanese were aware of the fact that the fugu poison was mostly concentrated in the fish's liver, testes, ovaries, and eggs. Symptoms of TTX poisoning can occur within fifteen minutes to several hours after ingestion and start with paresthesias, floating feelings, nausea, vomiting, epigastric pain, and hypotension. Death can occur in 4-6 hours through respiratory depression as a result of paralysis of the respiratory nerves and musculature. Today, fugu is considered a great delicacy in Japan where it is eaten for its unique flavor accompanied by perioral and lingual paresthesias. Specially licensed chefs are trained to prepare the fish for consumption and most of the 100 annual poisonings are from ingestion by fisherman or through obtaining the blowfish from fishmarkets. An old Asian proverb gives insight to its special allure: "The man that eats fugu is stupid; the man that does not eat fugu is also stupid."

TTX is a prototypical sodium channel blocker that has been widely used as a neuropharmacologic probe. Sodium channel blockers act to block the diffusion of sodium through the sodium channel so as to prevent depolarization and propagation of action potentials in nerve cells. It has been recognized that many anticonvulsants beneficial for neuropathic pain as well as amide anesthetics given by injection to produce nerve block are also sodium channel blockers.

Black-saddled Sharpnose Puffer

(Canthigaster valentini)

Photograph by Carlos Villoch

 

Japanese researchers were the first to experiment with crude blowfish extract for pain control. TTX had been tested in animal models for the experimental treatment of opioid withdrawal. This led to the study of TTX as a systemic analgesic and long-acting anesthetic. Potentially the most ground-breaking studies involve the experimental use of TTX in humans as a powerful non-addictive systemic analgesic. In addition, large numbers of heroin addicts suffering from typical withdrawal pain symptoms have undergone treatment with purified TTX. Research done in China in the past four years at Beijing Medical University and other major institutions has resulted in a highly purified TTX which appears to be more potent with fewer side effects as compared to commercially-available TTX used in neurophysiology research. International Wex Technology (IWT), a publicly traded Canadian bio-pharmaceutical company that has licensed and patented this technology for clinical applications, manufactures this compound under the name Tetrodin™.

Tetrodin™ has been tested in Beijing, China for chronic malignant pain in open-label studies. Patients were suffering from metastatic cancer from various primaries (liver, stomach, and rectal), and complained of high levels of pain despite opioid treatment such as round-the-clock meperidine injections. With TetrodinTM, pain relief was noted at 5-30 minutes after the first injection. Patients were treated for only three days, and reported dramatic improvement and virtually no pain, with quality-of-life measurements assessed to be at much improved levels. These patients reported continued pain relief without known administration of additional analgesic agents at follow-up periods of 2-3 weeks. Phase II double blind studies will help confirm the significance of these dramatic findings.

IWT is currently completing North American Phase I safety studies for Tetrodin™. Significant side effects have included perioral/lingual paresthesia in all subjects, as well as mild nausea in some patients, and have essentially replicated the Chinese data. Phase II trials will test the drug for malignant and neuropathic pain, and also seek to confirm the Chinese experience in using the drug to treat withdrawal symptoms in opioid-dependent patients. Pre-clinical testing for the use of Tetrodin™ as a long-acting anesthetic is currently in progress.

TTX could represent a unique alternative to currently available analgesics without the risk of addiction. It appears to be long-acting and its mechanism of action may prove useful in managing both somatic/visceral as well as neuropathic pain states.

Close relatives of Pufferfish:

Boxfish   Photograph by Carlos Villoch © 2001 by Image Quest 3-D Read our copyright notice	Spotted Porcupinefish (Diodon hystrix) Photograph by Carlos Villoch © 2001 by Image Quest 3-D Read our copyright notice

 

References

1. Kao CY, Tetrodotoxin, Saxitoxin and their significance in the study of excitation phenomena. Pharmacologic Reviews, Vol 18, No 2, 1966

2. Shuping S, Qingbin D, Clinical Study Report of Tetrodin™ Treating Cancer Pain, Data on File, Nanning Maple Leaf Pharmaceutical Co.

3. Light WH, "Eye of Newt, Skin of Toad,Bile of Pufferfish." California Wild, Summer 1998

4. Hunter JC, Loughhead D, Voltage-gated sodium channel blockers for the treatment of chronic pain, Current Opinions in CPNS Investigational Drugs 1999 1(1) :72-81

5. Zheng JW, Lu SN, Preliminary Test on the Analgesia Pharmacodynamics of TTX, National Institute on Drug Dependence, Beijing Medical University (1996)

 

For more information, please contact the authors:

Howard Cohen, MD of Dallas, tel: (214) 826-3200, email: saratoga@jump.net

Byron Law-Yone, MD of Dallas, tel: (972) 243-3343, email: headoc01@aol.com