An Open-Label, Multi-Dose Efficacy and Safety Study of Intramuscular Tetrodotoxin in Patients with Severe Cancer-Related Pain

Abstract

Cancer pain is a prevalent and serious public health issue, and more effective treatments are needed. This study evaluates the analgesic activity of tetrodotoxin, a highly selective sodium channel blocker, in cancer pain. A Phase IIa, open-label, multicenter, dose-escalation study of intramuscular tetrodotoxin was conducted in patients with severe, unrelieved cancer pain. The study design called for six ascending dose levels of intramuscular tetrodotoxin, administered over a four-day treatment period in hospitalized patients, with six patients to be enrolled within each successive dose level. Twenty-four patients underwent 31 courses of treatment at doses ranging from 15 to 90 microg daily, administered in divided doses, over four days. Most patients described transient perioral tingling or other mild sensory phenomena within about an hour of each treatment. Nausea and other toxicities were generally mild, but two patients experienced a serious adverse event, truncal and gait ataxia, that resolved over days. Seventeen of 31 treatments resulted in clinically meaningful reductions in pain intensity, and relief of pain persisted for up to two weeks or longer. Two patients had opioids held due to narcosis concurrent with relief of pain. Somatic, visceral, or neuropathic pain could all respond, but it was not possible to predict which patients were more likely to have an analgesic effect. Tetrodotoxin was overall safe. It effectively relieved severe, treatment-resistant cancer pain in the majority of patients and often for prolonged periods after treatment. It may have a novel mechanism of analgesic effect. Further study is warranted.

A Multicentre Open-Label Safety and Efficacy Study of Tetrodotoxin for Cancer Pain

“…A range of other symptoms, including irritation at the administration site, were also reported. The adverse events presented during successive cycles were similar to those described during the first cycle, and the range and prevalence of events reported in the present study were similar in nature to those reported in previous trials 14,15 .…”

“…Second, in patients who describe an analgesic effect, relief of chronic cancer pain is persistent within successive treatment cycles up to and beyond 1 year, without evidence of tolerance: the anti-nociceptive effect of ttx is maintained for an average of 3 weeks, and this pain relief does not diminish with repeated cycles of the drug. Previous studies have reported the range of acute toxicity with administration of ttx at the dose used in the present work 14,15 . Typically, toxicity has been mild and primarily sensory, with transient peri-oral numbness or tingling as the predominant experience.…”

“…The ttx was administered 2 or 3 times daily for a total of 4 days. The study showed that 17 of the 31 treatments resulted in a clinically meaningful reduction in pain intensity and that relief of pain persisted for up to 2 weeks or longer 14 . This dose escalation study found that 30 μg twice daily for 4 days provided an acceptable toxicity and analgesic profile.…”

Toxins and Drug Discovery

“…It is, therefore, perhaps surprising that tetrodotoxin, which blocks most subtypes of sodium ion channels, is also in clinical trials. Most of the clinical work has been in Canada with patients suffering from severe cancer-related pain (Hagen et al, 2007(Hagen et al, , 2008(Hagen et al, , 2011. Results show some promise, with some patients noting improvements in symptoms, but more extensive testing may prove to be more demanding.…”

Puffer fish and its consumption: To eat or not to eat?

“…Therefore, higher forms of animals and humans are more sensitive to TTX, which can be toxic at extremely low concentrations (70) . The minimum lethal dose for humans is 2 mg (71,72,73,26,74) .…”