Tetrodotoxin for Moderate to Severe Cancer-Related Pain: A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Trial

Abstract

Objective This study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain. Methods Eligible patients were randomized to receive TTX (30 μg) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints (including pain and quality of life measures), and safety was evaluated using standard measures. Results 165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis “intent-to-treat” population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (p = 0.0460). The p value was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient. Conclusions Although underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care. This clinical study is registered with ClinicalTrials.gov (NCT00725114).

The influence of voltage‐gated sodium channels on human gastrointestinal nociception

“…As a result of the issues described above, investigators have been searching for more selective VGSC antagonists and agonists in order to develop more targeted pain therapies with fewer side effects. Subcutaneously injected TTX has shown efficacy for control of moderate–severe pain in the setting of cancer when other analgesics have failed . Subcutaneous TTX has also demonstrated promise for management of gastrointestinal pain associated with intracolonic instillation of capsaicin or mustard oil in murine models .…”

“…Subcutaneously injected TTX has shown efficacy for control of moderate-severe pain in the setting of cancer when other analgesics have failed. 104 Subcutaneous TTX has also demonstrated promise for management of gastrointestinal pain associated with intracolonic instillation of capsaicin or mustard oil in murine models. 21 Studies evaluating the impact of TTX on human visceral perception are lacking but careful administration of this agent could prove to be useful for this purpose.…”

From identification to functional characterization of cyriotoxin‐1a, an antinociceptive toxin from the spider Cyriopagopus schioedtei

“…Indeed, this subtype is highly expressed in the sensory nervous system, principally in small and large dorsal root ganglia (DRG) neurons, the anatomical support of pain signalling from the skin and organs to the spinal cord (Dib-Hajj, Yang, Black, & Waxman, 2013). Moreover, it is well established that low MW compounds that target Na V channels, such as tetrodotoxin (TTX), attenuate chronic and debilitating pain in humans (Hagen et al, 2017). Moreover, it is well established that low MW compounds that target Na V channels, such as tetrodotoxin (TTX), attenuate chronic and debilitating pain in humans (Hagen et al, 2017).…”

“…Furthermore, a multitude of genetic mutations of the Na V 1.7 protein are linked to painless or painful phenotypes (de Lera Ruiz & Kraus, 2015;Vetter et al, 2017). Moreover, it is well established that low MW compounds that target Na V channels, such as tetrodotoxin (TTX), attenuate chronic and debilitating pain in humans (Hagen et al, 2017). However, pronounced side effects have been described, such as nausea, dizziness, oral numbness, and tingling, due to a lack of selectivity (Hagen et al, 2017).…”

“…Moreover, it is well established that low MW compounds that target Na V channels, such as tetrodotoxin (TTX), attenuate chronic and debilitating pain in humans (Hagen et al, 2017). However, pronounced side effects have been described, such as nausea, dizziness, oral numbness, and tingling, due to a lack of selectivity (Hagen et al, 2017). The current challenge is thus to identify a new therapeutic class of analgesic molecules that blocks the Na V 1.7 channel with high selectivity compared to other Na V channels, particularly the Na V 1.5 and the Na V 1.6 and 1.4 channels, because of cardiac and neuromuscular safety issues, respectively.…”