Background & Aims

Tetrodotoxin (TTX) is a small molecule sodium channel blocker currently under investigation as a treatment for chemotherapy-induced neuropathic and cancer-related pain, with ongoing phase 2b and completed phase 3 clinical trials, respectively. We have previously shown that TTX can alleviate mechanical allodynia in a rat model of chemotherapy induced peripheral neuropathy (CIPN). In the present study, we investigated whether the administration of TTX prior to the establishment of CIPN can prevent CIPN pain symptoms induced by oxaliplatin in a rat model.

Methods

TTX, at a dose of 6?g/kg or 8?g/kg, was administered to rat daily by subcutaneous injections for 18 days from day 1 to day 18. The negative control was saline and positive control was duloxetine at 15 mg/kg. Starting from day 3, rats were concurrently treated with oxaliplatin twice a week until CIPN was developed in saline control rats on day 13. Paw withdrawal threshold (PWT), as a measure of the degree of mechanical allodynia and neuropathic pain state, was assessed daily using a series of graduated Von Frey hairs from day 3 to day 18, then as follow ups on days 20, 23 and 27. Cage side observations were performed daily.

Results

TTX at 8 ?g/kg robustly suppressed the development of oxaliplatin induced neuropathic pain in rats. PWT remained at 14.81 ± 0.19 g from pre-dosing to day 7, 14.62 ± 0.26 g for both day 14 and day 18, the 5th day after final oxaliplatin injection. It decreased to 4.85 ± 0.42 g on day 27, the 9th day after last TTX injection, but remained significantly higher than the saline group.
TTX at 6 ?g/kg also achieved similar effects but to a lesser extent. PWT decreased from 15.00 ± 0.00 g to 11.27 ± 0.79 g on day 7, then to 8.96 ± 0.99 g on day 14, but increased to 10.08 ± 1.12 g on day 18.
Duloxetine partially suppressed the development of neuropathic pain. PWT decreased from 14.81 ± 0.19 g to 9.62 ± 0.84 g on day 7, then to 7.35 ± 0.51 g on day 14, also increased to 8.81 ± 0.47 g on day 18.
Normal saline had no effect on the development of neuropathic pain. PWT decreased from 15.00 ± 0.00 g to 8.27 ± 0.53 g on day 7, and to 3.62 ± 0.21 g on day 14, then to 3.15 ± 0.25 g on day 27.

Conclusions

In this study, we investigated the effects of prophylactic dosing with TTX or duloxetine on the development of oxaliplatin- induced neuropathic pain in rats.
TTX at 8 µg/kg robustly prevented the demonstration of oxaliplatin- induced neuropathic pain. After cessation of treatment, PWT gradually decreased, but remained significantly higher than that of the normal saline group after 9 days. TTX at 6 µg/kg also suppressed the pain development but less vigorously. Duloxetine at 15 mg/kg was only partly effective. Normal saline (negative control) alone had no effect. The difference between TTX 6 µg/kg, TTX 8 µg/kg and Duloxetine at 15 mg/kg was statistically significant at specific time points. These results suggest that TTX prevented the demonstration of oxaliplatin-induced neuropathic pain in rats and that this effect is dose-dependent.

References

1. Hagen NA, Cantin L, Constant J, Haller T, Blaise G, Ong-Lam M, du Souich P, Korz W, Lapointe B. Tetrodotoxin for Moderate to Severe Cancer-Related Pain: A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Trial. Pain Res Manag. 2017;2017:7212713. Epub 2017 May 7.
2. Goldlust SA, Kavoosi M, Nezzer J, Kavoosi M, Korz W, Deck K. Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial. Toxins (Basel). 2021 Mar 25;13(4):235.

Presenting Author

Donald Wong

Poster Authors

Donald Wong

PhD

WEX Pharmaceuticals Inc

Lead Author

Walter Korz

WEX Pharmaceuticals Inc.

Lead Author

Haifeng Wei

PhD

Cerebrasol Ltd

Lead Author

Fei-Yue Zhao

PhD

Cerebrasol Ltd

Lead Author

David Spanswick

PhD

Cerebrasol Ltd

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Neuropathic Pain - Peripheral