Human cold pain: a randomized crossover trial.

The mechanism causing cold pain in humans is unresolved. Animal data suggest a nonredundant contribution to cold pain for transient receptor potential channels TRPM8 and TRPA1 for detection and voltage-gated sodium channels Na V 1.7 and Na V 1.8 for conduction at these temperatures. We established an intradermal injection-based cold pain model, which allows pharmacologically addressing molecular targets at the site of cooling. Lidocaine, added to the injection solution as positive control, largely reduced cold-induced pain in 36 volunteers. The 4 mentioned molecular targets were blocked by antagonists in a double-blinded crossover trial. Pain induced by 3°C intradermal fluid was not reduced to a relevant extent by any of the 4 antagonists alone or by the quadruple combination. However, the temperature threshold for cold pain appeared shifted by the inhibition of TRPA1, TRPM8, and Na V 1.7 and to a lesser extent by Na V 1.8 inhibition, 4-fold inhibition decreased the threshold by 5.8°C. Further mechanisms contributing to human cold pain need to be considered.