Mutations in the SCN9A gene, which encodes the sodium channel Nav1.7, cause primary erythromelalgia (PEM) characterized by recurrent attacks of erythema, burning pain, and warmth in the extremities. The study showed that mepyramine inhibits PEM-associated mutant hNav1.7 channels. Using recordings in HEK 293 cells, mepyramine was shown to block three PEM mutations—I848T, L858F, and L1267V—regardless of changes in channel activation or inactivation. A high-dose topical formulation of mepyramine was administered to patients with PEM intolerant of conventional pain medications, including those with identified SCN9A mutations. The treatment quickly and permanently reduced the burning pain and erythema. The results suggest that mepyramine may be a new therapeutic approach for patients with PEM.