Background and Objectives The antidepressant amitriptyline is used as an adjuvant in the treatment of a variety of chronic pain conditions. This drug interacts with many receptors and ion channels, such as Na⁺ channels. In a randomized, double-blinded, and placebo-controlled trial, we investigated whether amitriptyline also is capable of providing cutaneous analgesia when applied topically in 14 healthy volunteers.

Methods Amitriptyline hydrochloride was prepared as a 45% water/45% isopropanol/10% glycerin solution and titrated to pH 8.5 with sodium hydroxide. Four areas, 2 on each arm, of approximately 1 cm² each were marked on the ventral aspect of the upper arm. A piece of gauze, placed on each of the marked areas and affixed to the arm with an occlusive plastic dressing, was saturated via syringe with placebo and amitriptyline solutions (10 mmol/L, 50 mmol/L, and 100 mmol/L). After 1 hour, the dressings and gauze were removed. A 16-G blunt needle was used to grade the pain at the marked area once per hour (1 = complete analgesia, 10 = normal pain sensation).

Results The analgesic effects of 50 mmol/L and 100 mmol/L solutions of amitriptyline were significantly higher than those of the placebo or the 10 mmol/L solution. However, no significant difference was found between the analgesia provided by the placebo solution versus the 10 mmol/L solution or between the 50 mmol/L versus the 100 mmol/L solution. The only side effect observed was a concentration-dependent redness of the skin.

Conclusions Topically applied amitriptyline is effective as an analgesic in humans. Different vehicles may improve its efficacy and decrease the skin redness observed.