Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been explored in topical formulations for the first time in 1981. Since that time, a number of case reports and studies have been published to evaluate the role of TCAs in itch and peripheral neuropathic pain. For the treatment of itchiness, doxepin was more effective compared to a first generation antihistaminic in a topical formulation and more tolerable. Amitriptyline was first formulated as a transdermal formulation, and its percutaneous absorption was established in an animal model. However, it remained unclear whether amitriptyline was supposed to lessen pain via central, peripheral or cutaneous mechanisms. This absence of clarity was never thematized and led to confusing drug development steps. Formulations could not be optimized given this lack of focus. In the absence of adequate animal models and dose-range studies, the biological optimal dose could not be selected and most clinical studies were inconclusive, most probably due to the selection of an insufficient dose. The question whether topically applied amitriptyline can reduce localized peripheral neuropathic pain has therefore never been properly addressed.