Severe chronic neuropathic pain is a challenge to treat, and due to adverse effects of classical oral medication, optimal and effective dose levels are difficult to reach. Therefore, administration of topical analgesics might be an option, due to reduced adverse effects, and increased patient compliance. The aim of this article is to describe two cases treated effectively with topical amitriptyline 5% and 10%, the highest dosage described to date. The first patient was a 39-year-old man, suffering from severe intractable neuropathic pain in feet and hands, due to diabetes mellitus type II (DM-II). After application of amitriptyline 5% the patient experienced a complete relieve only in the hands, whereas after application of amitriptyline 10%, a total reduction of pain occurred within 20 minutes, lasting the whole day. The second patient was a 57-year-old man, suffering for 10 years from progressive sensory disturbances in both feet and increasing pain due to chronic idiopathic axonal polyneuropathy (CIAP). Amitriptyline 5% cream reduced pain in the toes nearly completely, but this was not the case in the heels. Amitriptyline 10% reduced pain in the feet, however, systemic adverse effects occurred, mainly drowsiness. The patient decided to stop topical treatment because of these adverse effects. These two cases suggest an analgesic dose-response effect of topical amitriptyline in painful neuropathy. Systemic adverse effects should be taken into account. © 2011 The Authors. Pain Practice © 2011 World Institute of Pain.