Small-diameter nerve fibers, which subserve nociception, can be affected early in peripheral neuropathies, although their injury may not be detectable by routine neurophysiologic tests. On the other hand, skin biopsy has proved to be a reliable tool to examine nonmyelinated nerve fibers, as assessed by the quantification of intra-epidermal nerve fiber (IENF) density not only along with the degenerative process but, noteworthy, IENF density could be very helpful in evaluating drug efficacy such as erythropoietin (EPO) treatment.