Emerging targets and uses of neuromodulation for pain.

INTRODUCTION: There has been great development in the testing of invasive and non-invasive neuromodulation for chronic pain. To date, it is known that central and peripheral stimulation targets, combined or not, may influence chronic pain sensation. Although most of the significant results of chronic pain studies come from motor cortex stimulation, novel targets are being explored to increase effect sizes and to induce pain relief in non-responders. Areas covered: In this article, we discuss three emerging targets of non-invasive neuromodulation for chronic pain: (i) a central target: prefrontal cortex stimulation; (ii) a peripheral target: vagal nerve stimulation (VNS); and (iii) a combined peripheral-central target: combination of central and peripheral neural stimulation. Expert commentary: Clinical trials' results on novel targets for chronic pain are at an earlier stage and the mechanisms involved with their combination remain unclear. An important challenge to validate new targets is to determine whether they may be equivalent or even more effective than traditional ones. In spite of the significant advance in this field, especially in refractory chronic pain, mechanistic elements are yet to be comprehended. Thus, exploring multifactorial aspects of novel brain stimulation approaches is fundamental to achieve meaningful results and further augment clinical practice.