Opioid-induced hyperalgesia (OIH) refers to the phenomenon of increased pain sensitivity after exposure to opioid therapy. Clinically, the process manifests as pain intensification or emergence of a new pain with loss of analgesic benefits despite drug dose escalation. Distinct neuroanatomical sites and signaling systems have been implicated in OIH: peripherally, enhanced nociception mediated by the glutamatergic system/N-methyl-D-aspartate (NMDA) excitatory neurotransmitters, activation of descending signaling pathways arising from the rostral ventromedial medulla (RVM) resulting in upregulation of spinal dynorphin, and enhanced production of nociceptive neurotransmitters substance P and calcitonin gene-related peptide (CGRP) within the dorsal root ganglia.