Neuro-endocrine-immune dysfunction in chronic pain patients helps to explain some of our clinical failures in this arena. The endocrine and autonomic nervous systems play a role in controlling inflammation. The autonomic nervous system regulates physiological systems by integrating afferent inputs from internal and external environments with the neuronal system, endocrine system, and cell modulated responses. Various immune cells including lymphocytes and monocytes have receptors for corticosteroids, insulin, prolactin, growth hormone, somatostatins, estrogens, testosterone, leptin, ghrelin, opioids, corticosteroids, neuropeptide Y, and vasoactive intestinal polypeptide. In the chronic pain patient, there are multiple pathways that are disrupted or altered. The primary afferent continues through the dorsal root to the dorsal column where the first synapse occurs.