It has been long recognized that chronic pain is a signifi cant public health concern. After many decades of research and development investment for alternatives, the most effective pharmacological tools for managing diverse chronic pains remain the opioid analgesics. Several serious side effects including, the risks of addiction or diversion of opioid-containing dosage forms to nonpatient populations render the use of opioid medication for treatment of pain complicated. At the same time, it been asserted repeatedly that patients with established chronic pain demonstrate reduced propensity to acquire addiction to opioids than the general population. For over 30 years, neuropharmacological studies in rodent models of opioid self-administration have suggested that responding for opioids is, in fact, significantly altered under conditions of established chronic pain, and often reduced. However, with the introduction of the sustained release opioid preparations, the expansion of opioid prescribing, and appropriately heightened concerns regarding opioid-related addiction and mortality by respiratory depression, this long-standing assertion that patients with chronic pain are less susceptible to addiction has been recently challenged. In response to this challenge the opportunity arises, perhaps, to consider that chronic pain is a generic term that refers to a broad spectrum of painful conditions; these pain conditions may have common neurobiological mechanisms, but also key distinctions. Understanding the neurobiology underlying distinct chronic pain conditions as they relate to opioid addiction may help to better predict the therapeutic window and side effect risks associated with chronic opioid therapy. Progress has been made in this area, but it is currently recognized that more specific information is greatly needed. As a primer to planning such future studies, the present chapter is intended to summarize the prior three and a half decades of neuropharmacological studies that have systematically evaluated opioid (and nonopioid) analgesic responding in animal models of opioid addiction.