Pain has a useful protective role; through avoidance learning, it helps to decrease the probability of engaging in tissue-damaging, or otherwise dangerous experiences. In our modern society, the experience of acute post-surgical pain and the development of chronic pain states represent an unnecessary negative outcome. This has become an important health issue as more than 30% of the US population reports experiencing “unnecessary” pain at any given time. Opioid therapies are often efficacious treatments for severe and acute pain; however, in addition to their powerful analgesic properties, opioids produce potent reinforcing properties and their inappropriate use has led to the current opioid overdose epidemic in North America. Dissecting the allostatic changes occurring in nociceptors and neuronal pathways in response to pain are the first and most important steps in understanding the physiologic changes underlying the opioid epidemic. Full characterization of these adaptations will provide novel targets for the development of safer pharmacotherapies. In this review, we highlight the current efforts toward safer opioid treatments and describe our current knowledge of the interaction between pain and opioid systems.