Chronic pain is a disease that encompasses both sensory and emotional elements. Opioids are highly effective analgesics because they target both of these elements, by inhibiting pain pathways and alleviating negative affect (including depression) by engaging reward or hedonic pathways. Unfortunately, chronic opioid use is limited by the development of unwanted side effects, such as tolerance, hyperalgesia, and abuse liability. Thus, the challenge of providing effective pain treatment while minimizing these unwanted side effects is an ongoing issue with significant clinical and societal impact. In this review, we posit that neuroinflammation within the central nervous system is a shared phenomenon between chronic pain and opioids that contributes to pain sensitization and negative affect. The implications for pain progression, addiction liability, and alternative treatment strategies are discussed.