In 2014, drug overdose surpassed automobile accidents as the number one cause of accidental death for the first time in the history of the United States. The overdose epidemic is largely driven by opioids, and genuine prescription opioid analgesics play the biggest role in this phenomenon. Despite advancements in abuse deterrent formulations, prescription drug monitoring programmes and clinical assessments for the detection of abuse potential, drug overdoses continue to escalate. The Center for Disease Control has recently issued new guidelines for opioid prescription, yet even these recommendations have their shortcomings. Furthermore, undertreated pain in patients with comorbid substance use disorder poses a major clinical challenge, particularly for patients on opioid replacement therapy. Despite the seemingly obvious interaction between the presence of pain and the abuse of pain-relieving opioids, there is surprisingly little mechanistic data to further our understanding of this vitally important topic. The need for novel pain interventions that minimize abuse liability is critical. Without a fundamental characterization of pain neurobiology and the interaction between chronic pain and the brain's reward system, we are unlikely to make progress in the alleviation of the opioid epidemic. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.