Hijacking the endogenous opioid system to treat pain: who thought it would be so complicated?
In this issue, there is an especially interesting and important special review by Ballantyne and Sullivan entitled, “The discovery of endogenous opioid systems: what it has meant for the clinician's understanding of pain and its treatment”.1 This review adds to these authors' significant prior contributions to the pain field, as they are now proposing that many of the problems associated with opioid therapy can be understood mechanistically as being off-target effects on the endogenous opioid system. They describe how our emerging understanding of the endogenous opioid system might allow us to better understand how exogenous opioids can “hijack” this system to produce unexpected and undesired consequences, both when they are used for pain relief, and when they are misused or abused. They especially focus on how acute or chronic opioid therapy (COT) may impair some of the nonanalgesic functions of the endogenous opioid system, including on stress, mood, reward, and social bonding. The review also highlights a growing literature on how endogenous opioidergic tone may impact opioid system responsiveness in various acute and chronic pain states. The authors do not attempt to delve deeply into opioid neuroscience—but instead purposefully cover a wide number of topics somewhat superficially to help posit biological mechanisms that may underlie some of the observed clinical phenomenon of opioid treatment.