Harnessing endogenous opioids for pain relief: Fantasy vs reality

Objective: To review evidence demonstrating efficacy and feasibility of harnessing the activity of endogenous opioid analgesic systems for pain management.Methods: The authors sought to summarize a wealth of data that establish proof of concept that the analgesic activity of endogenous opioids can be exploited to clinically benefit from the enormous pain-relieving abilities of these peptides without contributing to the current crisis of death by synthetic opioid overdose.Results: There is a plethora of studies demonstrating that not only can endogenous opioids mediate placebo-induced antinociception but they are also active in modulating clinical pain. Earlier studies convincingly demonstrate the effectiveness of psychological strategies to coopt endogenous opioid analgesic systems to produce pain relief. The challenge is to define pharmacological targets for activating endogenous opioid analgesia reliably in a clinical setting. Based on insights gleaned from mechanisms underlying the ebb and flow of analgesic responsiveness to the spinal application of endomorphin 2, multiple signaling proteins were identified that activate endogenous spinal opioid analgesia. Notably, this was achieved in the absence of any exogenous synthetic opioid.Conclusions: Utilization of drugs that harness endogenous opioid antinociception in accordance with varying physiological states represents a novel approach for effective pain management while mitigating the present epidemic of death by synthetic opioid overdose.