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Predictive mechanisms linking brain opioids to chronic pain vulnerability and resilience

Chronic pain is a major global healthcare problem that is currently inadequately treated. In addition, the current use of opioids for treatment has reached far beyond the paucity of evidence for long‐term benefits relative to risks. Benefit–risk models for opioid and non‐opioid treatments would benefit from a rational, mechanism‐based understanding of neuroplastic and neurochemical contributions to chronic pain. Here, we evaluate the findings and limitations of representative research investigating brain neuroplasticity and neurochemistry in chronic pain. In sum, the mechanisms of pain‐related neuroplasticity in the brain remain poorly understood because neuroimaging studies have been largely descriptive. We argue that definition is needed of optimal (pain‐resilient) and suboptimal (pain‐vulnerable) functioning of the endogenous opioid system in order to identify neurochemical contributions to aberrant neuroplasticity in chronic pain. We outline the potential benefits of computational approaches that utilize evolutionary and statistical optimality principles, illustrating this approach with mechanistic hypotheses on opioid function. In particular, we discuss the role of predictive mechanisms in perceptual and associative plasticity and evidence for their modulation by endogenous opioids. Future research should attempt to utilize formal computational models to provide evidence for the clinical validity of this approach, thereby providing a rational basis for future treatment and, ideally, prevention.