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In other words, it is plausible that the mechanisms that promote the above two phenomena might synergize and ultimately aggravate NP when patients are treated with opioids [48,65,66], which may be useful to address the failure of strong opioids in NP, the commonness of which is reflected in similar changes at the tissue level, remarkably showing the downregulation of opioid receptors in the central nervous system (CNS) [67] and peripheral nervous system (PNS) [68] accompanied by increased expression of pronociceptive neurotransmitters (e.g., cholecystokinin, calcitonin gene-related peptide, substance P, etc.) [69] and chemokines [70]

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