Herein, we summarize the steps of a common scientific path taken by the two Guest Editors, an Anesthesiologist (EA) and an Immunologist (AS), and started 25 years ago at the National Cancer Institute in Rome. When in 1980 WHO codified the usage of
opioids for
cancer pain relief, it was matter of debate whether only
disease progression rather than
opioid tolerance were the driving force of
opioid escalation. The selective intratumoral accumulation of
morphine observed in an experimental xenograft model - the initial scenario of our scientific collaboration - revealed a surprising interaction between the
opioid and the
opioid receptors expressed by cells of tumor microenvironment. This link could explain the peculiar
opioid tolerance and likely
hyperalgesia that were observed in the emerging clinical experience of
cancer paradoxical
pain and suggestive of
opioid ambiguity. More elegant
cancer pain experimental models, in particular of
bone cancer, demonstrated the relevance of inflammatory mediators produced and released by tumor microenvironment cells. These factors were the words of an immune-mediated cross-talk between the
tumor and the peripheral and central nervous systems leading to
neuroinflammation and consequent
pain hypersensitivity, chronicization of
acute pain and maladaptive neuroplasticity. Immunology identified in the microglia activation a crucial hub of
neuroinflammation and
pain centralization. Subsequently the discovery of TLR-4 capacity to bind to
opioids on glial cells revealed that they shared the same neuroinflammatory mechanisms underlying
cancer and non
cancer pain, and could also worsen
pain for which they were used. The late awareness of this knowledge and the poor integration between immunological and
pain sciences contributed to the recent severe opioid crisis in the USA (opioid epidemic) with a consequent limitation of long-term use of these drugs in non
cancer pain, and generated a new wave of opiophobia. Immunological evidence-based
pain therapies are currently quite sophisticated, but only little clinically exploited yet. To save the
analgesic use of
opioids would require the overcome of their intrinsic ability to cause both
analgesia and
hyperalgesia in a very ambiguous manner. At moment not to hijack and not to usurp the immune system appears still a very far goal.