The ambiguity of opioids revealed by immunology is changing the knowledge and the therapeutic approach in cancer and non-cancer pain: A narrative review.

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.