Cancer pain is mainly an inflammatory process embedded around a tetrapartite system of neurons(pre- and post-synaptic)-microglia-astrocytes. Inflammation is triggered by pattern recognition Toll-like receptors, which when activated by endogenous danger signal molecules released by damaged tissue causes the synthesis and release of pro-inflammatory cytokines. This results in peripheral sensitization with eventual relay to the brain to cause central sensitization resulting in the chronic pain behavior. Opioids remain the major pharmacotherapy for cancer pain, but apart from their known adverse effects, the dose-response may be bell-shaped with a ceiling dose beyond which pain actually increases; this is likely caused by opioid-induced hyperalgesia. The mechanisms are due to an interaction between opioids and the innate immune system whereby opioids also cause the release of proinflammatory cytokines such as IL6, IL1ß and TNFa, which counteract the neuronal mu receptor activation mechanism for pain relief. Polymorphisms in various pro-inflammatory cytokines and TLRs are associated not only with cancer pain severity, but with the degree of opioid pain relief and adverse effects. A better understanding that opioids and some of their metabolites can also be pro-inflammatory contributing to pain and not pain relief, necessitates a rethink of their role in chronic cancer pain therapy. An enhanced individualisation of cancer pain treatment based on peripheral pain biomarkers, such as cytokines or general inflammatory markers, together with pharmacokinetic and pharmacogenetic factors may better inform which opioid drug and dose would be appropriate at different stages of patients’ cancer progression and remission.