Pain management: physiopathology, future research and endpoints.

In this article, first, the different stages of acquisition and processing of nociceptive information from peripheral receptor to brain are reviewed and the plastic changes that accompany tissue injury are underlined. For instance, the subclassification of peripheral receptors in nociceptors and non-nociceptors (e.g., mechanoreceptors, thermoreceptors) must be understood in the light of peripheral sensitization. This phenomenon is the probable explanation for primary hyperalgesia, the decrease in pain threshold at the site of injury. The observation that substance P enhances N-methyl-D-aspartate (NMDA)-elicited responses suggests that these two receptors may operate in concert to prolong and amplify the afferent input generated by peripheral tissue injury. Such afferent barrage induces a state of central sensitization. Second, the major problems in the management of cancer pain, i.e. the development of tolerance to opioids and opioid-insensitive pain, are discussed. The loss of drug effect observed after chronic exposure of the opioid receptor (tolerance) may be the consequence of the down-regulation or desensitization phenomenon (where the total number of receptors coupled to the second messenger is reduced). The agonist dose-response begins to shift to the right. The dramatic analgesic improvement obtained with subanaesthetic doses of ketamine, an NMDA receptor antagonist, in those of our cancer patients who have become resistant to morphine is intriguing. As shown for tolerance, insensitivity to opioids may represent a rightward shift in the opioid dose-response curve and the analgesic effect of ketamine the reversal of that shift.