Opioid analgesics are frequently used for the long-term management of chronic
pain states, including
cancer pain. The prolonged use of
opioids is associated with a requirement for increasing doses to manage
pain at a consistent level, reflecting the phenomenon of
analgesic tolerance. It is now becoming clearer that patients receiving long-term
opioid therapy can develop unexpected abnormal
pain. Such paradoxical
opioid-induced
pain, as well as tolerance to the antinociceptive actions of
opioids, has been reliably measured in animals during the period of continuous
opioid delivery. Several recent studies have demonstrated that such
pain may be secondary to neuroplastic changes that result, in part, from an activation of descending
pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM). One mechanism which may mediate such
pain facilitation is through the increased activity of CCK in the RVM. Secondary consequences from descending facilitation may be produced. For example,
opioid-induced upregulation of spinal
dynorphin levels seem to depend on intact descending pathways from the RVM reflecting spinal neuroplasticity secondary to changes at supraspinal levels. Increased expression of spinal
dynorphin reflects a trophic action of sustained
opioid exposure which promotes an increased
pain state. Spinal
dynorphin may promote
pain, in part, by enhancing the evoked release of excitatory transmitters from primary afferents. In this regard,
opioids also produce trophic actions by increasing CGRP expression in the dorsal root ganglia. Increased
pain elicited by
opioids is a critical factor in the behavioral manifestation of
opioid tolerance as manipulations which block abnormal
pain also block antinociceptive tolerance. Manipulations that have blocked enhanced
pain and antinociceptive tolerance include reversible and permanent ablation of descending facilitation from the RVM. Thus,
opioids elicit systems-level adaptations resulting in
pain due to descending facilitation, upregulation of spinal
dynorphin and enhanced release of excitatory transmitters from primary afferents. Adaptive changes produced by sustained
opioid exposure including trophic effects to enhance
pain transmitters suggest the need for careful evaluation of the consequences of long-term
opioid administration to patients.