Aside from cure, the fear of pain and suffering ranks as the second greatest concern of a patient diagnosed with cancer. Control of that pain is recognized to enhance the likelihood of survival and promote well-being.
In their article on adjuvant analgesics, Drs. Farrar and Portenoy consider the fact that opiatesa mainstay in the management of cancer painmay display, during the course of the disease, a diminished capacity to produce adequate pain relief at doses that are not associated with unacceptable side effects. The premise of their review is that the addition of other mechanistically distinct classes of agents can augment pain control with diminished side effects. This concept of using polypharmacy for the management of evolving cancer pain is rationally grounded in several principles.
Changes in Pain Intensity and Analgesic Efficacy
The stimuli, secondary to cancer, that initiate a pain state may arise from several sources, including the cancerous cell (eg, bulk distention of tissues, changes in the local milieu such as increased hydrogen ion concentrations, release of cytokines from tumor cells and local inflammatory cells) and from the treatments targeted at the cell’s destruction (surgical trauma secondary to resection, chemotherapy, and radiation). Increased tumor mass, presence of metastasis, or the development of pain states incidental to primary pathology (bowel stasis, urinary retention, septic bladder/kidney) and the distribution of disease to other dermatomes may increase the intensity of the peripheral stimulus. These events can lead to an increased discharge in small afferents that are believed to encode sensory information.
As with an increase in temperature, a slight increase in stimulus intensity will result in a rightward shift in the analgesic dose-response curve. Such a shift reduces the therapeutic ratio of the drug to the point that the analgesic effect overlaps the dose-response curve for side effects. Moreover, as the stimulus intensity rises, it is possible that the agonist itself may not have sufficient intrinsic efficacy to activate the opiate receptor enough to prevent the excitatory drive. In such a case, the agonist begins to behave as a partial agonist, ie, even at full receptor occupancy, it may not be able to produce a complete block of the afferent input, and the analgesic dose-effect curve plateaus. Such a phenomenon has been shown to occur with mu opiates, such as morphine(Drug information on morphine) and sufentanil(Drug information on sufentanil).[2,3]
Under these conditions, concurrent activation of other receptor classes such as the alpha-2 receptor can yieldby a mechanism independent of the opiate receptorenhanced suppression of the afferent-evoked central nervous system (CNS) excitation. Because the side-effect profiles of mu opioids and alpha-2-adrenergic agonists are distinct, such drug interactions can be expected to enhance the antinociception without increasing the side effects produced by the other agent. In the case of these two drug classes, the agents are believed to interact to reduce the magnitude of the afferent traffic generated by the peripheral stimulus.
Changes in Pain Mechanisms