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
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 and 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
Changes in Pain Mechanisms
1. Yaksh TL: Preclinical models of nociception, in Yaksh TL, Lynch C, Zapol
WM, et al (eds): Anesthesia: Biologic Foundations, pp 685-718. Philadelphia,
Lippincott-Williams & Wilkins, 1997.
2. Saeki S, Yaksh TL: Suppression of nociceptive responses by spinal mu
opioid agonists: Effects of stimulus intensity and agonist efficacy. Anesth
Analg 77:265-274, 1993.
3. Dirig DM, Yaksh TL: Differential right shifts in the dose-response curve
for intrathecal morphine and sufentanil as a function of stimulus intensity.
Pain 62:321-328, 1995.
4. Yaksh TL, Malmberg AB: Interaction of spinal modulatory receptor systems,
in Fields HL, Liebeskind JC (eds): Progress in Pain Research and Management, vol
1, pp 151-171. Seattle, IASP Press, 1994.
5. Yaksh TL, Hua XY, Kalcheva I, et al: The spinal biology in humans and
animals of pain states generated by persistent small afferent input. Proc Natl
Acad Sci 96:7680-7686, 1999.
6. Yaksh TL: Spinal systems and pain processing: Development of novel
analgesic drugs with mechanistically defined models. Trends Pharmacol Sci
7. Yaksh TL, Malmberg AB: Central pharmacology of nociceptive transmission,
in: Wall P, Melzack R (eds): Textbook of Pain, 4th edition, pp 253-308.
Edinburgh, UK, Churchill Livingstone, 1999.
8. Watkins LR, Maier SF: Implications of immune to brain communication for
sickness and pain. Proc Natl Acad Sci 96:7710-7713, 1999.
9. Honore P, Rogers SD, Schwei MJ, et al: Murine models of inflammatory,
neuropathic and cancer pain each generates a unique set of neurochemical changes
in the spinal cord and sensory neurons. Neuroscience 98:585-598, 2000.