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THE NERVOUS SYSTEM

Colon Cancer

A 75-year-old man developed cancer of the colon. The cancer resulted in severe pain, because of both
visceral pain and metastases to bone of the vertebral column. Morphine controlled the pain initially, but
eventually the pain became so severe that the required high doses of morphine interfered with the ability
of the patient to think clearly. Several options were considered to improve the quality of the patient's life
during his terminal period: 1) installation of a patient-controlled epidural morphine pump; 2) bilateral
cordotomies; and 3) deep brain stimulation.

1. Why was morphine able to control the cancer pain initially? That is, where and how does morphine act
when given systemically to control pain?

2. How would epidural infusion of morphine be able to control the pain of colon cancer? What is the
advantage of allowing a patient to control a morphine pump?

3. What can be done if an inadvertent overdose of morphine leads to respiratory arrest?

4. What are the advantages and disadvantages of anterolateral cordotomy?

5. What would be a suitable target for deep brain stimulation to control cancer pain?

1. Morphine given systemically may act primarily at the level of the periaqueductal gray in the midbrain.
This area is richly provided with opiate receptors, and microinjection of opiates here produces
analgesia. The mechanism of the opiate action may reduce the activity of inhibitory interneurons, and
the reduced activity may disinhibit the descending analgesia pathways that originate in the
periaqueductal gray. These analgesia pathways in turn inhibit nociceptive transmission (e.g., by
inhibiting spinothalamic tract neurons) in the spinal cord dorsal horn.

2. Opiate receptors also occur in the spinal cord dorsal horn. For effective activation, these receptors
require a higher dose of systemic morphine than do those in the periaqueductal gray. However, they
can be directly activated if morphine is applied to the spinal cord. This can be done by epidural
injection. (Morphine readily penetrates the dura because of its solubility in lipid membranes.) Thus
epidural infusion of morphine can be used to block nociceptive transmission at the spinal cord level.
Patient-controlled analgesia is becoming a widely accepted technique. In the usual hospital setting,
morphine doses are given too infrequently to allow the plasma concentration to remain at a stable
level. Thus the plasma concentration swings between a level that is insufficient for analgesia and one
that causes somnolence. With patient control, the morphine level is kept optimal for analgesia.
Interestingly, the total dose is less than that usually given with the alternative regimen.

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3. Respiratory depression is a potential complication of a morphine overdose, whether the morphine is
given systemically or by epidural pump. The opiate receptor antagonist, naloxone, can be used to
counteract the action of morphine.

4. Anterolateral cordotomy used to be the procedure of choice to control cancer pain, especially when
the cancer was at a low segmental level. However, the original open procedure required surgical
exposure of the spinal cord. More recently, percutaneous cordotomy has become feasible, so that
lesions are made by inserting a needle through the intervertebral foramen between C1 and C2. This
can be done in conscious patients. However, destructive procedures are now generally thought to be
less desirable than the use of analgesics to control pain. In the case of pelvic cancer pain, there is the
further disadvantage that the pain originates bilaterally; therefore a bilateral cordotomy would likely
be required. Bilateral percutaneous cordotomies run the risk of interrupting the descending
respiratory control pathways.

5. Deep brain stimulation is an experimental procedure that is not used in ordinary practice. When it has
been used experimentally to control cancer pain that results from the activation of peripheral
nociceptors, the main target has been the periventricular gray (just rostral to the periaqueductal
gray). Stimulation in the periaqueductal gray has the disadvantage that eye movements generally
result. In addition, stimulation in this area can evoke a sensation of fear. The effectiveness of
periventricular gray stimulation is controversial.