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SOME
FUNDAMENTAL QUESTIONS ABOUT CLINICAL TRIALS OF TREATMENTS
FOR PAIN (CONTINUED)
In
terms of underlying mechanisms, is pain one or many? For
example, will a clinical trial finding that a new drug relieves
postoperative pain or diabetic neuropathy pain generalize
to pain arising in different tissues or from different disease
processes?
This
is one of the most controversial issues in pain research
and will remain so until more types of pain have been rigorously
studied with many classes of analgesics. Basic scientists
have demonstrated many different pain mechanisms, some unique
to particular disease models and some shared across many
models (see Yaksh
et al., 1999 and accompanying symposium papers).
The
splitters' arguments: The top panel in Figure
1.1 (from Woolf
and Mannion, 1999) shows "normal" sensory
function in undamaged tissue.
Brief
application of a noxious stimulus like heat or pinprick
causes small nerve fibers ("nociceptors") to discharge.
These impulses are carried to the fibers' central termination
in the dorsal horn of the spinal cord, and excite dorsal
horn neurons that can carry information to the brain. Diseases
that injure nerve introduce several additional unique pain
mechanisms. The middle panel shows that injured nerve fibers
accumulate additional sodium channels and alpha adrenoreceptors.
In the absence of peripheral stimulation, sodium currents
that enter the cell via the new channels and stimulation
of the new adrenoreceptors by circulating catecholamines
can cause spontaneous nerve discharge and ongoing pain.
The bottom panel shows that after nerve injury, spinal cord
dorsal horn pain signalling neurons may begin to discharge
spontaneously. Studies in animal models of nerve injury
suggest unique effectiveness of drugs that block the new
sodium or adrenergic channels on injured nerve fibers or
that inhibit spontaneous discharge of spinal neurons.
To take
another example of mechanistic splitting, scientists, studying
pain arising in hollow viscera, have claimed that these
pain syndromes may have mechanistic features distinct from
pain arising in bone, joint, skin, or soft tissues, including
a particularly high content of peptide neurotransmitters
in visceral nociceptors (Levine
et al., 1993), transmission of visceral pain information
via the spinal cord's dorsal column postsynaptic tract (Willis
et al., 1999), and reduction in visceral pain by peripheral
application of kappa receptor opioids to the organ (Sengupta
et al., 1999).
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