Intractable Pain and Its Treatment

Abstract

1. Nociceptive pain

Physiology of pain transmission:

Pain is felt when noxious impulses reach a conscious brain along myelinated (A delta) and unmyelinated (C) nociceptive nerve fibers. All information relaying pain from the periphery crosses a synaptic structure on its entry into the central nervous system; this system resides in the dorsal hom of the spinal cord.

The entrance of this information requires the excitation of secondary spinal cord neurons (WDRN, NS neuron) by a neurotransmitter. Two main transmitters are excitatory amino acid (glutamine) and neurokinins (substance P).

These spinal cord neurons receive descending inhibitory modulation from the various brain sites. Two transmitters (noradrenaline and serotonin) contribute to descending inhibition of spinal pain transmission.

Pathophysiology of the pain process

Peripheral sensitization

Inflammation or tissue damage generates the synthesis of arachidonic acid metabolites from adjunct membranes and the release of peptides such as substance P and CGRP from the C fibers via the axon reflex. This inflammatory soup also contains 5 HT, K ions, histamine, etc. The effects of these chemical mediators at the site of tissue damage underlies peripheral hyperalgesia. Pain is enhanced by this activations on the terminal of nociceptive peripheral sensory fibers.

Central sensitization

Another major pathophysiologic process is increased gain (amplification) in the spinal cord and brain processing circuit. Such amplification is called central sensitization. Whenever a noxious event occurs, the spinal cord amplification setting is turned up, resulting in augumentation of pain (Wind-up). This noxious input-triggered form of central sensitization appears to involve the activation of NMDA receptors.

The most remarkable thing about central sensitization is that weak stumuli capable of activating only A β afferent nerve fibers may evoke pain (Allodynia).

The c-fos proto-oncogene is an immediate-early gene, rapidly induced in neuronal and nonneuronal cells by various physiological and pathological stimuli. C-fos expression may be related to the neurons’ ability to convert short-term synaptic stimulation into long-term responses and may thus contribute to the adaptive alteration involved in neuronal plasticity and memory formation.

In the spinal cord c-fos is rapidly and transiently expressed in the appropriate post-synaptic dorsal hom neurons following noxious peripheral stimulation. Expression of c-fos in the dorsal horn of the rat spinal cord following noxious stimulation is reduced by the morphine dose- dependently. An increase in intracellular Ca ion is assumed to be the trigger event for c-fos induction in neural tissue.

The increase in Ca can increase the activity of NO synthase and phospholipase. NO as a freely diffusible transmitter, feeds back in a positive way to increase the release of C-fiber transmitters and so further enhances pain transmission. Phospholipase generates prostanoids and thus contributes to hyperalgesia in the spinal cord.

2. Neuropathic pain

Neuropathic pain is initiated by injury to the nervous system. The mechanism behind neuropathic pain is entirely different from nociceptive types of pain. This mechanism is summarized in the followings.

1. Peripheral nerve ending

2. Dorsal root ganglion cell

3. Spinal cord

4. Treatment of intractable pain

Including the drug challenge test, the rational approach to the treatment of intractable pain will be discussed.