CANCER PAIN: NEUROPHYSIOLOGY
Pain is caused by stimulation of free nerve endings (nociceptors), causing impulses to be carried along the peripheral nerve to the dorsal horn of the spinal cord. There they synapse with cells of the spinothalamic tract which carry the impulses up the spinal cord, through the brain stem to the thalamus. From the thalamus, impulses are delivered to various areas of the cerebral cortex which allow the perception of, and reaction to, pain.
Free nerve endings in the skin and connective tissues (somatic nociceptors) and viscera (visceral nociceptors) may be stimulated physically (pressure, heat, visceral distention) but are more commonly activated by chemical stimuli consequent upon tissue injury or inflammation. Tissue injury results in the production and accumulation of a variety of algesic substances including prostaglandins, bradykinin, serotonin, histamine, potassium and hydrogen ions which have been shown to affect nociceptors. Prostaglandins play a major role in the tissue
injury-nociceptive pain cycle, explaining the usefulness of prostaglandin synthetase inhibitors in the treatment of pain. The algesic substances may also act on other nerve endings, such as those responsible for heat or pressure, reducing their stimulation threshold and facilitating activation.
Nerve fibres from somatic nociceptors pass along peripheral nerves and enter the spinal cord by the dorsal root. In the case of fibres from visceral nociceptors, about 20% enter by the ventral route, explaining why surgical sectioning of the dorsal roots (dorsal rhizotomy) may fail to control visceral pain. Visceral and somatic afferent fibres converge on the same neurons in the spinal cord, the ascending spinal fibres being common for impulses from both viscera and skin. This is the anatomic basis for referred pain, in which visceral pain is accompanied by cutaneous pain in particular dermatomes.
In the dorsal horn of the spinal cord the afferent sensory nerves synapse with fibres of the ascending spinothalamic tract, either directly or via a complex system of connecting fibres or intemeurons, employing a variety of neurotransmitters including substance P and glutamate. The presynaptic terminal of the afferent sensory fibre contains opioid receptors which bind endogenous opioid substances (endorphins) or exogenous opioid medications. Such binding reduces or blocks the release of neurotransmitter by the afferent sensory fibre, reducing or relieving the sensation of pain. This is the prime site of action of exogenous opioid drugs. Similarly, activation of the inhibitory neurons in the dorsal horn, known to have endorphins as neurotransmitters, will reduce pain. The inhibitory neurons are stimulated by activity in the descending pathways from the brain or by activity in other sensory fibres in the same segment, explaining why massage, heat or electrical stimulation applied to a painful area may reduce pain. Other receptors, including those for N-methyl D-aspartate (NMDA receptor) may facilitate or perpetuate the sensation of pain by sensitisation of cells in the dorsal horn and are possibly responsible for reducing opioid sensitivity.
The ascending spinothalamic tract is the major route for transmission of information regarding pain to the brain, but there are several other ascending pathways which are involved to a lesser extent. These additional pathways explain why surgical interruption of the spinothalamic tract does not produce complete pain relief.
Pain impulses transmitted to the thalamus are relayed to several areas of the cerebral cortex: the sensory areas of the parietal lobe which allow localisation and interpretation of the pain; the limbic system which is involved in both the affective and autonomic response to the pain; the temporal lobe which is involved in pain memory; and the frontal lobe where cognitive function assesses the significance of the pain and the emotional response to it.
The major endogenous mechanism of pain inhibition is the suppression of pain impulses at the dorsal horn by pathways descending from the midbrain and brain stem. These centres receive input from the cortex, the thalamus and other midbrain centres and, by a variety of descending pathways, stimulate the inhibitory intemeurons in the dorsal horn of the spinal cord, producing analgesia or reducing pain. The neurotransmitters involved with the descending inhibitory pathways are noradrenaline and serotonin. This is a possible explanation why drugs which block presynaptic reuptake and augment the postsynaptic action of these substances, such as amitriptyline, may augment analgesia.
Neuropathic pain results from damage to nerves or neural tissue rather than the stimulation of nociceptors by tissue injury or inflammation. Pain results from spontaneous electrical activity of the damaged nerves or to increased sensitivity to exogenous stimuli; the neural pathways involved are the same as for nociception. Damage to sensory afferent fibres results in a significant reduction in the number of opioid receptors in the presynaptic terminals of the affected fibres in the dorsal horn, possibly explaining the reduced opioid sensitivity of neuropathic pain. Damage to sympathetic nerve fibres may lead to sympathetic type pain in which neuropathic pain is accompanied by signs of autonomic dysfunction, including vasomotor instability and sudomotor changes.
Although all the anatomical, physiological and pharmacological relationships involved in pain remain incompletely documented, it is apparent that the major site of modulation of pain impulses is in the dorsal horn of the spinal cord, as was originally proposed in the 1960's by Melzack and Wall in their 'gate control, theory. The modulation of pain in the dorsal horn of the spinal cord provides a basis for explaining why painful stimuli can be modified by cortical, subcortical and other spinal activity, including psychological factors, pain at other sites and simultaneous stimulation of sensory fibres in the same peripheral nerve.
Chronic pain leads to other changes in the nervous system. Alterations in receptors and transmitters occur in the spinal cord and brain which may lead to perpetuation of pain or reduced opioid sensitivity. The physiological changes remain incompletely defined at present but the clinical inference is obvious:
• Chronic pain should be well controlled, as quickly as possible.