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Recent developments in management of pain |
The physiology of pain has been well understood for many years now. However, in the last decade, there has been greater understanding in the physiology of pain with a greater understanding of the importance of the role of the spinal cord.
Physiology of pain
Pain pathways are most simply understood in three components; the periphery, the nerve and the cord.
The periphery
Receptors in the periphery detect various stimuli and in the case of pain these receptors are known as nociceptors. We don’t talk about pain receptors and pain stimuli, we talk in terms of nociceptors and noxious stimuli, ie. a noxious stimulus causes sensitisation of nociceptors. These impulses are carried to the brain via the spinal cord and it is in the brain where we 'feel pain'. An analogy of this is hearing; our ears do not hear sound, the nerve endings in our middle ear are stimulated by vibration. This is in turn transmitted via nerves to our brains, which then interpret the stimuli as sound, eg. speech. In this way nociceptors signal pain occurrence and intensity because the greater the stimulus the greater the discharge rate of the nociceptors. A noxious stimulus such as tissue injury causes cell damage and this in turn leads to the release of 'algesic' substances, eg. leukotrienes, hydrogen ions, bradykinin, histamine, serotonin. It is interesting to note that prostaglandin, in itself is not algesic, but increases the algesic effects of bradykinins and serotonin.
The nerve
This 'chemical soup' of algesic substances sensitises the nociceptors producing three responses:
1. They discharge spontaneously. This is in part responsible for producing the ongoing soreness that follows an injury.
2. Their threshold for activation is decreased. This can produce allodynia. This is pain from a non-painful stimulus, eg. a feather touch on a burn.
3. Their stimulus response curves are shifted to the left. This can produce hyperalgesia which is an exaggerated pain response, eg. slap on a sunburnt back.
Once the nociceptors have been stimulated, the impulse is transmitted in the nerves via A delta fibres which are myelinated. These are fast transmitters. The other fibres involved are C fibres, which are slower and carry the prolonged nociceptive impulse which continues after the injury has taken place.
The cord
Neurones enter the cord via the posterior route and synapse with interneurones in the dorsal horn. In pain physiology, there are three principle pathways of note.
1. At the first synapse, the impulses are modulated in three ways:
a) Local interneurones release opioid peptides. These are naturally occurring substances in our bodies such as endorphins and encephalin. They dampen down the incoming signal.
b) There is a descending pathway comprised of noradrenergic and serotonergic fibres from the brain stem. This is where, we believe, anti-depressants act as co-analgesics, via this descending inhibitory pathway.
c) The descending fibres themselves are activated by opioid peptides.
Clinically, this is how morphine and the other opioids work via stimulation of the opioid peptide receptor sites. This supra-spinal modulation accounts for our social and emotional influence on pain perception, eg. depression or anxiety or agitation, can profoundly influence an individual’s pain perception.
2. In the cord, some nociceptive impulses pass directly to the anterior horn where they stimulate sympathetic neurons and produce reflex responses, eg. the release of noradrenaline.
3. Some nociceptive impulses cross the cord and ascend in the spinothalamic tract to the brain stem and brain. The thalamus is where we 'feel pain'. Cerebral processing through the limbic system and cortex determine pain behaviour, eg. flinching, crying, immobilisation or escape from further injury.
More recent developments in the understanding of pain mechanisms have centred on the dorsal horn and in particular regarding 'central sensitisation' and the role of the NMDA receptors. These recent advances have brought us a possible understanding of neuropathic pain.
Central sensitisation
C fibres and nociceptors release glutamate, aspartate and substance P as neurotransmitters. The receiving interneurones in the dorsal horn express different subtypes of glutaminergic receptor, namely NMDA (N-methyl-D-asparate) and AMPA receptors.
High levels of afferent input depolarises the cell. The AMPA then NMDA receptors are depolarised. This causes a cascade of events which causes further depolarisation. The mechanisms are self propagating. Positive feedback loops may induce and maintain central sensitisation. This hyperexcitability state may result in change of genetic expression, which can influence the long-term changes in cellular function, eg. development of 'pain memory'. In summary, central sensitisation is caused by the continued stimulation of the NMDA receptor, which evokes a change in the sensitivity of the post-synaptic cell, such that it responds more strongly to all of its inputs. The clinical expression of central sensitisation is:
1. Increased response to afferent input, ie. hyperalgesia (exaggerated pain response to a painful stimulus).
2. An expansion of the receptive fields of peripheral nociceptors, i.e. allodynia (a painful response to a non-painful stimulus).
3. An increase in spontaneous activity, i.e. spontaneous pain.
4. Neuroplasticity (if a prolonged stimulation), i.e. pain memory (pain in the absence of stimulus e.g. phantom limb pain).
5. The symptoms are blocked by NMDA antagonists.
Neuropathic pain
When a peripheral nerve is damaged there are thought to be several responses.
1. The regenerating sprout may discharge spontaneously (producing spontaneous pain).
2. Damaged axons become extremely sensitive to mechanical, thermal or chemical stimulation producing hyperalgesia.
3. Similar but less pronounced changes in adjacent but undamaged axons can occur causing allodynia.
Treatment for neuropathic pain has historically been difficult. However, the mainstays of treatment have been tricyclic antidepressants, anticonvulsants, local anaesthetics, opioids, steroids and nerve blocks.
At the level of the spinal cord it is thought that NMDA receptor activation may also have a role in neuropathic pain. NMDA activation and subsequent central sensitisation also produces allodynia, hyperalgesia, spontaneous pain and pain in the absence of stimulation.
Thus it follows that treatment with an NMDA antagonist may alleviate neuropathic pain.
The most commonly used NMDA receptor antagonist is ketamine, which has for many years been used as a dissociative anaesthetic. In low doses, as a subcutaneous infusion it has been shown to have a great benefit in treating neuropathic pain for many patients, although clinical trials are yet to be published and clear protocols are yet to be established. Other NMDA antagonists include dextromethorphan, amantadine and dextropropoxyphene. It is a contentious issue whether methadone is a NMDA receptor antagonist or not. Animal studies suggest not, although it clinically can give benefit over morphine in the treatment of neuropathic pain.
Case study
A 57-year old man was admitted to the Palliative Care Unit with an adenocarcinoma of unknown primary. He gave a 4-month history of a painful shoulder which had initially been diagnosed as a rotator cuff injury. Unfortunately, on CT scan, this was shown to be a soft tissue metastases involving his left scapula, ribs and muscle. His predominant pain features were pain on movement with allodynia and hyperalgesia. His morphine was gradually titrated to a dose of 300mg per day. This provided him with incomplete pain relief and he became morphine toxic with hallucinations and narcosis. Due to the clinical situation he was deemed too unwell for chemotherapy.
He was admitted to the palliative care ward and given a ketamine infusion subcutaneously for 5 days. This not only bought about improved pain control, but his opioid requirements were greatly reduced, hence his narcosis and hallucinations ceased. He was sufficiently well to actually commence chemotherapy.
Opioid tolerance
It has also been suggested that NMDA antagonists have a role in the prevention or treatment of opioid tolerance. In a situation where there appears to be 'wind up' phenomenon which clinically usually presents as escalating doses of opioids with hyperalgesia. Again this phenomenon can be blocked with NMDA antagonists. Unfortunately, there are no clear clinical guidelines as yet.
Reference
‘The Pathophysiology of Pain’, ASTRA Pharmaceuticals Education Booklet.
Journal of Pain and Symptom Management January 2000, Vol 19, Number 15
Any queries or questions contact Dr Joanne Doran, area medical director of palliative care, jdoran@nor.com.au, Northern Rivers Area Health Service, Lismore, NSW, Australia.
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