Nerve injury or dysfunction and neuropathic pain
Introduction
Neurological injury or dysfunction is the basis of neuropathic pain. Neuropathic and nociceptive pain coexist in many circumstances to varying degrees. While physical nerve trauma may be obvious (eg accidental injury, surgery), other causes of nerve injury are not (such as microvascular disease [eg diabetes], degenerative diseases [eg multiple sclerosis], and chemical injury [eg vincristine]). Nerve injury results in effective partial or complete transection of the nerve and cessation of afferent input from those neurones affected. This is perceived as a region of numbness or hypoaesthesia from the area supplied by those afferents, although the actual size of this zone varies depending on the density of innervation and the degree of overlap of receptive fields.
Neuropathic pain is especially common after many surgical procedures including hernia repair, knee arthroplasty, chest wall surgery (eg thoracotomy, mastectomy) and amputation, being present in 20% to 60% of patients at six months after the procedure and described as moderate to severe in up to 10% of these. Although only a minority of these individuals will need specialist pain management, clinicians should be aware of this problem.
The interruption to the normal flow of impulses results in alterations in the injured neurone. The dorsal root ganglion cell produces peptides that travel to the site of injury by axonal transport, including nerve growth factor (NGF). If the nerve sheaths are intact, axon regrowth might successfully restore normal sensation, otherwise a disorganised regrowth or neuroma can occur.
Neuroma formation is associated with spontaneous ectopic discharges, especially from C fibres. Spontaneous activity may also arise in the cell bodies of dorsal root ganglion neurones. The intensity of this spontaneous activity can be sufficient to induce central hypersensitivity and initiate the establishment of neuropathic pain.
This spontaneous activity is in part due to low-threshold sodium channels being expressed at the injury site during regrowth and possibly also in dorsal horn neurones. This is the basis for the use of sodium channel blockers (eg lignocaine infusions, oral mexiletine) in patients with some forms of peripheral neuropathic pain.
Sympathetic innervation can be altered in some situations following nerve injury. Sympathetically maintained pain is a recognised clinical entity. Complex regional pain syndrome (CRPS) includes both sympathetically and non–sympathetically maintained pain. Clinical characteristics of a sympathetically maintained component include vasomotor symptoms, swelling, and trophic changes in the region affected.
Central responses to nerve injury
The increased ectopic or spontaneous neuronal discharge associated with peripheral nerve injury results in a barrage of high frequency input via C fibres that initiates physiological responses in the dorsal horn (ie ‘wind-up’ and central hypersensitivity). These changes amplify the response of the dorsal horn second-order cells to the continuing input and a persistent cycle becomes established. There is clearly a temporal component to the development of hypersensitivity and neuropathic pain and structural changes may also be important, but these require time to develop. These structural and functional changes include cell death and degeneration of dorsal root ganglion cells, altered gene-expression within surviving dorsal horn cells (the induction of the immediate early genes c-fos and c-jun), and sprouting of non-nociceptive afferent dendrites into lamina II of the dorsal horn, although sprouting of non-nociceptive afferent dentrites into lamina II of the dorsal horn remains controversial. The role of glial cell responses in maintaining central hypersensitivity is also an area of much current interest.
Alteration of A-beta-fibre behaviour or connectivity, and altered responsiveness of wide dynamic range neurones, helps explain the clinical experience of the stimulation of low-threshold follicular afferents (eg by brushing the skin gently) being interpreted as painful or burning (allodynia). It would also explain the relative resistance of such neuropathic pain to opioids, as the A-beta terminals do not normally have opioid receptors (and may lack other presynaptic inhibitory sites). This concept of plasticity (‘wind-up’) in neuropathic pain is important, as it underlies any strategies that might be used to modify it clinically.
Important spinal cord level inhibitory processes, especially involving glycine and GABA-ergic neurones, may be suppressed or altered by the pathological processes involved. This is a likely cause of chronic pain due to spinal cord injury.
Physiology of the treatment of neuropathic pain
The key elements maintaining neuropathic pain are sustained input from the injured nerve(s) and sensitisation and ‘wind-up’ of the CNS, especially at a spinal cord level. Sodium channel blockers may help by decreasing spontaneous discharge peripherally. In some conditions (eg trigeminal neuralgia), anticonvulsants such as carbamazepine are effective. The anticonvulsants gabapentin and pregabalin probably exert their effect in reducing neuropathic pain by combining with a subunit of the neuronal calcium channel and decreasing excitability in the spinal cord nociceptive pathways.
Neuropathic pain is different from nociceptive pain, and is less likely to respond to conventional analgesics (eg paracetamol, NSAIDs and opioids). However, many patients present with a mixture of different pain types. This is why a careful pain history is necessary in order to select the most appropriate treatment strategy for each individual.
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