Mechanisms of neuropathic pain

Abstract

Neuropathic pain is defined as 'pain initiated or caused by a primary lesion or dysfunction in the nervous system'.94 The spectrum of neuropathic pain covers a variety of disease states (Table 1) and presents in the clinic with a variety of symptoms.145 Neuropathic pain is often reported as having a lancinating or continuous burning character and is often associated with the appearance of abnormal sensory signs, such as allodynia (pain as a result of a stimulus which does not normally provoke pain) or hyperalgesia (an increased response to a stimulus which is normally painful) (Figure 1). The sensory phenomena can be further characterized into static or dynamic sub-types. The mechanistic implication of allodynia is that elements of the sensory nervous system, which normally signal innocuous sensation have begun to encode painful stimuli, whilst in hyperalgesia the structures that sub-serve nociception have become hyperexcitable. Neuropathic pain is an area of largely unmet therapeutic need. The current pharmacological mainstays of clinical management are tricyclic anti-depressants and certain anti- convulsants,92 119 but these only achieve clinically signifi- cant (greater than 50%) pain relief in less than 50% of patients and are associated with sub-optimal side effect profiles. Opioids are generally considered to be less effective in neuropathic pain than in inflammatory pain, with the dose response curve of opioids in neuropathic pain shifted to the right of that for inflammatory pain, although the extent of this difference is controversial.112 The majority of research into neuropathic pain mechan- isms has concentrated on changes in the peripheral nerve or spinal cord after peripheral nerve injury and, therefore, most available evidence relates to changes in these parts of the nervous system and the review will, therefore, focus on these aspects. Nevertheless, it is important to recognize that alterations in the brain have also been demonstrated following peripheral nerve injury, but much less is known about the significance of these changes. For example, phantom limb pain has been shown to be associated with re- organization of the cortex of humans.43 The degree of cortical re-organization, as determined by BTi neuro- magnetic imaging, was linked in a linear fashion to the intensity of pain, with an increase in re-organization being associated with greater pain intensity.43 A more recent study indicated that cortical re-organization was evident only in patients with phantom limb pain, and not in patients with non-painful phantom limb phenomena or congenital absence of the limb.44