Evaluation of Predictors for Persistent Pain Post-total Knee Replacement

Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. This review focuses on the current understanding, clinical assessment and pharmalogical management of neuropathic pain. Introduction In 1994, the International Association for the Study of Pain (IASP) defined neuropathic pain as, “Pain initiated or caused by a primary lesion or dysfunction in the nervous system. ”(1) This definition has been useful in differentiating neuropathic pain from other types of pain, but it is neither precise nor specific. The IASP subsequently reviewed the definition of neuropathic pain in 2008 to be: “Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. ”(2) This revised definition of neuropathic pain emphasizes on the concept of aberrant somatosensory processing (far in excess of normal plasticity of the undamaged nociceptive system) which is the hallmark of neuropathic pain. Neuropathic pain can be classified into either central (spinal, brainstem, thalamus or cortex) or peripheral (nerve, plexus, dorsal root ganglion or root), depending on the anatomic location of the lesion or disease. Epidemiology In France, neuropathic pain has been approximated to affect 6.9% of the French general population. (3) In the United States of America, an estimated 35% of USA general population suffer from chronic pain, and 17.9% of those chronic pain sufferers have neuropathic pain. (4) 83 Due to the complex nature of neuropathic pain, it is often under diagnosed(5) and not treated appropriately. To add to the complexity of neuropathic pain, sufferers of chronic/neuropathic pain also tend to have higher depression and anxiety scores and more sleep disturbances. (6, 7) Pathophysiology Most of our understanding on the pathophysiology of neuropathic pain is based on animal studies. The general mechanisms of neuropathic pain are peripheral and central sensitisation. The specific mechanisms are ectopic nerve activity, structural re-organization and loss of inhibitory interneurons Following axonal injury (nerve lesion), a cascade of events takes place. There is an upregulation in the α2δ Ca2+ subunits in the dorsal root ganglion neurons, which causes prolonged membrane depolarization of the calcium channels. (8) A downregulation in μ opioid receptors has also been observed in animal studies of neuropathic pain states. (9, 10) The nerve lesion causes upregulation of nerve growth factor (NGF), tumour necrosis factor α (TNFα), transient receptor potential vanilloid type 1 (TRPV1) and pro-inflammatory cytokines. (11-13) The release of these products trigger the expression of sodium channels and sensitisation of the TRPV1 receptors in the nearby healthy nerve fibres. Peripheral sensitisation sets in following a nerve lesion. Peripheral sensitization is a physiological event where there is increased responsiveness and reduced threshold of nociceptors to stimulation of their receptive fields. Injury and inflammation of the damaged tissues leads to profound changes in chemical milieu of nociceptors, which leads to a decrease in nociceptors threshold and increased responsiveness to subsequent stimuli. Phosphorylation dramatically alters activity of receptors and ion channels. Changes in nociceptor properties, altered receptor-ion channels, increased membrane excitability, activation signalling cascades (phosphorylation proteins; gene transcription) and phenotypic switch (where the way the nerve fibres (C, Aβ, Aδ) function 84 changes as it relates to light touch driving sensitivity) are the hallmarks of peripheral sensitization. (14) Alterations in sodium channels (increased expression) and potassium channels (inhibition) occur following nerve lesion. (15-19) This alteration in sodium and potassium channels, coupled with peripheral sensitization, causes ectopic nerve activity to occur. The ectopic nerve activity is the primary driver of central sensitization in neuropathic pain. Central sensitization is a physiological event where there is increased responsiveness of nociceptive neurons in the central nervous system to their normal or sub-threshold input. (20) This phenomenon is activity-independent (does not require ongoing nociceptive input). Phosphorylation of the NMDA and AMPA receptors dramatically increases their sensitivity. Phosphorylation of the NMDA receptor increases its distribution to the synaptic membrane and its responsiveness to glutamate, which causes increased excitability to the cell membrane. (14) The physiologic principles of central sensitization are similar to that of peripheral sensitization. The main difference is that the processes occur in the central nociceptors transmission neurons in the dorsal horn or in the spinal nucleus of the trigeminal. There is also phenotypic switch of nociceptor specific neurons to wide dynamic range neurons. The low threshold Aβ and Aδ fibres are then able to activate the second order nociceptive neurons in the dorsal root ganglion. Selective loss of inhibitory GABAergic interneurons has been shown to occur in an animal model. (21) Some animal studies have also shown a decrease in efficacy of descending inhibitory pathways and the endogenous endorphin system in neuropathic pain conditions. (22, 23) The loss of inhibitory interneurons, decrease in efficacy of the descending inhibitory pathways and endogenous endorphin system, contributes to the complexity of managing neuropathic pain.