Pain is not only a frequent complaint among patients with a confirmed diagnosis of MS, but it has been reported as a harbinger of the disease.^2,3 Headache is the most common type of central neuropathic pain experienced by patients with MS (affecting >50% of individuals), followed by dysesthetic limb pain, Lhermitte’s sign, trigeminal neuralgia, and pain associated with optic neuritis.^4-6 In PD, a recent case-control study found the disease to be significantly associated with the occurrence of central neuropathic pain (eg, burning, tingling, or formication).⁷ In light of this observation, the investigators advised that pain should henceforth be considered a nonmotor feature of PD.

Although patients with neurodegenerative diseases may also suffer from peripheral or nociceptive pain, this brief review will focus on central neuropathic pain arising from neural injury to the brain or spinal cord.

Recent research has clearly demonstrated that inflammatory and immune mechanisms in the central nervous system play important roles in neuropathic pain.⁸ In response to nervous system damage, infiltration of inflammatory cells and activation of resident immune cells lead to the production and secretion of an array of inflammatory mediators. These mediators cause neuroimmune activation and sensitization of primary afferent neurons, resulting in a hypersensitivity to pain.⁸ In the case of MS, the pathophysiology of neuropathic pain is thought to involve any of a variety of factors: glial cell inflammatory immune mechanisms, plaques that disrupt the spinothalamic and quintothalamic pathways, acquired channelopathy in specific nerves, and abnormal impulses through motor axons.² Headache, particularly migraine, in patients with MS is believed to result from inflammatory lesions in the trigeminocervical complex, rostral brainstem, and periaqueductal gray matter.^9,10 A possible contributor to pain in patients with PD may be nigrostriatal damage leading to dysfunction of the control exerted by the basal ganglia on cerebral areas responsible for processing nociceptive input.^7,11

Brain activation studies using various imaging techniques have yielded additional insights into the structural and functional underpinnings of neuropathic pain, although this line of investigation is just beginning to evolve. Studies assessing responses to painful stimuli in patients with chronic neuropathic pain have shown that the areas noted in the Table are the most commonly activated areas of the brain.^12-14

These areas of the brain are frequently referred to as the “pain matrix,” although both the concept and the composition of such a matrix remain controversial¹⁵; no “pain matrix” unique to neuropathic pain has yet been fully defined.¹⁵