The development of debilitating central neuropathic pain (CNP), defined as pain caused by a lesion or dysfunction of the central nervous system (CNS),^1,2 can occur after any lesion of the CNS, including demyelinating, vascular, infectious, inflammatory, and traumatic events. In contrast to CNP after stroke (including thalamic stroke resulting in Dejerine-Roussy syndrome), multiple sclerosis, and tumors,^3,4 the prevalence of CNP after spinal cord injury (SCI) is high; most cite a prevalence ranging from 50% to 66%.^5–8 With the number of individuals in the United States who have SCIs estimated to be as high as 1,275,000 and estimated lifetime costs from SCI ranging from $681,843 to more than $3 million if the injury is sustained at age 25 years,⁹ CNP after SCI has become a growing public health concern.

Lesions of the spinal cord, particularly those caused by trauma, are also associated with lesions of adjacent nerve roots, including the cauda equina; therefore, CNP is typically associated with peripheral neuropathic pain (PNP). CNP may also be associated with visceral pain through sympathetic and vagal nerve input and pain secondary to musculoskeletal overuse, muscle spasms, or mechanical instability of the spine.¹⁰ The primary insult to the somatosensory pathway may be limited, with only mild sensory loss on clinical examination, or extensive, with complete anesthesia on clinical examination. Notably, refractory deafferentation pain may be associated with only mild sensory loss on examination.

Traumatic SCIs account for 65% of CNP, and other causes include iatrogenic (12%), inflammatory (9%), neoplastic (6%), skeletal (2%), and vascular (2%).^11,12 At the time of injury, typical symptoms of CNP are often not present but may appear during the rehabilitation phase. The distribution of these lesions is 42% in the cervical spine, 21% in T1 to T9, and 37% in T10 to L2.^12,13

Although several different heterogeneous pain syndromes may develop after SCI, CNP is potentially the most problematic. CNP is characterized as spontaneous pain (e.g., allodynia and hyperalgesia with temporal and spatial summation) in a distribution from which spinal and supraspinal mechanisms may be inferred. Moreover, negative or positive sensory signs are present at or below the level of injury or in the distribution of the area of pain. Therefore, in 2000, the International Association for the Study of Pain proposed a classification based on the distribution of pain relative to the level of injury: (1) at-level pain, distributed segmentally at the border of normal and interrupted sensory innervation, and (2) below-level pain, distributed diffusely below the level of injury.¹³ At-level pain typically presents within two to three segments above and below the level of injury¹³ and often involves a lesion to the spinothalamic tract or changes in the spinal cord dorsal horn, producing hyperexcitability in the pain pathways. Nerve root injuries contribute to an increased impulse generation.^14–16 Below-level pain involves sensory hypersensitivity and neuronal hyperactivity at the level of injury;^17,18 pathophysiologic changes at supraspinal levels may include spinothalamic tract lesions, such as a spinothalamic dysrhythmia, or thalamic structural reorganization.^19,20 A longitudinal study suggests that the onset of at-level pain may precede that of below-level pain.⁵ Above-level pain has been typically associated with compressive mononeuropathies and other lesions and syndromes not directly caused by cord damage at the level of injury; however, animal models of CNP after thoracic spinal cord lesions show behavioral changes above the level of injury that are associated with peripheral and central sensitization and reactive glia in the uninjured cervical cord.^21–23

Syringomyelia may also be an important source of neuropathic pain and often presents long after the initial injury.^24–26 It involves the dilation of the central canal (termed cyst) within the spinal cord that expands and damages the center cord. Patient may present initially with a small injury and later develops progressively worsening painful symptoms.^25,26

Experimental rodent models of CNP after SCI have contributed to our understanding of pathophysiological mechanisms (Figs. 47-1 and 47-2). Models include ischemic, traumatic (hemisection, contusion, compression, anterolateral cut, electrolytic), and neurotoxic (quisqualate).²² Behavioral assays include measures of evoked hyperalgesia and allodynia, such as mechanical and thermal withdrawal thresholds; however, the development of central spasticity in these models is a potential confounder.²⁷ Excitatory amino acids such as glutamate are briefly released in and around the site of injury, resulting in neuronal hyperexcitability.^28,29 Data also suggest that the dysfunction of descending inhibitory control mechanisms after lesions of the dorsal or dorsolateral quadrant of the spinal cord results in a component of spontaneous pain that is associated with CNP.^30,31 Inhibitory neurons containing γ-aminobutyric acid (GABA) are highly susceptible to hypoxia, and the loss of tonic central inhibitory actions and their participation in descending inhibitory tracts may also contribute to an increased responsiveness of neurons in pain pathways.^32,33

Functional changes of receptor and ion channels include the altered expression of sodium channels in the spinal cord and thalamus³⁴ and the upregulation of voltage-gated calcium channel α2δ-1 subunit protein in the spinal cord.³⁵ Other neurochemical changes with a possible role in SCI pain include elevation of intracellular calcium, calcium activation of phospholipase A2, protein kinase C activation, and changes in nitric oxide and peptides such as substance P and dynorphin.³⁶ Neuroinflammation involving the activation of a complex network of neuroimmune processes also contributes to regeneration and degeneration of the injured tissue after SCI; glial (astrocytes and microglia) cells are inherently involved in the activation and dysfunction of central neurons in the spinal cord^36–42 and contribute to the development of “gliopathy,” which results in sensory dysfunction. Structural and functional abnormalities in several brain regions are also associated with nociceptive processing.^43–45

Given the range of molecular mechanisms involved in CNP, combination therapy is typically prescribed; however, clinically available treatments for neuropathic pain are associated with unacceptable side effects that can interfere with activities of daily living, such as cognitive, anticholinergic, or motor dysfunction in an ambulating patient.^46–49

Among the tricyclic antidepressants, only amitriptyline has been studied in CNP after SCI, with one positive clinical trial evaluating 150 mg/day (n = 38)⁵⁰ and one negative clinical trial at 125 mg/day (n = 84).⁵¹ Duloxetine is the only serotonin norepinephrine reuptake inhibitor to have been evaluated in CNP to date; Vranken et al.⁵² failed to show an analgesic effect in 48 subjects at a daily dose of 120 mg versus placebo, although the clinical trial was likely to have been underpowered.