AbstractBackgroundIt is unknown if different etiologies or lesion topographies influence central neuropathic pain (CNP) clinical manifestation.MethodsWe explored the symptom–somatosensory profile relationships in CNP patients with different types of lesions to the central nervous system to gain insight into CNP mechanisms. We compared the CNP profile through pain descriptors, standardized bedside examination, and quantitative sensory test in two different etiologies with segregated lesion locations: the brain, central poststroke pain (CPSP, n = 39), and the spinal cord central pain due to spinal cord injury (CPSCI, n = 40) in neuromyelitis optica.ResultsResults are expressed as median (25th to 75th percentiles). CPSP presented higher evoked and paroxysmal pain scores compared to CPSCI (p < 0.001), and lower cold thermal limen (5.6°C [0.0–12.9]) compared to CPSCI (20.0°C [4.2–22.9]; p = 0.004). CPSCI also had higher mechanical pain thresholds (784.5 mN [255.0–1078.0]) compared to CPSP (235.2 mN [81.4–1078.0], p = 0.006) and higher mechanical detection threshold compared to control areas (2.7 [1.5–6.2] vs. 1.0 [1.0–3.3], p = 0.007). Evoked pain scores negatively correlated with mechanical pain thresholds (r = −0.38, p < 0.001) and wind‐up ratio (r = −0.57, p < 0.001).ConclusionsCNP of different etiologies may present different pain descriptors and somatosensory profiles, which is likely due to injury site differences within the neuroaxis. This information may help better design phenotype mechanism correlations and impact trial designs for the main etiologies of CNP, namely stroke and spinal cord lesions. This study provides evidence that topography may influence pain symptoms and sensory profile. The findings suggest that CNP mechanisms might vary according to pain etiology or lesion topography, impacting future mechanism‐based treatment choices.