Indicators of central sensitization in chronic neuropathic pain after spinal cord injury

Abstract

Background: Central sensitization is considered a key mechanism underlying neuropathic pain (NP) after spinal cord injury (SCI).

Methods: Two novel proxies for central sensitization were investigated in thoracic SCI subjects with (SCI-NP) and without NP (SCI-nonNP) compared to healthy controls (HC). Specifically, temporal summation of pain (TSP) was investigated by examining pain ratings during a 2-min tonic heat application to the volar forearm. Additionally, palmar heat-induced sympathetic skin responses (SSR) were recorded in order to reveal changes in pain-autonomic interaction above the lesion level. Pain extent was assessed as the percentage of the body area and the number of body regions being affected by NP.

Results: Enhanced TSP was observed in SCI-NP (+66%) compared to SCI-nonNP (-75%, p = 0.009) and HC (-59%, p = 0.021). In contrast, no group differences were found (p = 0.685) for SSR habituation. However, pain extent in SCI-NP was positively correlated with deficient SSR habituation (body area: r = 0.561, p = 0.024; body regions: r = 0.564, p = 0.023).

Conclusions: These results support the value of TSP and heat-induced SSRs as proxies for central sensitization in widespread neuropathic pain syndromes after SCI. Measures of pain-autonomic interaction emerged as a promising tool for the objective investigation of sensitized neuronal states in chronic pain conditions.

Significance: We present two surrogate readouts for central sensitization in neuropathic pain following SCI. On the one hand, temporal summation of tonic heat pain is enhanced in subjects with neuropathic pain. On the other hand, pain-autonomic interaction reveals potential advanced measures in chronic pain, as subjects with a high extent of neuropathic pain showed diminished habituation of pain-induced sympathetic measures. A possible implication for clinical practice is constituted by an improved assessment of neuronal hyperexcitability potentially enabling mechanism-based treatment.

FIGURE 1

Representative examples of pain ratings during tonic heat application for two healthy controls. (a) Adaptation magnitude and with −100% temporal summation of pain (TSP). (b) Adaptation magnitude with +43.8% TSP magnitude. Markers are set for the start and end of adaptation (green) as well as for the resulting temporal summation of pain (red). The tonic heat profiles are shown on a numerical rating scale (NRS, left) as well as normalized to the rating at the ramp (right axis). Negative values illustrate lower pain ratings and positive values illustrate higher pain ratings compared to the ramp.

FIGURE 2

Pain ratings and temporal summation of pain (TSP) during tonic heat application. (a) Grand averages of tonic heat pain ratings in the three groups (SCI‐NP in red, SCI‐nonNP in green and HC in black). The grand averages are shown normalized to the rating at the ramp, and are plotted as the mean and standard error of the mean. (b) Quantification of the TSP magnitude for the three groups. Negative values illustrate lower pain ratings and positive values illustrate higher pain ratings compared to the ramp. HC, healthy controls; SCI‐nonNP, SCI subjects without neuropathic pain; SCI‐NP, SCI subjects with neuropathic pain; TSP, temporal summation of pain; VAS, visual analogue scale.

FIGURE 3

Habituation of contact heat pain ratings and SSR (sympathetic skin response) in the three groups. (a) no group difference was found with regard to pain rating habituation. (b) Habituation of SSR amplitude also revealed no group difference. HC, healthy controls; SCI‐nonNP, neuropathic pain‐free subjects; SCI‐NP, neuropathic pain subjects.

FIGURE 4

Correlation of SSR (sympathetic skin response) habituation with neuropathic pain characteristics. (a) Positive correlation of SSR habituation with body area affected by NP. (b) Positive correlation of SSR habituation with a number of body regions affected by NP. (c) no significant correlation of SSR habituation with NP intensity. NP, neuropathic pain; NRS, numeric rating scale.

FIGURE 5

Representative examples of SSR (sympathetic skin response) habituation and neuropathic pain extent. (a) SCI subject with 34.2% of the total body area affected by spontaneous neuropathic pain and a deficient SSR habituation (+7.3% compared to baseline). (b) SCI subject with 4.9% neuropathic pain extent and a pronounced SSR habituation (−59.7% compared to baseline). (c) Healthy control with a pronounced SSR habituation (−54.4% compared to baseline). SCI, spinal cord injury; SSR, sympathetic skin response.