Pain-autonomic measures reveal nociceptive sensitization in complex regional pain syndrome

Abstract

Background: Allodynia and hyperalgesia are common signs in individuals with complex regional pain syndrome (CRPS), mainly attributed to sensitization of the nociceptive system. Appropriate diagnostic tools for the objective assessment of such hypersensitivities are still lacking, which are essential for the development of mechanism-based treatment strategies.

Objectives: This study investigated the use of pain-autonomic readouts to objectively detect sensitization processes in CRPS.

Methods: Twenty individuals with chronic CRPS were recruited for the study alongside 16 age- and sex-matched healthy controls (HC). All individuals underwent quantitative sensory testing and neurophysiological assessments. Sympathetic skin responses (SSRs) were recorded in response to 15 pinprick and 15 noxious heat stimuli of the affected (CRPS hand/foot) and a control area (contralateral shoulder/hand).

Results: Individuals with CRPS showed increased mechanical pain sensitivity and increased SSR amplitudes compared with HC in response to pinprick and heat stimulation of the affected (p < 0.001), but not in the control area (p > 0.05). Habituation of pinprick-induced SSRs was reduced in CRPS compared to HC in both the affected (p = 0.018) and slightly in the control area (p = 0.048). Habituation of heat-induced SSR was reduced in CRPS in the affected (p = 0.008), but not the control area (p = 0.053).

Conclusions: This is the first study demonstrating clinical evidence that pain-related autonomic responses may represent objective tools to quantify sensitization processes along the nociceptive neuraxis in CRPS (e.g. widespread hyperexcitability). Pain-autonomic readouts could help scrutinize mechanisms underlying the development and maintenance of chronic pain in CRPS and provide valuable metrics to detect mechanism-based treatment responses in clinical trials.

Significance: This study provides clinical evidence that autonomic measures to noxious stimuli can objectively detect sensitization processes along the nociceptive neuraxis in complex regional pain syndrome (CRPS) (e.g. widespread hyperexcitability). Pain-autonomic readouts may represent valuable tools to explore pathophysiological mechanisms in a variety of pain patients and offer novel avenues to help guide mechanism-based therapeutic strategies.

FIGURE 1

Pain–autonomic interaction. Recordings of sympathetic skin responses (SSRs) in response to noxious heat or pinprick stimulation of the affected and control area.

FIGURE 2

Quantitative sensory testing. The frequencies of pathological QST z‐scores (±1.96 SD) in complex regional pain syndrome (CRPS) are shown for the affected (a) and control areas (b). The shift in the stimulus–response function in terms of mechanical pain sensitivity is shown for the CRPS (red) compared to HC (blue) in both the affected (c) and control areas (d). *p < 0.05, ***p < 0.001. DMA, dynamic mechanical allodynia; HPT, heat pain threshold; MPT, mechanical pain threshold.

FIGURE 3

Pinprick and heat pain ratings. Mean pinprick pain ratings (a) and habituation of pinprick ratings (b) from the ‘first’, ‘middle’ and ‘last’ stimulation blocks are shown in the top panel. Mean heat pain ratings (c) and habituation of heat pain ratings (d) are shown in the bottom panel. Pain ratings are shown after stimulation of the control and affected areas in patients with complex regional pain syndrome (CRPS—red) and healthy controls (HC—blue). Significances are shown for comparisons between areas: **p < 0.01 and between cohorts: ^## p < 0.01

FIGURE 4

An illustrative example of pinprick‐induced sympathetic skin responses (SSRs) in complex regional pain syndrome (CRPS) and healthy control (HC). Pinprick‐induced SSRs are higher in the individual with CRPS (a, b) compared to HC (c, d). In the patient with CRPS, pinprick‐induced SSRs are still prominent in the last stimulation block (i.e., reduced habituation) in both the affected (a) and control areas (b). In the HC, pinprick‐induced SSRs are no longer present in the last stimulation block (i.e., normal physiological habituation). Please note the different y‐axis scales for CRPS and HC.

FIGURE 5

Pinprick‐ and heat‐induced sympathetic skin responses (SSRs). Mean pinprick‐induced SSRs (a) and SSR habituation (b) from the ‘first’, ‘middle’ and ‘last’ stimulation blocks are shown in the top panel. Mean heat‐induced SSRs (c) and SSR habituation (d) are shown in the bottom panel. SSR amplitudes are shown in response to stimulation of the affected and control areas in individuals with complex regional pain syndrome (CRPS—red) and healthy controls (HC—blue). Significances are shown for comparisons between areas: *p < 0.05, **p < 0.01, ***p < 0.001 and between cohorts: ^# p < 0.05, ^## p < 0.01, ^### p < 0.001.

FIGURE 6

Association between sympathetic skin response (SSR) amplitudes and pain ratings in response to noxious heat (a) and pinprick stimulation (b) for complex regional pain syndrome (CRPS‐red) and healthy control (HC‐blue).