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

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

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

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  0.05). 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

Anti- and Pro-Nociceptive mechanisms in neuropathic pain after human spinal cord injury

BACKGROUND Deficient endogenous pain modulation and increased nociceptive excitability are key features of central sensitization and can be assessed in humans by conditioned pain modulation (CPM, anti-nociceptive) and temporal summation of pain (TSP, pro-nociceptive), respectively. This study aimed to investigate these measures as proxies for central sensitization in subjects with chronic neuropathic pain (NP) after spinal cord injury (SCI). METHODS In paraplegic subjects with NP (SCI-NP; n = 17) and healthy controls (HC; n = 17), parallel and sequential sham-controlled CPM paradigms were performed using pressure pain threshold at the hand, that is, above lesion level, as test stimulus. The conditioning stimulus was a noxious cold (verum) or lukewarm water bath (sham) applied contralaterally. Regarding pro-nociceptive mechanisms, a TSP protocol with individually-adjusted pressure pain stimuli at the thenar eminence was used. CPM and TSP magnitudes were related to intensity and spatial extent of spontaneous NP. RESULTS Neither the parallel nor sequential sham-controlled CPM paradigm showed any significant inhibition of above-level pressure pain thresholds for SCI-NP or HC. Accordingly, no group difference in CPM capacity was found, however, subjects with more intense spontaneous NP showed lower inhibitory CPM capacity. TSP was observed for both groups but was not enhanced in SCI-NP. CONCLUSIONS Our results do not support altered above-level anti- or pro-nociceptive mechanisms in SCI-NP compared with HC; however, they also highlight the relevance of spontaneous NP intensity with regards to the capacity of endogenous pain modulation in SCI subjects. SIGNIFICANCE Central sensitization encompasses deficient endogenous pain modulation and increased nociceptive excitability. These two mechanisms can be assessed in humans by conditioned pain modulation and temporal summation of pain, respectively. Our data demonstrates a lack of descending pain inhibition only in subjects with severe neuropathic pain which may hint towards central sensitization at spinal and/or supra-spinal levels. Disentangling the mechanisms of endogenous pain modulation and neuronal hyperexcitability might improve mechanism-based treatment of neuropathic pain in subjects with spinal cord injury

Contact-Heat Evoked Potentials: Insights into Pain Processing in CRPS Type I

PURPOSE: The pathophysiological mechanisms underlying the development of chronic pain in complex regional pain syndrome (CRPS) are diverse and involve both peripheral and central changes in pain processing, such as sensitization of the nociceptive system. The aim of this study was to objectively distinguish the specific changes occurring at both peripheral and central levels in nociceptive processing in individuals with chronic CRPS type I. PATIENTS AND METHODS: Nineteen individuals with chronic CRPS type I and 16 age- and sex-matched healthy controls (HC) were recruited. All individuals underwent a clinical examination and pain assessment in the most painful limb, the contralateral limb, and a pain-free control area to distinguish between peripheral and central mechanisms. Contact-heat evoked potentials (CHEPs) were recorded after heat stimulation of the three different areas and amplitudes and latencies were analyzed. Additionally, quantitative sensory testing (QST) was performed in all three areas. RESULTS: Compared to HC, CHEP amplitudes in CRPS were only increased after stimulation of the painful area (p=0.025), while no increases were observed for the pain-free control area (p=0.14). None of the CHEP latencies were different between the two cohorts (all p>0.23). Furthermore, individuals with CRPS showed higher pain ratings after stimulation of the painful limb compared to their contralateral limb (p=0.013). Lastly, compared to HC, mechanical (p=0.012) and thermal (p=0.046) sensitivity was higher in the painful area of the CRPS cohort. CONCLUSION: This study provides neurophysiological evidence supporting an intact thermo-nociceptive pathway with signs of peripheral sensitization, such as hyperexcitable primary afferent nociceptors, in individuals with CRPS type I. This is further supported by the observation of mechanical and thermal gain of sensation only in the painful limb. Additionally, the increased CHEP amplitudes might be related to fear-induced alterations of nociceptive processing

Priming of the autonomic nervous system after an experimental human pain model

Modulated autonomic responses to noxious stimulation have been reported in experimental and clinical pain. These effects are likely mediated by nociceptive sensitization, but may also, more simply reflect increased stimulus-associated arousal. To disentangle between sensitization- and arousal-mediated effects on autonomic responses to noxious input, we recorded sympathetic skin responses (SSRs) in response to 10 pinprick and heat stimuli before (PRE) and after (POST) an experimental heat pain model to induce secondary hyperalgesia (EXP) and a control model (CTRL) in 20 healthy females. Pinprick and heat stimuli were individually adapted for pain perception (4/10) across all assessments. Heart rate, heart rate variability, and skin conductance level (SCL) were assessed before, during, and after the experimental heat pain model. Both pinprick- and heat-induced SSRs habituated from PRE to POST in CTRL, but not EXP (P = 0.033). Background SCL (during stimuli application) was heightened in EXP compared with CTRL condition during pinprick and heat stimuli (P = 0.009). Our findings indicate that enhanced SSRs after an experimental pain model are neither fully related to subjective pain, as SSRs dissociated from perceptual responses, nor to nociceptive sensitization, as SSRs were enhanced for both modalities. Our findings can, however, be explained by priming of the autonomic nervous system during the experimental pain model, which makes the autonomic nervous system more susceptible to noxious input. Taken together, autonomic readouts have the potential to objectively assess not only nociceptive sensitization but also priming of the autonomic nervous system, which may be involved in the generation of distinct clinical pain phenotypes.NEW & NOTEWORTHY The facilitation of pain-induced sympathetic skin responses observed after experimentally induced central sensitization is unspecific to the stimulation modality and thereby unlikely solely driven by nociceptive sensitization. In addition, these enhanced pain-induced autonomic responses are also not related to higher stimulus-associated arousal, but rather a general priming of the autonomic nervous system. Hence, autonomic readouts may be able to detect generalized hyperexcitability in chronic pain, beyond the nociceptive system, which may contribute to clinical pain phenotypes

Central sensitization in CRPS patients with widespread pain: A cross-sectional study.

OBJECTIVE Widespread pain hypersensitivity and enhanced temporal summation of pain (TSP) are commonly reported in patients with complex regional pain syndrome (CRPS) and discussed as proxies for central sensitization. This study aimed to directly relate such signs of neuronal hyperexcitability to the pain phenotype of CRPS patients. METHODS Twenty-one CRPS patients and 20 healthy controls (HC) were recruited. The pain phenotype including spatial pain extent (assessed in % body surface) and intensity were assessed and related to widespread pain hypersensitivity, TSP, and psychological factors. Quantitative sensory testing (QST) was performed in the affected, the contralateral and a remote (control) area. RESULTS CRPS patients showed decreased pressure pain thresholds in all tested areas (affected: t(34)=4.98, p < 0.001, contralateral: t(35)=3.19, p = 0.005, control: t(31)=2.65, p = 0.012). Additionally, patients showed increased TSP in the affected area (F(3,111)=4.57, p = 0.009) compared to HC. TSP was even more enhanced in patients with a high compared to a low spatial pain extent (F(3,51)=5.67, p = 0.008), suggesting pronounced spinal sensitization in patients with extended pain patterns. Furthermore, the spatial pain extent positively correlated with the Bath Body Perception Disturbance Scale (ρ = 0.491; p = 0.048). CONCLUSION Overall, we provide evidence that the pain phenotype in CRPS, i.e., spatial pain extent, might be related to sensitization mechanism within the central nociceptive system. This study points towards central neuronal excitability as a potential therapeutic target in patients with more widespread CRPS

Central sensitization in CRPS patients with widespread pain: A cross-sectional study

OBJECTIVE: Widespread pain hypersensitivity and enhanced temporal summation of pain (TSP) are commonly reported in patients with complex regional pain syndrome (CRPS) and discussed as proxies for central sensitization. This study aimed to directly relate such signs of neuronal hyperexcitability to the pain phenotype of CRPS patients. METHODS: Twenty-one CRPS patients and 20 healthy controls (HC) were recruited. The pain phenotype including spatial pain extent (assessed in % body surface) and intensity were assessed and related to widespread pain hypersensitivity, TSP, and psychological factors. Quantitative sensory testing (QST) was performed in the affected, the contralateral and a remote (control) area. RESULTS: CRPS patients showed decreased pressure pain thresholds in all tested areas (affected: t(34)=4.98, p < 0.001, contralateral: t(35)=3.19, p = 0.005, control: t(31)=2.65, p = 0.012). Additionally, patients showed increased TSP in the affected area (F(3,111)=4.57, p = 0.009) compared to HC. TSP was even more enhanced in patients with a high compared to a low spatial pain extent (F(3,51)=5.67, p = 0.008), suggesting pronounced spinal sensitization in patients with extended pain patterns. Furthermore, the spatial pain extent positively correlated with the Bath Body Perception Disturbance Scale (ρ = 0.491; p = 0.048). CONCLUSION: Overall, we provide evidence that the pain phenotype in CRPS, i.e., spatial pain extent, might be related to sensitization mechanism within the central nociceptive system. This study points towards central neuronal excitability as a potential therapeutic target in patients with more widespread CRPS

Sensory phenotypes in complex regional pain syndrome and chronic low back pain-indication of common underlying pathomechanisms

INTRODUCTION First-line pain treatment is unsatisfactory in more than 50% of chronic pain patients, likely because of the heterogeneity of mechanisms underlying pain chronification. OBJECTIVES This cross-sectional study aimed to better understand pathomechanisms across different chronic pain cohorts, regardless of their diagnoses, by identifying distinct sensory phenotypes through a cluster analysis. METHODS We recruited 81 chronic pain patients and 63 age-matched and sex-matched healthy controls (HC). Two distinct chronic pain cohorts were recruited, ie, complex regional pain syndrome (N = 20) and low back pain (N = 61). Quantitative sensory testing (QST) was performed in the most painful body area to investigate somatosensory changes related to clinical pain. Furthermore, QST was conducted in a pain-free area to identify remote sensory alterations, indicating more widespread changes in somatosensory processing. RESULTS Two clusters were identified based on the QST measures in the painful area, which did not represent the 2 distinct pain diagnoses but contained patients from both cohorts. Cluster 1 showed increased pain sensitivities in the painful and control area, indicating central sensitization as a potential pathomechanism. Cluster 2 showed a similar sensory profile as HC in both tested areas. Hence, either QST was not sensitive enough and more objective measures are needed to detect sensitization within the nociceptive neuraxis or cluster 2 may not have pain primarily because of sensitization, but other factors such as psychosocial ones are involved. CONCLUSION These findings support the notion of shared pathomechanisms irrespective of the pain diagnosis. Conversely, different mechanisms might contribute to the pain of patients with the same diagnosis

Sensory phenotypes in complex regional pain syndrome and chronic low back pain-indication of common underlying pathomechanisms.

INTRODUCTION First-line pain treatment is unsatisfactory in more than 50% of chronic pain patients, likely because of the heterogeneity of mechanisms underlying pain chronification. OBJECTIVES This cross-sectional study aimed to better understand pathomechanisms across different chronic pain cohorts, regardless of their diagnoses, by identifying distinct sensory phenotypes through a cluster analysis. METHODS We recruited 81 chronic pain patients and 63 age-matched and sex-matched healthy controls (HC). Two distinct chronic pain cohorts were recruited, ie, complex regional pain syndrome (N = 20) and low back pain (N = 61). Quantitative sensory testing (QST) was performed in the most painful body area to investigate somatosensory changes related to clinical pain. Furthermore, QST was conducted in a pain-free area to identify remote sensory alterations, indicating more widespread changes in somatosensory processing. RESULTS Two clusters were identified based on the QST measures in the painful area, which did not represent the 2 distinct pain diagnoses but contained patients from both cohorts. Cluster 1 showed increased pain sensitivities in the painful and control area, indicating central sensitization as a potential pathomechanism. Cluster 2 showed a similar sensory profile as HC in both tested areas. Hence, either QST was not sensitive enough and more objective measures are needed to detect sensitization within the nociceptive neuraxis or cluster 2 may not have pain primarily because of sensitization, but other factors such as psychosocial ones are involved. CONCLUSION These findings support the notion of shared pathomechanisms irrespective of the pain diagnosis. Conversely, different mechanisms might contribute to the pain of patients with the same diagnosis

Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area

Introduction: In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain. Objectives: The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON). Methods: Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile). Results: Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed. Conclusion: Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP