Virtual reality in managing Complex Regional Pain Syndrome (CRPS): a scoping review.

Background: Complex Regional Pain Syndrome (CRPS) is a severe pain disorder that does not yet have a specific treatment. Patients with CRPS not only suffer from a wide range of symptoms that affect their quality of life but also present psychological affections to the way they see their body and specifically their affected limb. Virtual Reality (VR) modalities have become a targeted treatment for chronic pain and in the case of CRPS, may be a valuable approach to the mechanisms that affect these patients. Objectives: Using the PRISMA Scoping Review guidelines, we intend to uncover the key information from the studies available about VR modalities in the treatment of CRPS. We focus on the improvement of pain levels, body perception disturbances (BPD), and limb movement/daily function. Results: Our search strategy resulted in 217 articles from PubMed. Twenty were assessed for eligibility and seven were included in the final qualitative synthesis. Of these seven articles, we included a clinical trial, three pilot studies, a blinded randomized controlled trial, a crossover double-blind trial, and a randomized controlled trial. These studies provide important subjective patient findings, along with some statistically significant results in the experiences of VR therapies modulating pain, BPD, and improving limb movement/daily function. However, not all the studies included statistical analysis, and there are contradicting data found from some patients that did not perceive any improvement from VR therapies. Conclusions: We describe the results found in 7 articles that focus on the treatment of CRPS with VR modalities. Overall, the articles have various limitations, but the strategies related to immersive virtual reality, cardiac signaling, body switching and limb modulation have shown the most promising results for pain reduction and BPD improvement. These strategies reflect on pathophysiological mechanisms that are hypothesized to be affected in CRPS patients leading to the chronic pain and BPD that they experience. Not much evidence was found for improvement in limb movement and daily function. This review is a pathway for future studies on this topic and a more extensive data synthesis when more information is available.

Differences between chronic low back pain patients in Germany and Thailand in terms of nature of disease and socioeconomic and psychological factors.

BACKGROUND: Worldwide, chronic low back pain (CLBP) is one of the most common causes of physical and psychological disabilities. The factors that affect low back pain (LBP) between Western and Eastern countries are different. OBJECTIVE: We assessed the factors associated with LBP and their impact in German and Thai CLBP participants. METHODS: This cross-sectional study was conducted in 100 Thai and 100 German CLBP participants. Data were collected before the participants received treatment in the outpatient rehabilitation clinic. We used standardized questionnaires to assess the demographic and socioeconomic data, clinical features of the pain, the impact of pain during daily activities, and psychological consequences. RESULTS: We found a statistically significant difference between the two groups for minimal pain intensity (NRS German = 3.01, Thai = 1.83), and the participants' acceptable pain intensity (NRS German = 1.97, Thai = 3.88). The German participants had a higher negative impact score in their daily living compared to the Thai participants (German = 23.5, Thai = 10). Also, the German participants suffered more often from depression (CES-D score; German = 17, Thai = 4). However, the average back pain intensity was the same for both groups. CONCLUSION: German CLBP participants had significantly more depressive symptoms and pain-related impairments compared to the Thai participants. On the other hand, there were no differences in maximum and average pain severities.

The Short-Term Kinetics of sICAM-1 after Induction of Acute Experimental Pain in Healthy Volunteers.

Intercellular adhesion molecule-1 (ICAM-1) mediates extravasation of leukocytes, releasing proinflammatory cytokines or endogenous opioids in the inflamed tissue. Thus, ICAM-1 is a crucial component of peripheral antinociception. Previously, we demonstrated a significant correlation between the soluble form of ICAM (sICAM-1) in serum and pain intensity reported by chronic pain patients. The present study examines the role and kinetics of sICAM-1 in experimentally induced acute pain. Three groups of 10 subjects were exposed to 10 min of high (capsaicin-enhanced) or low-intensity heat pain or cold pain, respectively. Thermal stimuli were induced using a device for quantitative sensory testing. Topical capsaicin significantly increased heat pain intensity without the risk of thermal tissue damage. Pain intensity was recorded every minute during testing. sICAM-1 concentrations in serum were determined by ELISA before, immediately after, and 60 min after test termination. Among all experimental groups, sICAM-1 significantly decreased immediately after pain induction. After 60 min, sICAM-1 concentrations returned towards initial values. Interestingly, a linear correlation was found between the extent of sICAM-1 changes and the initial concentrations. Whereas high initial values led to a distinct decrease of sICAM-1, low concentrations tended to increase. There was no statistically significant correlation between levels or alterations of serum sICAM-1 and pain intensity reported by the test subjects. In contrast to our previous findings in chronic pain patients, the present results show that sICAM-1 values do not correlate with the intensity of acute experimental pain. However, we were able to detect short-term changes of sICAM-1 after induction of nociceptive thermal stimuli, suggesting that this marker is part of a demand-oriented homeostatically controlled system.

Clinical and psychological phenomenology of pain in autoinflammatory diseases.

BACKGROUND: Pain is the clinical hallmark of patients in patients with autoinflammatory diseases (AID) caused by variants of the NLRP3-, MEFV- or TNFRSF1A gene. However, no systematical analysis of the clinical and psychological presentation of pain has been performed to date. METHODS: Twenty-one symptomatic patients with variants in the NLRP3-, MEFV- and TNFRSF1A gene and clinical signs suggestive of an AID were retrospectively included in this monocentric cross-sectional case-series study. Patients were examined and interviewed using the German pain questionnaire. The hospital anxiety and depression scale (HADS) was applied to screen patients for anxiety and depression. RESULTS: Twenty out of 21 AID patients (95%) reported pain at the time of examination. Mean current pain intensity in all AID patients comprised 3.6 ± 1.3 and mean maximum pain intensity was 7.0 ± 1.6 on a 11-point numeric ranging scale (NRS). In 15 patients (71%), pain was present for more than 60 months. Ten patients (48%) experienced recurrent attacks with asymptomatic intervals and 7 patients (33%) suffered from constant pain, while 4 patients (19%) experienced both. Nociceptive pain including musculoskeletal and visceral affection was the most prominent type of pain (n = 20; 95%). Pain symptoms were treated continuously with analgesic or co-analgesic drugs in 10 patients (48%). Five patients (24%) have been positively screened for concomitant depression or anxiety. CONCLUSIONS: Early and prompt diagnosis is necessary to provide multimodal pain treatment and to avoid the development of chronic pain in patients with AID.

[Exergames for patients with complex regional pain syndrome : A feasibility study]. / Exergames für Patienten mit komplexem regionalem Schmerzsyndrom : Eine Machbarkeitsstudie.

BACKGROUND: Complex regional pain syndrome (CRPS) is a disease of the limbs composed of various disorders and defined by the cardinal symptom of pain. So-called exergames with a combination of physical activity and fun are increasingly being offered as part of treatment. Exergame therapy could also provide CRPS patients with repetitive training, reward and motivation. METHOD: In this study 10 adult patients with CRPS of the hand (50% acute) received a 30 min therapy session using MindMotion™GO. MindMotion™GO is a software that enables control of the integrated games through visual feedback. Outcomes were the subjectively perceived workload (National Aeronautics and Space Administration-task load index, NASA-TLX), user-friendliness (system usability scale, SUS) and pain (numeric rating scale, NRS). RESULTS: The CRPS patients rated the average workload as appropriate with a total score of 50.9 points (SD ± 18.13). The user-friendliness of the system was judged to be acceptable with an average total score of 89.5 ± 7.53 points. There were no significant changes in pain intensity after the exergames. The subgroup analysis (acute versus chronic) showed differences in the assessment of the individual dimensions of the workload. CONCLUSION: In this study the use of exergames proved to be a suitable tool for rehabilitation of the hand in adult CRPS patients. Whether exergames represent an effective rehabilitation strategy should be examined by means of functional and activity-related target criteria in a representative sample in a randomized controlled study.

Smoking Associated T-Cell Imbalance in Patients With Chronic Pain.

INTRODUCTION: Smoking is associated with several diseases and affects the immune system. Recently, published data demonstrate an involvement of T helper 17 cells (Th17) and regulatory T cells (Tregs) in the pathogenesis of chronic pain and pain intensity. The role of these T-cell subsets in smoking patients with chronic pain is nebulous so far. We therefore analyzed Th17 cells and Tregs in smokers and nonsmokers with chronic pain. METHODS: Analyses of T-cell subsets, mRNA expression and T-cell related cytokine profiles were done in 44 patients with chronic pain. Twenty-two of these patients were smokers. Numbers of T-cell subsets were quantified by flow cytometry. mRNA expression of the Th17- (RAR-related orphan receptor gamma) and Treg (forkhead box protein P3)-specific transcription factors was determined by quantitative real-time PCR, and levels of cytokines were measured by Human Cytokine Multiplex Immunoassay. RESULTS: Compared to nonsmokers, smokers showed significantly enhanced pain levels. On cellular basis, the number of pro-inflammatory Th17 cells (smokers: 2.2 ± 2.5% vs. nonsmokers: 0.5 ± 0.4%; p = .04) was increased, whereas the number of anti-inflammatory Tregs (smokers: 2.5 ± 0.9% vs. nonsmokers: 3.1 ± 1.1%; p = .02) was significantly decreased, resulting in an altered Th17/Treg ratio (Th17/Treg ratio: 0.9 ± 1.0 in smokers vs. 0.2 ± 0.1 in nonsmokers; p < .01). These findings were confirmed by quantitative real-time PCR. Analyses of cytokines revealed only marginal changes. CONCLUSIONS: In patients with chronic pain, smoking is associated with enhanced pain levels together with an imbalance of the Th17/Treg ratio. The shift of the Th17/Treg ratio toward inflammation may explain in part the increased pain intensity in these patients. IMPLICATIONS: Smoking is associated with increased pain levels and a pro-inflammatory Th17/Treg shift. The altered Th17/Treg ratio in smoking patients with chronic pain may partly explain their increased pain intensity. GERMAN CLINICAL TRIAL REGISTER (DRKS): Registration Trial DRKS00005954.

Implications of the putamen in pain and motor deficits in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) develops after-limb injury, with persistent pain and deficits in movement frequently co-occurring. The striatum is critical for mediating multiple mechanisms that are often aberrant in CRPS, which includes sensory and pain processing, motor function, and goal-directed behaviors associated with movement. Yet, much remains unknown with regards to the morphological and functional properties of the striatum and its subregions in this disease. Thus, we investigated 20 patients (15 female, age 58 ± 9 years, right-handed) diagnosed with chronic (6+ months of pain duration) CRPS in the right hand and 20 matched, healthy controls with anatomical and resting-state, functional magnetic resonance imaging. In addition, a comprehensive clinical and behavioral evaluation was performed, where each participant's pain, motor function, and medical history were assessed. Complex regional pain syndrome patients harbored significant abnormalities in hand coordination, dexterity, and strength. These clinical pain- and movement-related findings in CRPS patients were concomitant with bilateral decreases in gray matter density in the putamen as well as functional connectivity increases and decreases among the putamen and pre-/postcentral gyri and cerebellum, respectively. Importantly, higher levels of clinical pain and motor impairment were associated with increased putamen-pre-/postcentral gyri functional connectivity strengths. Collectively, these findings suggest that putaminal alterations, specifically the functional interactions with sensorimotor structures, may underpin clinical pain and motor impairment in chronic CRPS patients.

Can self-reported pain characteristics and bedside test be used for the assessment of pain mechanisms? An analysis of results of neuropathic pain questionnaires and quantitative sensory testing.

Hyperalgesia and allodynia are frequent in neuropathic pain. Some pain questionnaires such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) and the Neuropathic Pain Scale (NPS) include self-assessment or bedside testing of hyperalgesia/allodynia. The aim of this study was to determine to what extent LANSS and NPS data are congruent with findings on quantitative sensory testing (QST). Self-reported presence of dynamic mechanical allodynia (DMA) and descriptors of hot, cold, or deep ongoing pain (the NPS and LANSS) as well as bedside findings of mechanical allodynia (LANSS) were compared with signs of DMA and thermal hyperalgesia on QST in 617 patients with neuropathic pain. Self-reported abnormal skin sensitivity (LANSS) showed a moderate concordance with DMA during bedside test (67.9%, κ = 0.391) or QST (52.8%, κ = 0.165). Receiver operating curve analysis for self-reported DMA yielded similar area-under-the-curve values for the LANSS (0.65, confidence interval: 0.59%-0.97%) and NPS (0.71, confidence interval: 0.66%-0.75%) with high sensitivity but low specificity. Self-reported deep pain intensity was higher in patients with blunt pressure hyperalgesia, but not in patients with DMA or thermal hyperalgesia. No correlations were observed between self-reported hot or cold pain quality and thermal hyperalgesia on QST. Self-reported abnormal skin sensitivity has a high sensitivity to identify patients with DMA, but its low specificity indicates that many patients mean something other than DMA when reporting this symptom. Self-reported deep pain is related to deep-tissue hypersensitivity, but thermal qualities of ongoing pain are not related to thermal hyperalgesia. Questionnaires mostly evaluate the ongoing pain experience, whereas QST mirrors sensory functions. Therefore, both methods are complementary for pain assessment.

Altered regulation of the T-cell system in patients with CRPS.

The aim of this study was to investigate T-cell subsets and immunomodulatory factors in patients with complex regional pain syndrome (CRPS). We found decreased numbers of pro-inflammatory Th17 cells in patients with CRPS as compared to healthy volunteers. The expression of Th17 related RORγT mRNA was also significantly decreased. Patients with CRPS showed an increased proportion of CD39+ Tregs. CD39 is a known inhibitor of Th17 cell differentiation. Systemic cytokine levels were almost unchanged in patients with CRPS. These findings suggest that the decrease in Th17 cells in CRPS is regulated by an increase in CD39+ Tregs and that this anti-inflammatory T-cell shift may be a mechanism to control inflammation in CRPS. GERMAN CLINICAL TRIAL REGISTER: Registration Trial DRKS00005954.

Pain therapy for the elderly patient: is opioid-free an option?

PURPOSE OF REVIEW: Chronic noncancer pain is an increasing problem in elderly because of rising life expectancy together with an increase of potentially painful medical conditions. Concomitantly, adequate treatment of elderly is often limited by coexisting diseases and polypharmacy.This review summarizes the most important specifics presented by elderly patients and discusses the pharmacological and nonpharmacological options of pain management. RECENT FINDINGS: A comprehensive pain assessment is a prerequisite for effective pain management. However, this can be a major challenge in patients who are unable to communicate adequately, that is, in patients with dementia. A recently developed electronic tool assessing automated facial expression and clinical behavioral indicators may help to solve this problem. The discussion about benefits and harms of opioids in elderly goes on. Although some authors underline the lack of efficacy together with the potential problems, such as, abuse, others report a beneficial effect in terms of pain relief, functional activities and disability. In addition, opioids have become an important treatment option in patients with restless legs syndrome. Various topical treatment options (i.e. capsaicin patch) and nonpharmacological interventions have been proven to be beneficial in elderly. SUMMARY: Adequate pain management of elderly patients constitutes numerous pharmacological options including nonopioids, opioids, coanalgesics and topical agents. Due to age-related characteristics, all systemic analgesics have to be given very cautiously ('start low, go slow'). Whenever possible, treatment should be performed as a multimodal approach based on the biopsychosocial model of chronic pain.

Oculomotor Disturbances in Patients with Chronic Nonspecific Spinal Pain.

Objective: There is increasing evidence that the cerebellum has a role in pain processing. The present study investigates whether chronic pain patients, who are likely to have altered pain processing, exhibit signs of subtle cerebellar dysfunction. We used oculomotor tasks to assess dysfunction of the associated neuronal networks, including the cerebellum. Methods: Thirty patients with chronic nonspecific spinal pain and 30 age- and sex-matched controls were enrolled. Using a head-mounted eye tracker (EyeSeeCam), eye movements were quantified during predictable and unpredictable saccade and smooth pursuit tasks in the horizontal plane. Results: The initial latency and the velocity variability of smooth pursuit were significantly increased in the chronic spinal pain patients compared with controls (initial latency: 198 ± 20 vs 185 ± 11 ms, P < 0.01; slow phase velocity standard deviation: 3.31 ± 1.02 vs 2.70 ± 0.83°/s, P < 0.05). Moreover, the latency of predictable saccades was prolonged in patients (rightward: 161 ± 20 vs 152 ± 12 ms, P < 0.05; leftward: 164 ± 22 vs 153 ± 18 ms, P = 0.05). Conclusions: Our results show that chronic spinal pain patients display subtle but significant oculomotor changes as compared with healthy controls. Considering the networks involved in the generation of saccades and smooth pursuit, the results would be consistent with a dysfunction of cerebellar regions, especially parts of the cerebellar hemispheres. Alternatively, they could also point toward a dysfunction in the frontal eye field and/or pontine oculomotor nuclei.

Challenging equipotency calculation for hydromorphone after long-term intravenous application.

In advanced stages, most cancer patients suffer from pain which can usually be well controlled following the World Health Organization (WHO) level scheme. While the majority of patients report adequate pain relief by strong opioids (WHO III), some require an opioid rotation. Despite the existence of conversion tables, these rotations mea lead to inadequate pain control or life threatening events. Here, we report about a patient with urothelial cell carcinoma presenting in our Department of Pain Medicine with massive pain aggravation up to NRS values of 10/10 despite administration of the highest dose of intravenously applied hydromorphone. After a small single dose of the far less potent opioid piritramide with exceptionally good response, we conducted a stepwise opioid rotation from hydromorphone to piritramide within one week without any signs of abstinence or withdrawal. After the opioid rotation, we discharged the patient nearly free of pain with piritramide doses far less than equianalgesic dose tables would have recommended. Our report impressively points out that even after long-term intravenous application of highly potent opioids, new titrations are necessary for rotation to avoid overdosage and discusses several mechanisms underlying individual response to different opioids.

Soluble intercellular adhesion molecule-1: a potential biomarker for pain intensity in chronic pain patients.

AIM: Pain therapy is strongly guided by patients' self-reporting. However, when self-reporting is not an option, pain assessment becomes a challenge and may lead to undertreatment of painful conditions. Pain is a complex and multifactorial phenomenon. Recent work has connected pain pathophysiology also with the inflammatory system. We therefore hypothesized that pain intensity could be predicted by cytokine-levels. PATIENTS & METHODS: In this observational, single-center study, we investigated 30 serum cytokines to predict pain intensity in a screening/follow-up set of 95 chronic pain patients and controls. We then prospectively validated soluble intercellular adhesion molecule-1 (sICAM-1)'s discriminatory capability (n = 21). RESULTS & CONCLUSION: sICAM-1 was significantly associated with patient-reported pain intensity and yielded differential serum levels in patients of varying degrees of pain intensity. Changes in pain ratings over time correlated with changes in sICAM-1 levels. Our findings suggest the possibility of a clinical use of sICAM-1 as a potential biomarker for pain intensity.

Expression of miRNA-124a in CD4 Cells Reflects Response to a Multidisciplinary Treatment Program in Patients With Chronic Low Back Pain.

STUDY DESIGN: A prospective evaluation of microRNA (miRNA) expression in patients with chronic low back pain (CLBP). OBJECTIVE: The aim of this study was to evaluate whether pain- and T cell-related miRNAs are differentially expressed in CLBP when compared with healthy volunteers and whether these miRNAs may distinguish between responders and nonresponders to a multidisciplinary treatment program. SUMMARY OF BACKGROUND DATA: CLBP is a common health problem worldwide. Multidisciplinary pain treatment programs have been proven as an effective treatment option. miRNAs are known to be important mediators of gene regulation in various processes, including pathophysiology of pain. The expression of miRNAs in CLBP and changes due to a multidisciplinary treatment programs are still unknown. METHODS: Thirty-four patients with CLBP were enrolled (46.5 ±â€Š12.7 yrs). CLBP was defined as low back pain with an average intensity of numerical rating scale (NRS) ≥3 during the last 4 weeks, persisting longer than 6 months, and not attributable to a recognized specific pathological condition. Expression of pain- and T cell-related miRNAs in human CD4 cells were determined using TaqMan assays and RealTime PCR. MiRNA expression in patients with CLBP was compared with the expression in healthy volunteers before a multidisciplinary treatment program started. The multidisciplinary outpatient program (4 weeks, 5 days a week, 8 h per day) is a clinically established outpatient program and comprises medical (examination, education), physical (exercise), work-related, and psychological therapy components. After the program, differentially expressed miRNAs in CLBP (before treatment) were analyzed once more. Expression of these miRNAs in patients who respond to the treatment (n = 14) was compared with those who did not respond (n = 20). Response to therapy was defined as reduction of pain of ≥50% (NRS) from baseline. RESULTS: MiRNA-124a (patients: 0.79 ±â€Š0.63 vs. healthy volunteers: 0.30 ±â€Š0.16; P < 0.001), miRNA-150 (patients: 0.75 ±â€Š0.21 vs. healthy volunteers: 0.56 ±â€Š0.20; P = 0.025), and miRNA-155 (patients: 0.55 ±â€Š0.14 vs. healthy volunteers: 0.38 ±â€Š0.16; P = 0.017) were significantly upregulated in CLBP patients when compared with healthy volunteers. After the multidisciplinary treatment program, patients who respond to the treatment showed only an increase of miRNA-124a expression (before treatment: 0.54 ±â€Š0.26 vs. after treatment: 1.05 ±â€Š0.56, P = 0.007). CONCLUSION: MiRNA-124a upregulation is associated with therapy response in a multidisciplinary treatment programs and might help to identify more specific and mechanism-based treatment strategies for CLBP. LEVEL OF EVIDENCE: 3.

miR-124a and miR-155 enhance differentiation of regulatory T cells in patients with neuropathic pain.

BACKGROUND: Accumulating evidence indicates that neuropathic pain is a neuro-immune disorder with enhanced activation of the immune system. Recent data provided proof that neuropathic pain patients exhibit increased numbers of immunosuppressive regulatory T cells (Tregs), which may represent an endogenous attempt to limit inflammation and to reduce pain levels. We here investigate the molecular mechanisms underlying these alterations. METHODS: Our experimental approach includes functional analyses of primary human T cells, 3'-UTR reporter assays, and expression analyses of neuropathic pain patients' samples. RESULTS: We demonstrate that microRNAs (miRNAs) are involved in the differentiation of Tregs in neuropathic pain. We identify miR-124a and miR-155 as direct repressors of the histone deacetylase sirtuin1 (SIRT1) in primary human CD4(+) cells. Targeting of SIRT1 by either specific siRNA or by these two miRNAs results in an increase of Foxp3 expression and, consecutively, of anti-inflammatory Tregs (siRNA: 1.7 ± 0.4; miR-124a: 1.5 ± 0.4; miR-155: 1.6 ± 0.4; p < 0.01). As compared to healthy volunteers, neuropathic pain patients exhibited an increased expression of miR-124a (2.5 ± 0.7, p < 0.05) and miR-155 (1.3 ± 0.3; p < 0.05) as well as a reduced expression of SIRT1 (0.5 ± 0.2; p < 0.01). Moreover, the expression of these two miRNAs was inversely correlated with SIRT1 transcript levels. CONCLUSIONS: Our findings suggest that in neuropathic pain, enhanced targeting of SIRT1 by miR-124a and miR-155 induces a bias of CD4(+) T cell differentiation towards Tregs, thereby limiting pain-evoking inflammation. Deciphering miRNA-target interactions that influence inflammatory pathways in neuropathic pain may contribute to the discovery of new roads towards pain amelioration. TRIAL REGISTRATION: German Clinical Trial Register DRKS00005954.

Differential expression of P2X7 receptor and IL-1ß in nociceptive and neuropathic pain.

BACKGROUND: Despite substantial progress, pathogenesis and therapy of chronic pain are still the focus of many investigations. The ATP-gated P2X7 receptor (P2X7R) has previously been shown to play a central role in animal models of nociceptive inflammatory and neuropathic pain. Recently, we found that the adaptive immune system is involved in the pathophysiology of chronic nociceptive and neuropathic pain in humans. So far, data regarding P2X7R expression patterns on cells of the adaptive immune system of pain patients are scarce. We therefore analyzed the P2X7R expression on peripheral blood lymphocytes and monocytes, as well as serum levels of IL-1ß in patients suffering from chronic nociceptive and neuropathic pain in comparison to healthy volunteers in order to identify individuals who might benefit from a P2X7R modulating therapy. METHODS: P2X7R messenger RNA (mRNA) and protein expression were determined in patients with either chronic nociceptive low back pain (CLBP) or neuropathic pain (NeP), and in healthy volunteers by quantitative real-time PCR (qPCR) and by fluorescence-assisted cell-sorting (FACS), respectively. IL-1ß serum levels were measured with a multiplex cytokine assay. RESULTS: Compared to healthy volunteers, P2X7R mRNA (1.6-fold, p = 0.038) and protein levels were significantly increased on monocytes (NeP: 24.6 ± 6.2, healthy volunteers: 17.0 ± 5.4; p = 0.002) and lymphocytes (NeP: 21.8 ± 6.5, healthy volunteers: 15.6 ± 5.2; p = 0.009) of patients with NeP, but not in patients with CLBP. Similarly, IL-1ß serum concentrations were significantly elevated only in NeP patients (1.4-fold, p = 0.04). CONCLUSIONS: A significant upregulation of P2X7R and increased IL-1ß release seems to be a particular phenomenon in patients with NeP. P2X7R inhibitors may therefore represent a potential option for the treatment of this frequently intractable type of pain. German Clinical Trial Register (DRKS): Registration Trial DRKS00005954.

Anti-inflammatory T-cell shift in neuropathic pain.

BACKGROUND: The classification of pain into nociceptive and neuropathic pain is based on characteristic symptoms and different pathophysiological mechanisms. In a recent investigation, we found a disrupted TH17/Treg balance in patients suffering from chronic unspecific low back pain (CLBP). These patients did not show any signs of neuropathy. There is evidence for a considerable impact of the immune system also in neuropathic pain. However, the role of the adaptive immune system is still unclear. In the present study, we investigated systemic T-cell subset responses and T-cell related cytokine profiles in patients with chronic neuropathic pain. METHODS: We analyzed T-cell subsets, mRNA expression and T-cell-related cytokine profiles in 26 patients suffering from neuropathic pain in comparison to 26 healthy controls. Using multicolor flow cytometry (FACS), we quantified the number of T helper cells 1 (TH1), TH2, TH17 and regulatory T-cells (Tregs). Forkhead-Box-Protein 3 (FoxP3), Transforming growth factor-ß (TGF-ß) and RAR-related orphan receptor-γT (ROR-γT) mRNA expression was determined by quantitative real-time PCR (qPCR) and levels of pain-related cytokines were measured by Human Cytokine Multiplex Immunoassay (Macrophage inflammatory protein-1α (MIP-1α), Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), Interleukin (IL) -4, IL-6, IL-10, IL-17, and IL-23). RESULTS: We found a TH17/Treg imbalance with significantly increased anti-inflammatory Tregs and decreased pro-inflammatory TH17 cells in patients with neuropathic pain as compared to healthy controls. These results were confirmed on mRNA level: Treg-related FoxP3 and TGF-ß mRNA expression was elevated, whereas expression of TH17-related RORγT was reduced. Cytokine analyses revealed only marginal changes. CONCLUSIONS: Our investigation revealed a clear shift of T-cell subsets towards anti-inflammation in patients with neuropathic pain. Interestingly, this is quite similar to our previous findings in CLBP patients, but even more pronounced. Therefore, it remains to be elucidated in future investigations whether the immune changes represent an underlying pathophysiological mechanism or an epiphenomenon induced by ongoing pain and stress. GERMAN CLINICAL TRIAL REGISTER (DRKS): Trial registration number: DRKS00005954.

Disrupted TH17/Treg balance in patients with chronic low back pain.

UNLABELLED: Chronic low back pain (CLBP) is a leading cause of disability and costs in health care systems worldwide. Despite extensive research, the exact pathogenesis of CLBP, particularly the individual risk of chronification remains unclear. To investigate a possible role of the adaptive immune system in the pathophysiology of CLBP, we analyzed T cell related cytokine profiles, T cell related mRNA expression patterns and the distribution of T cell subsets in 37 patients suffering from nonspecific CLBP before and after multimodal therapy in comparison to 25 healthy controls. Serum patterns of marker cytokines were analyzed by Luminex technology, mRNA expression of cytokines and specific transcription factors was measured by real-time PCR, and distribution of TH1-, TH2-, TH17- and regulatory T cell (Tregs) subsets was determined by multicolor flow cytometry. We found that CLBP patients exhibit an increased number of anti-inflammatory Tregs, while pro-inflammatory TH17 cells are decreased, resulting in an altered TH17/Treg ratio. Accordingly, FoxP3 and TGF-ß-mRNA expression was elevated, while expression of IL-23 was reduced. Serum cytokine analyses proved to be unsuitable to monitor the adaptive immune response in CLBP patients. We further show that even after successful therapy with lasting reduction of pain, T cell subset patterns remained altered after a follow-up period of 6 months. These findings suggest an involvement of TH17/Treg cells in the pathogenesis of CLBP and emphasize the importance of these cells in the crosstalk of pain and immune response. TRIAL REGISTRATION: German Clinical Trial Register: Registration Trial DRKS00005954.