Seasonal impact on the outcome of multidisciplinary pain therapy.

Multidisciplinary pain treatment programs (MPTP) have been considered to be the most effective treatment of chronic pain. In this study, we analyzed the influence of seasons on the outcome of chronic pain patients undergoing MPTP. Therefore, a prospective, observational trial was conducted in patients with chronic pain undergoing a 5-week interdisciplinary treatment program. Psychological stabilization (measured by ADS - Allgemeine Depressionsskala) and pain levels (measured by NRS - numeric rating scale) were considered as primary endpoints. As a result of this study, we could show that chronic pain patients (exempt patients with chronic headache) showed a highly significant better improvement in terms of ADS after MPTP when participating in autumn (coefficient: -11.67, p = .004). Patients treated during winter showed a tendency towards a better improvement in ADS scores (coefficient: -6.89, p = .051). These effects were not found in patients suffering from chronic headache. Finally, patients participating in MPTPs during summer, autumn, and winter presented a tendency of higher reduction in pain scores when compared to patients participating in spring. In conclusion, the effect of MPTPs in terms of psychological stabilization is considered to be best during autumn. This should be therefore considered in planning an MPTP in all patients who do not need immediate psychological stabilization. The treatment effect of MPTP on pain seems not being dependent on a specific season.

Personality disorders and outcome after multidisciplinary pain therapy.

OBJECTIVES: Interdisciplinary treatment programmes are the gold standard for patients suffering from chronic pain. However, several patient-related factors seem to influence the patients' outcome. The aim of our study was to inquire whether patients with personality disorders (PD) might benefit less from an interdisciplinary treatment programme compared to patients without PD. METHODS: A prospective, observational study with chronic pain patients attending a 5-week interdisciplinary treatment programme was performed. Main outcome parameters were psychological stabilization and pain intensity before and after the programme. RESULTS: Out of the 104 included patients, 71 (68.3%) showed personality accentuations and 16 (15.4%) were diagnosed with PDs. PDs were mostly classified as histrionic, followed by borderline and narcistic personality. Patients diagnosed with histrionic accentuation showed a significantly better treatment response in terms of pain. Reduction in ADS (Allgemeine Depressionsskala - depression scale) was 3.4 in patients with PD and 11.1 in those without PD. Borderline patients showed a significant increase of ADS (by 2.0; p < 0.05) after programme completion. DISCUSSION: Patients with chronic pain and personality accentuations or disorder only showed a slightly different outcome after interdisciplinary treatment programme and should therefore not be excluded from these programmes. Registered at German Clinical Trials Register (DRKS-ID: DRKS00015141).

A review of the totality of evidence supporting the development and approval of a pegfilgrastim biosimilar (LA-EP2006).

OBJECTIVE: The totality-of-evidence approach requires that similarity between a proposed biosimilar and a reference biologic is demonstrated across a range of analytical, preclinical, and clinical parameters to establish biosimilarity. We describe the totality of evidence for Sandoz biosimilar pegfilgrastim (LA-EP2006 [marketed as Ziextenzo]) that supported its regulatory approval in Europe and the United States. METHODS: Analytical similarity to the reference biologic [marketed by Amgen as Neulasta] was first investigated with regard to physiochemical quality attributes such as primary structure, pegylation, higher-order structures, variants and impurities, molecular size variants, and formulation (protein content, pH, excipients, etc.). In vitro biological activity studies were performed to examine the primary mechanism of action of pegfilgrastim. Bioequivalence (clinical pharmacokinetics [PK] and pharmacodynamics [PD]) of Sandoz biosimilar pegfilgrastim to the reference biologic was studied in healthy volunteers; efficacy, safety, and immunogenicity were assessed during confirmatory clinical efficacy studies in patients undergoing treatment for breast cancer. RESULTS: No meaningful or relevant differences were identified between Sandoz biosimilar pegfilgrastim and the reference biologic during analytical testing. Similar receptor binding and induction of cellular proliferation in vitro confirmed no functional differences between the biologics. Clinical studies in healthy adult participants demonstrated PK/PD biosimilarity and a similar safety profile between biosimilar and reference pegfilgrastim. Clinical studies in a sensitive patient population also demonstrated similar efficacy, safety, and immunogenicity between Sandoz biosimilar pegfilgrastim and the reference biologic. CONCLUSIONS: The totality of evidence confirms that Sandoz biosimilar pegfilgrastim matches the reference biologic and will therefore provide equivalent efficacy and safety in all eligible indications.

Survey of German medical students during the COVID-19 pandemic: attitudes toward volunteering versus compulsory service and associated factors.

Due to the spread of COVID-19, a key challenge was to reduce potential staff shortages in the healthcare sector. Besides recruiting retired healthcare workers, medical students were considered to support this task. Commitment of medical students in Germany during the COVID-19 pandemic was evaluated using an online survey, with particular focus on their burdens and anxieties. This survey was distributed to students within a 2-week period in April and May 2020. Ultimately, 1241 participants were included in the analysis. During the pandemic, 67.9% (65.3% to 70.5%) of the participants reported that they had volunteered. Furthermore, 88.9% (86.9% to 90.5%) stated that they were against compulsory recruitment in this context. Students who volunteered (committed students) had a significantly lower anxiety index than non-committed students. Additionally, students were more concerned about infecting other patients and relatives than themselves. Higher levels of anxiety were related to lower levels of commitment. A mandatory assignment during the pandemic was rejected by the students and does not seem to be necessary due to the large number of volunteers.

Incidence of injury and pain in referees in German national handball leagues: a cohort study.

BACKGROUND: Handball referees play an important role during a handball match. Surprisingly, not much is known about their sports-related injuries and resulting pain, therefore the purpose of our study was to focus on injuries and sports-related pain in referees in German handball leagues. METHODS: During the 2018/19 national German handball season, referees of the German Federation of Handball (DHB) were contacted and asked to complete an injury and pain questionnaire on the penultimate matchday of the first and the second round of the season. RESULTS: Seventy referees participated in the study. One in three referees reported an injury during the last year and perceived some form of pain. Of those suffering from pain, 16.7% referees reported chronic pain disorders. During the season, 31.4% of referees incurred an injury and the majority of the 70 referees officiated despite pain (n = 43). Prospectively-enrolled data suggested an incidence of 11.6 (95% CI: 10.3 to 13.0) injuries per 1000 match hours, and 19.0 (95% CI: 16.8 to 21.3) sports-related pain events per 1000 match hours. The most common injuries were foot and knee injuries and a substantial number of the referees (n = 25) reported taking analgesics for the pain. CONCLUSION: German handball referees are at risk of sports-related injuries with subsequent pain. Considering the injury profile, the incidence of sports-related pain events, and the high physiological demands of refereeing, it appears that prevention programs should be developed and integrated into the routine of the referee.

EuroScore and IL-6 predict the course in ICU after cardiac surgery.

BACKGROUND: Despite modern advances in intensive care medicine and surgical techniques, mortality rates in cardiac surgical patients are still about 3%. Considerable efforts were made to predict morbidity and mortality after cardiac surgery. In this study, we analysed the predictive properties of EuroScore and IL-6 for mortality in ICU, prolonged postoperative mechanical ventilation, and prolonged stay in ICU. METHODS: We enrolled 2972 patients undergoing cardiac surgery. The patients either underwent aortic valve surgery (AV), mitral valve surgery (MV), coronary artery bypass grafting (CABG), and combined operations of aortic valve and coronary artery bypass grafting (AV + CABG) or of mitral and tricuspid valve (MV + TV). Different laboratory and clinical parameters were analysed. RESULTS: EuroScore as well as IL-6 were associated with increased mortality after cardiac surgery. Furthermore, a higher EuroScore and elevated levels of IL-6 were predictors for prolonged mechanical ventilation and a longer stay in ICU. Especially, highly significant elevated IL-6 levels and an increased EuroScore showed a strong association. Statistics suggested superiority when both parameters were combined in a single model. CONCLUSION: Our results suggest that EuroScore and IL-6 are helpful in predicting the course in ICU after cardiac surgery, and therefore, the use of intensive care resources. Especially, the combination of highly elevated levels of IL-6 and EuroScore may prove to be excellent predictors for an unfortunate postoperative course in ICU.

Bilirubin and lactate: easy to determine and valuable to predict outcome in cardiac surgery.

BACKGROUND: Cardiopulmonary bypass during cardiac surgery is associated with metabolic changes after operation and results inter alia in increased levels of lactate and bilirubin. Since prediction of the course after operation has become very important for the management of an ICU and the patients themselves, we evaluated easily assessable markers (lactate and bilirubin), regarding their potential to predict mortality 90 days after surgery and the length of stay in ICU. METHODS: All patients within a period of five years undergoing cardiac surgery were enrolled in the study. Among others peak levels of lactate and bilirubin within 48 hours after operation were recorded. A Cox proportional hazard model as well as a logistic regression model were used to predict mortality or rather length of stay in ICU. RESULTS: Increased levels of bilirubin and lactate were associated with a significantly increase in mortality and length of stay in ICU (in a concentration-related manner). Interestingly, creatinine serum levels before operation showed a similar performance. CONCLUSIONS: Three easily assessable and cheap laboratory parameters (bilirubin, lactate, and creatinine) are useful to predict 90-day mortality and length of stay in ICU. These findings might be helpful to give patients a reliable prediction about short and mid-term-survival and to improve the management of an ICU.

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.

Remifentanil for abdominal surgery is associated with unexpectedly unfavorable outcomes.

Insufficient perioperative pain treatment is known as a highly predictive risk factor for the development of chronic postoperative pain. Remifentanil is an ultrashort-acting opioid that provides quick and efficient analgesia but is associated with the induction of opioid-induced hyperalgesia. Despite these well-known characteristics, this substance is being increasingly used in anesthesia and in a variety of medical fields, such as intensive-care medicine and obstetrics. The aim of our study was to reveal whether remifentanil influences postoperative pain, the requirement for postoperative analgesics, and requirement of antiemetics (as indirect indicator of postoperative nausea and vomiting), as well as the effects on time to extubation and length of stay in the postanesthesia care unit in daily clinical routine. From an electronic medical records database of 55,693 anesthesias, we analyzed data from all patients receiving intraabdominal surgery (visceral, gynecological, and urological) under general anesthesia or combined general-epidural anesthesia by propensity score matching. The administration of remifentanil was associated with higher postoperative pain scores despite a higher requirement of postoperative analgesics. Additional epidural analgesia was not able to avoid this finding. The intraoperative use of remifentanil is associated with a deterioration of pain levels and postoperative analgesic requirement, wherefore the potential benefit of this substance seems to be outweighed by its potential disadvantages. Especially in operative procedures in which high postoperative pain scores are expected, the unreflective use should be critically questioned.

Smoking and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients: a substudy from the randomized TROPICAL-ACS trial.

AIMS: Prior analyses disclosed variations in antiplatelet drug response and clinical outcomes between smokers and non-smokers, thus the safety and efficacy of any dual antiplatelet therapy (DAPT) de-escalation strategy may differ in relation to smoking status. Hence, we assessed the impact of smoking on clinical outcomes and adenosine diphosphate-induced platelet aggregation following guided de-escalation of DAPT in invasively managed acute coronary syndrome (ACS) patients. METHODS AND RESULTS: The multicentre TROPICAL-ACS trial randomized 2610 biomarker-positive ACS patients 1:1 to standard treatment with prasugrel for 12 months (control group) or a platelet function testing guided de-escalation of DAPT. Current smokers (n = 1182) showed comparable event rates between study groups [6.6% vs. 6.6%; hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.64-1.56, P > 0.99]. In non-smokers (n = 1428), a guided DAPT de-escalation was associated with a lower 1-year incidence of the primary endpoint [cardiovascular death, myocardial infarction, stroke, or bleeding ≥ Grade 2 according to Bleeding Academic Research Consortium (BARC) criteria] compared with control group patients (7.9% vs. 11.0%; HR 0.71, 95% CI 0.50-0.99, P = 0.048). This reduction was mainly driven by a lower rate of BARC ≥ Grade 2 bleedings (5.2% vs. 7.7%; HR 0.68, 95% CI 0.45-1.03, P = 0.066). There was no significant interaction of smoking status with treatment effects of guided DAPT de-escalation (Pint = 0.23). Adenosine diphosphate-induced platelet aggregation values were higher in current smokers [median 28 U, interquartile range (IQR: 20-40)] vs. non-smoker [median 24 U (16-25), P < 0.0001] in the control group and in current smokers [median 42 U, IQR (27-68)] vs. non-smoker [median 37 U, IQR (25-55), P < 0.001] in the monitoring group. CONCLUSION: Guided DAPT de-escalation appears to be equally safe and effective in smokers and non-smokers. Regardless of smoking status and especially for those patients deemed unsuitable for 1 year of potent platelet inhibition this DAPT strategy might be used as an alternative antiplatelet treatment regimen.

Eighty years of Medication-Overuse Headache: what about Medication-Overuse Backpain?

INTRODUCTION: Although chronic low back pain (CLBP) is one of the most common pain syndromes, up to now, clear pathophysiological causes or specific treatment options are missing. Medication-overuse has been associated with chronic headache, but never with CLBP. HYPOTHESIS: Based on several similarities between CLBP and Medication-Overuse Headache (MOH), we hypothesized that medication-overuse might contribute to CLBP as well, maybe even as an own entity. Might there be something like Medication-Overuse Backpain (MOB)? METHODS: We substantiate our hypothesis with a preliminary case-series analyzing five patients suffering from CLBP with a marked medication-overuse. In these patients, a stepwise analgesic withdrawal was recommended. RESULTS: Within 6 months of recruitment, five patients fulfilled the inclusion criteria and successfully completed discontinuation of their medication. All patients reported noticeable pain relief, despite the discontinuation of their analgesics. Withdrawal was well tolerated in all cases. CONCLUSIONS: Considering our results, the described withdrawal method seems to be a simple and safe method to achieve pain reduction while simultaneously preventing organ damage. Despite the preliminary character of our results, our hypothesis might stimulate a new understanding of CLBP's pathophysiology.

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.

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.

Intronic miRNA-641 controls its host Gene's pathway PI3K/AKT and this relationship is dysfunctional in glioblastoma multiforme.

MicroRNAs have established their role as important regulators of the epigenome. A considerable number of human miRNA genes are found in intronic regions of protein-coding host genes, in many cases adopting their regulatory circuitry. However, emerging evidence foreshadows an unprecedented importance for this relationship: Intronic miRNAs may protect the cell from overactivation of the respective host pathway, a setting that may trigger tumor development. AKT2 is a well-known proto-oncogene central to the PI3K/AKT pathway. This pathway is known to promote tumor growth and survival, especially in glioblastoma. Its intronic miRNA, hsa-miR-641, is scarcely investigated, however. We hypothesized that miR-641 regulates its host AKT2 and that this regulation may become dysfunctional in glioblastoma. We found that indeed miR-641 expression differs significantly between GBM tissue and normal brain samples, and that transfection of glioma cells with miR-641 antagonizes the PI3K/AKT pathway. Combining clinical samples, cell cultures, and biomolecular methods, we could show that miR-641 doesn't affect AKT2's expression levels, but down-regulates kinases that are necessary for AKT2-activation, thereby affecting its functional state. We also identified NFAT5 as a miR-641 regulated central factor to trigger the expression of these kinases and subsequently activate AKT2. In summary, our study is the first that draws a connecting line between the proto-oncogene AKT2 and its intronic miRNA miR-641 with implication for glioblastoma development.

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.

Altered renal functions in patients with occlusion of an accessory renal artery after endovascular stenting of an infrarenal aneurysm.

OBJECTIVE: Coverage of an accessory renal artery (ARA) during endovascular aneurysm repair (EVAR) may result in renal infarction (RI) or decline in renal function. Until now, it remains vague which patients are at risk to develop these complications. We therefore analyzed the effect of ARA sealing by EVAR with respect to the occurrence of RI and renal function. METHODS: A retrospective analysis of the medical records and computed tomographic scans of patients who underwent EVAR within a period of 5 years was performed. Particular attention was paid to the presence or absence of accessory renal arteries and renal function before EVAR. Thirty-four patients with ARA were matched 1:3 to 102 patients without ARA. The results after EVAR were analyzed in patients with and without ARA. In patients with ARA, we further examined the results after EVAR in patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min and eGFR < 60 mL/min before EVAR. RESULTS: Before EVAR, the median eGFR was 74 mL/min (25th/75th percentiles, 57/89) in patients with ARA and 72 mL/min (25th/75th percentiles, 63/87) in patients without ARA. Alterations in eGFR were significantly pronounced in patients with ARA when compared with patients without ARA 1 week after EVAR (ARA, -10.7 ± 16.9 mL/min vs without ARA, 1.2 ± 13.3 mL/min; P = .002) and after 6 months (ARA, -10.8 ± 17.4 mL/min vs without ARA, 1.2 ± 13.3 mL/min; P = .001). RI only occurred in patients with ARA. Within the group of patients with ARA, patients with normal renal function (NF) showed a more pronounced decline in eGFR preoperatively when compared with patients with impaired renal function (IF) 1 week after EVAR (NF, -14.3 ± 18.0 mL/min vs IF, -1.3 ± 10.8 mL/min; P = .02) and after 6 months (NF, -15.8 ± 17.9 mL/min vs IF, 0.1 ± 15.2 mL/min; P = .007). CONCLUSIONS: The decrease in renal function was more pronounced in patients with ARA after EVAR when compared with patients without ARA undergoing EVAR. In patients with ARA, the observed decline in renal function was significantly distinct in patients presenting NF preoperatively. Consequently, the risk of IF after EVAR seems to be increased in patients with ARA and normal preoperative renal function.

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.

Combined Carotid Endarterectomy and Retrograde Stenting of the Supra-Aortic Trunk: Does Cervical Block Offer Advantages?

BACKGROUND: Atherosclerosis of the carotid artery is a major source of stroke. In some cases, atherosclerosis occurs at several positions within the carotid artery. Carotid endarterectomy (CEA) in combination with retrograde balloon angioplasty and stenting of a brachiocephalic or common carotid artery stenosis has been described as efficacious and safe procedure to prevent stroke in these cases. The aim of this study was to analyze the impact of anesthetic techniques on hemodynamic factors, operation time, duration of clamping, and postoperative pain. METHODS: A retrospective analysis of patients undergoing CEA in combination with retrograde stenting under either general anesthesia (GA) or cervical block (CB) was carried out. Preoperative risk factors were analyzed as well as operating and cross-clamping time, hemodynamic factors, perioperative complications, postoperative pain, application of pain killers, and duration of intensive care unit (ICU) and hospital stay. RESULTS: Operating (GA: 193 ± 91 min vs. CB: 125 ± 52 min, P = 0.029) and cross-clamping time (GA: 34 ± 12 min vs. CB: 26 ± 9 min, P < 0.001) were shorter under CB. Patients under CB were hemodynamically more stable and required less norepinephrine (GA: 1.1 ± 0.6 mg vs. CB: 0.1 ± 0.1 mg, P < 0.001) and crystalloids (GA: 2,813 ± 1,173 mL vs. CB: 1,088 ± 472 mL, P < 0.001). Postoperative pain levels (GA: numeric rating scale 4.3/10 vs. 2.0/10; P = 0.004) and requirement of pain killers were also lower within the CB group. CONCLUSIONS: Synchronous CEA and retrograde balloon angioplasty and stenting of a brachiocephalic or common carotid artery stenosis under CB is associated with reduction of operating and cross-clamping time, improved hemodynamical stability, lower postoperative pain, shorter ICU and hospital stay, and it offers the advantage of a continuous neurological monitoring.

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.