Translation of Experimental Findings from Animal to Human Biology: Identification of Neuronal Mineralocorticoid and Glucocorticoid Receptors in a Sectioned Main Nerve Trunk of the Leg.

The activation of the mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons seems to modify pain perception through both direct non-genomic and indirect genomic pathways. These distinct subpopulations of sensory neurons are not known for peripheral human nerves. Therefore, we examined MR and GR on subpopulations of sensory neurons in sectioned human and rat peripheral nerves. Real-time PCR (RT-PCR) and double immunofluorescence confocal analysis of MR and GR with the neuronal markers PGP9.5, neurofilament 200 (NF200), and the potential pain signaling molecules CGRP, Nav1.8, and TRPV1 were performed in human and rat nerve tissue. We evaluated mechanical hyperalgesia after intrathecal administration of GR and MR agonists. We isolated MR- and GR-specific mRNA from human peripheral nerves using RT-PCR. Our double immunofluorescence analysis showed that the majority of GR colocalized with NF200 positive, myelinated, mechanoreceptive A-fibers and, to a lesser extent, with peripheral peptidergic CGRP-immunoreactive sensory nerve fibers in humans and rats. However, the majority of MR colocalized with CGRP in rat as well as human nerve tissue. Importantly, there was an abundant colocalization of MR with the pain signaling molecules TRPV1, CGRP, and Nav1.8 in human as well as rat nerve tissue. The intrathecal application of the GR agonist reduced, and intrathecal administration of an MR agonist increased, mechanical hyperalgesia in rats. Altogether, these findings support a translational approach in mammals that aims to explain the modulation of sensory information through MR and GR activation. Our findings show a significant overlap between humans and rats in MR and GR expression in peripheral sensory neurons.

Supplementing transcranial direct current stimulation to local infiltration series for refractory neuropathic craniocephalic pain: A randomized controlled pilot trial.

Background: Some patients with neuralgia of cranial nerves with otherwise therapy-refractory pain respond to invasive therapy with local anesthetics. Unfortunately, pain regularly relapses despite multimodal pain management. Transcranial direct current stimulation (tDCS) may prolong pain response due to neuro-modulatory effects. Methods: This controlled clinical pilot trial randomized patients to receive anodal, cathodal or sham-tDCS stimulation prior to local anesthetic infiltration. Pain attenuation, quality-of-life and side effects were assessed and compared with historic controls to estimate effects of tDCS stimulation setting. Results: Altogether, 17 patients were randomized into three groups with different stimulation protocols. Relative reduction of pain intensity in per protocol treated patients were median 73%, 50% and 69% in anodal, cathodal and sham group, respectively (p = 0.726). Compared with a historic control group, a lower rate of responders with 50% reduction of pain intensity indicates probable placebo effects (OR 3.41 stimulation vs. non-stimulation setting, NNT 3.63). 76.9% (n = 10) of tDCS patients reported mild side-effects. Of all initially included 17 patients, 23.5% (n = 4) withdrew their study participation with highest proportion in the cathodal group (n = 3). A sample size calculation for a confirmatory trial revealed 120 patients using conservative estimations. Discussion: This pilot trial does not support series of anodal tDCS as neuro-modulatory treatment to enhance pain alleviation of local anesthetic infiltration series. Notably, results may indicate placebo effects of tDCS settings. Feasibility of studies in this population was limited due to relevant drop-out rates. Anodal tDCS warrants further confirmation as neuro-modulatory pain treatment option.

[Support of opioid rotation using online apps : Evaluation of applicability and comparison to the LONTS guidelines]. / Unterstützung der Opioidrotation mithilfe von Online-Apps : Evaluation der Anwendbarkeit und Vergleich mit der LONTS-Leitlinie.

BACKGROUND: Opioid rotation can be indicated due to drug side effects, drug interactions or inadequate effect of treatment with opioids. For the determination of the oral morphine equivalence, a practice tool has been published with the long-term use of opioids in chronic nontumor-related pain (LONTS) guidelines. In contrast, several apps are available that have not yet been evaluated. MATERIAL AND METHODS: Apps and web applications for opioid conversion were searched using Google Play Store®, iOS App Store® and the Google® search engine. German and English language apps with calculator functions were included. Using the apps, 16 test cases from clinical practice were calculated and the deviation from the recommendation of the LONTS guidelines was calculated. RESULTS: A total of 17 apps were identified, 11 named the origin of the algorithm and 3 of them defined the literature sources. None of the apps and web applications had a quality seal, and none could solve all cases. Deviations of the resulting oral morphine equivalents of up to 179% from the guideline-compliant conversion were identified and 4 apps warned for overdosing. CONCLUSION: Although the apps and web applications simplify conversion between opioids, there is high variance in conversion factors and sometimes a relevant deviation from evidence-based tables. Overall, there is a high risk of false opioid dosing.

[Transcranial alternating current stimulation to modulate oscillations in pain disorders]. / Transkranielle Wechselstromstimulation zur Modulation von Oszillationen bei Schmerzerkrankungen.

BACKGROUND: Chronic pain is a common health problem, for which the treatment is complex and challenging. Non-invasive brain stimulation techniques, specifically transcranial alternating current stimulation (tACS), show promise as a well-tolerated new therapeutic modality with few side effects. This is supported by growing evidence of an association between altered neuronal oscillations and chronic pain. However, to date, only a handful of studies with variable methodology have evaluated tACS for potential applicability to patients with chronic pain. OBJECTIVES: Presentation and discussion of the evidence thus far, evaluation of a potential therapeutic benefit for chronic pain patients. MATERIALS AND METHODS: Literature search in MEDLINE, Embase, Cochrane Library, and Google Scholar databases. RESULTS: To date, tACS for chronic pain therapy has been investigated in only three studies with very different methodological approaches and quality. DISCUSSION: These data currently do not provide sufficient evidence for the therapeutic use of tACS for chronic pain therapy. Future studies may address the question of a therapeutic benefit of tACS for this indication utilizing improved stimulation techniques and considering existing recommendations for the design and conduct of tACS studies.

Behaviour-based pain scales: Validity and interrater reliability of BPS-NI and PAINAD-G on general wards.

BACKGROUND: Measuring pain intensity in patients unable to communicate is a challenge on general wards. Observation-based pain scoring tools have been used for patients with dementia or in critically ill intensive care unit (ICU) patients. However, there is no established or validated assessment tool for non-ICU patients without dementia related cognitive deficiencies who cannot communicate. The "Behavioural Pain Scale Non-Intubated" (BPS-NI) and the "Pain Assessment In Advanced Dementia-German" (PAINAD-G) are potential tools to fill this gap. METHODS: This study was performed with verbal non-ICU patients on general wards at Charité Berlin. Two assessors independently rated pain intensity using the BPS-NI and the PAINAD-G along with patients' self-ratings on the Numeric Rating Scale (NRS). The interrater-reliability of BPS-NI and PAINAD-G was calculated and ROC-analyses were performed to identify cut-off values for medium and intense pain for each score. Effectiveness was calculated using percentage agreement. In total, 126 patients were included into analysis. RESULTS: The BPS-NI showed substantial congruence in interrater-reliability (Cohens-Kappa 0.71), whereas the PAINAD-G showed moderate congruence (Kappa 0.48). Based on ROC-analyses, for medium pain levels a cut-off 4 (BPS-NI) or 2 (PAINAD-G) and for severe pain levels cut-off 5 (BPS-NI) and 3 (PAINAD-G) would result in good accordance with self-reported NRS for pain. CONCLUSION: The BPS-NI shows a good validity in measuring pain intensity in patients on general wards and may possibly be used for patients unable to communicate. Using defined cut-off values for BPS-NI and PAINAD-G, clinically relevant pain intensities in patients can reliably be detected. SIGNIFICANCE: Measuring the pain intensity in patients unable to communicate is a common challenge on general wards. This study assessed reliability and applicability BPS-NI and the PAINAD-G in a general ward setting. Furthermore, it provides cut-off values in order to estimate pain intensity and support analgesic response.

[Practice of perioperative phantom limb pain prevention in Germany: a nationwide survey]. / Praxis der perioperativen Prävention von Phantomschmerz: eine deutschlandweite Umfrage.

BACKGROUND: The prevalence of phantom limb pain after major amputation remains high and affected patients suffer from relevant impairments in the quality of life. Perioperative treatment strategies may prevent phantom limb pain. This study aims to assess the state of the perioperative anesthesiological pain management for major amputations. Furthermore, it analyzes potentials for optimization and barriers towards a better treatment of patients with amputations. MATERIAL AND METHODS: This online survey was distributed by the German Society of Anesthesiology and Intensive Care Medicine (DGAI) mailing list of anesthesiological consultants. It was approved by the Charité ethics board. RESULTS: Overall, 402 persons participated in this survey. Mostly, general anesthesia (85%), regional anesthesia (63%) and neuraxial anesthesia (49%) were performed in different combinations. Furthermore, 72% of participants reported using i.v. opioids postoperatively, mostly applied via patient-controlled analgesia (PCA). In contrast, preoperative regional anesthesia (74%) and gabapentinoids (67%) were seen as potential methods to improve treatment; however, barrier analysis revealed that treatment options are limited especially by organizational aspects and intrinsic patient factors. CONCLUSION: This survey describes the current practice of phantom limb pain prevention in Germany. It shows an unmet need for specialized perioperative pain treatment. As the evidence regarding treatment recommendations is limited, further research questions can be deduced from this study.

Local infiltration analgesia versus peripheral nerve block anaesthesia in total knee arthroplasty: a pharmaco-economic comparison.

BACKGROUND: A superior analgesic method in perioperative pain-management of patients receiving total knee arthroplasty is the subject of controversial debate. Although higher cost-efficiency is claimed for the local infiltration analgesia (LIA), there is a lack of data on its costs compared to peripheral nerve block anaesthesia (PNBA). The goal of this study was to investigate the differences in immediate perioperative costs between the LIA and PNBA in treatment of patients receiving total knee arthroplasty. METHODS: The comparison was conducted based on a randomized controlled clinical trial examining 40 patients with elective, primary total knee arthroplasty (TKA, 20 patients with LIA and 20 patients with PNBA). The analysis included surgical case costs, anaesthesiological case costs, material, costs of postoperative opioid requirements and catheter review visits for patients receiving PNBA. RESULTS: The overall mean costs for the LIA-group were 4328.72€ and 4368.12€ for the PNBA (p = 0.851). While there was no statistically significant difference in surgical case costs, the anaesthesiological costs were lower with the LIA procedure (1370.26€ vs. 1542.45€, p = 0.048). Material costs in the LIA group were 4.18€/patient and 94.64€/patient with the PNBA. Costs for postoperative opioid requirements showed no statistically significant difference between the two procedures. CONCLUSIONS: There is no relevant difference in immediate perioperative costs between LIA and PNBA. Shorter induction times lead to lower anaesthesiological case costs with the LIA. Overall economic aspects seem to play a less important role for determining an adequate procedure for perioperative pain management. TRIAL REGISTRATION: The study was approved by the ethics-review-board of Charité Hospital Berlin (Ethikausschuss 4, Charité - Universitätsmedizin Berlin, on 16th February 2017) and registered with data safety authorities. Study patients provided written informed consent to participate in the trial. Study registry: ClinicalTrials.gov, NCT03114306 .