Therapeutic Use of Low-Dose Local Anesthetics in Pain, Inflammation, and Other Clinical Conditions: A Systematic Scoping Review.

The use of low-dose local anesthetics (LAs) has significantly transformed patient care by providing rapid and effective relief of pain and other clinical conditions while minimizing recovery time. This study aims to identify and describe the existing scientific evidence on the therapeutic use of low-dose LAs in various conditions and to identify gaps in the current literature in order to prioritize future research. This systematic scoping review adhered to the methodological guidelines outlined in the Arksey and O'Malley framework, which includes five distinct stages. Of the 129 studies included, 37.98% (n = 49) were clinical trials, 55.03% (n = 71) were observational studies, and 6.97% (n = 9) were systematic reviews. The most commonly reported indication for the use of low-dose LAs was chronic pain management (72.86%), followed by acute pain management (13.17%). Additionally, non-pain-related indications were also identified (13.95%). Overall, the administration of low-dose, short-acting LAs demonstrated favorable outcomes in terms of pain management and reduction in anxiety and depression scales, thereby having a positive impact on the patients' quality of life. This review represents the first systematic scoping review regarding the therapeutic role of LAs. To substantiate the reported positive effects on efficacy and safety, further rigorous research comprising larger, well-designed randomized controlled trials (RCTs) and long-term outcome monitoring is imperative.

A case of severe trigeminal neuralgia: recovery by means of stellate ganglion block with procaine. Discussion of possible mechanisms of action.

Drug and invasive treatment options for trigeminal neuralgia (TN) are often fraught with problems. Knowledge of the involvement of the autonomic nervous system, especially the sympathetic portion, in the pain process has grown rapidly in recent years. Both nociceptive and neuropathic pain can be maintained by the sympathetic nervous system, known as 'sympathetically maintained pain' (SMP). This current case report describes a patient with refractory TN that was treated with a stellate ganglion block (SGB). After the first SGB, the patient experienced significant pain relief that became long-lasting after repeated application of the SGB. These findings suggest that this patient had a high level of SMP. In patients with a low percentage of SMP, SGB may be less or not successful. A literature search did not find any case reports or studies about patients with refractory idiopathic TN treated with sympathetic blocks using local anaesthetics. From our point of view, it might be useful to test by means of SGB the extent to which an individual has SMP present, and, if that is the case, to perform a short series of SGB, as done in this current patient. Studies are needed to provide further insights.

Chronic Therapy-Resistant Neck Pain in a Fifty-Year-Old Man: The Role of Partially Impacted Third Molars - Case Report and New Pathophysiological Insights.

BACKGROUND: Inflammatory and mechanical stimuli in tooth/jaw pathologies can have far-reaching consequences via trigeminal and autonomic circuitry and can cause systemic (e.g., autoimmune) diseases and pain conditions outside the tooth/jaw region. In addition to a case report, we also describe new pathophysiological findings. CASE REPORT: We report on a patient with chronic, therapy-resistant neck pain whose cause lied in the tooth/jaw region, specifically, in wisdom teeth with space problems, and partially impacted. The tooth/jaw area itself was not painful; however, neck pain developed via the nucleus spinalis n. trigemini which extends into the cervical medulla. Surgical restoration of the wisdom teeth and subsequent neural therapy treatment of the extraction scars provided permanent pain relief. CONCLUSION: In case of therapy-resistant neck pain (among others), it is worthwhile to look for pathologies in the dental/jaw area, possibly allowing for a causal therapy.

The Influence of Modern Neurophysiology on the Previous Definitions of "Segment" and "Interference Field" in Neural Therapy.

BACKGROUND: In neural therapy, local anesthetics are injected for diagnostic and therapeutic purposes. In this process, therapy makes use of the regulatory functions and plastic properties of the nervous system, especially its autonomic part. Up until now, a distinction has been made between "local/segmental neural therapy" and "interference field therapy." This division dating back to the middle of the last century was based on the assumption that anatomical and clinical segments were identical. However, this is only true for the projection symptoms, which are limited to metamerism. All pathophysiological processes beyond this segment were called "interference field events" ("outside of any segmental order" and "not explainable by neuroanatomical circuitry"). SUMMARY: However, modern neurophysiology no longer recognizes segmental boundaries, taking into account the occurrence of cross-segmental sensitization processes, neuroplastic changes, immune processes, and neurogenic inflammation. In addition, new insights into neuroanatomical circuitry have also contributed to segmental expansion. Thus, in recent years, much of the interference field activity has been assigned to an "extended" segment; however, even there, no segment boundaries can be defined. Thus, the former definition of the interference field effect (considered to be outside any segmental order) is considered obsolete. Nowadays, interference fields are called "neuromodulatory triggers." They can act anywhere, both locally and fairly distant, and even systemically. KEY MESSAGES: Thus, it is no longer tenable to classify interference field therapy as "unscientific" and "not recognized" while local and segmental neural therapy is being scientifically recognized. In the work at hand, the interference fields discovered by the Huneke brothers become scientifically definable as "neuromodulatory triggers" by showing that clinically and pathologically, hardly any segmental boundaries exist.

Regulation of acute reflectory hyperinflammation in viral and other diseases by means of stellate ganglion block. A conceptual view with a focus on Covid-19.

Whereas the autonomic nervous system (ANS) and the immune system used to be assigned separate functions, it has now become clear that the ANS and the immune system (and thereby inflammatory cascades) work closely together. During an acute immune response (e. g., in viral infection like Covid-19) the ANS and the immune system establish a fast interaction resulting in "physiological" inflammation. Based on our knowledge of the modulation of inflammation by the ANS we propose that a reflectory malfunction of the ANS with hyperactivity of the sympathetic nervous system (SNS) may be involved in the generation of acute hyperinflammation. We believe that sympathetic hyperactivity triggers a hyperresponsiveness of the immune system ("cytokine storm") with consecutive tissue damage. These reflectory neuroimmunological and inflammatory cascades constitute a general reaction principle of the organism under the leadership of the ANS and does not only occur in viral infections, although Covid-19 is a typical current example therefore. Within the overreaction several interdependent pathological positive feedback loops can be detected in which the SNS plays an important part. Consequently, there is a chance to regulate the hyperinflammation by influencing the SNS. This can be achieved by a stellate ganglion block (SGB) with local anesthetics, temporarily disrupting the pathological positive feedback loops. Thereafter, the complex neuroimmune system has the chance to reorganize itself. Previous clinical and experimental data have confirmed a favorable outcome in hyperinflammation (including pneumonia) after SGB (measurable e. g. by a reduction in proinflammatory cytokines).

Investigation of the Sympathetic Regulation in Delayed Onset Muscle Soreness: Results of an RCT.

Sports-related pain and injury is directly linked to tissue inflammation, thus involving the autonomic nervous system (ANS). In the present experimental study, we disable the sympathetic part of the ANS by applying a stellate ganglion block (SGB) in an experimental model of delayed onset muscle soreness (DOMS) of the biceps muscle. We included 45 healthy participants (female 11, male 34, age 24.16 ± 6.67 years [range 18-53], BMI 23.22 ± 2.09 kg/m2) who were equally randomized to receive either (i) an SGB prior to exercise-induced DOMS (preventive), (ii) sham intervention in addition to DOMS (control/sham), or (iii) SGB after the induction of DOMS (rehabilitative). The aim of the study was to determine whether and to what extent sympathetically maintained pain (SMP) is involved in DOMS processing. Focusing on the muscular area with the greatest eccentric load (biceps distal fifth), a significant time × group interaction on the pressure pain threshold was observed between preventive SGB and sham (p = 0.034). There was a significant effect on pain at motion (p = 0.048), with post hoc statistical difference at 48 h (preventive SGB Δ1.09 ± 0.82 cm VAS vs. sham Δ2.05 ± 1.51 cm VAS; p = 0.04). DOMS mediated an increase in venous cfDNA -as a potential molecular/inflammatory marker of DOMS- within the first 24 h after eccentric exercise (time effect p = 0.018), with a peak at 20 and 60 min. After 60 min, cfDNA levels were significantly decreased comparing preventive SGB to sham (unpaired t-test p = 0.008). At both times, 20 and 60 min, cfDNA significantly correlated with observed changes in PPT. The 20-min increase was more sensitive, as it tended toward significance at 48 h (r = 0.44; p = 0.1) and predicted the early decrease of PPT following preventive stellate blocks at 24 h (r = 0.53; p = 0.04). Our study reveals the broad impact of the ANS on DOMS and exercise-induced pain. For the first time, we have obtained insights into the sympathetic regulation of pain and inflammation following exercise overload. As this study is of a translational pilot character, further research is encouraged to confirm and specify our observations.

Effects on hemodynamic variables and echocardiographic parameters after a stellate ganglion block in 15 healthy volunteers.

BACKGROUND: The sympathetic nervous system has an important role in generating pain. Various pathomechanisms are involved that respond well to the application of local anesthetics (LA), for example to the stellate ganglion block (SGB). OBJECTIVES: We wanted to know more about the effects of SGB on cardiovascular parameters. METHODS: We included 15 healthy volunteers; another 15 healthy volunteers as a control group (sham injection of LA). In order to produce a more precise SGB, we employed only a small volume of LA (3mL), a LA with a lower permeability (procaine 1%), and a modified injection technique. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), and echocardiographic parameters were recorded before and after SGB. We also investigated whether there are side differences (left and right SBG). RESULTS: At baseline all parameters were within the normal range. After performing right and left SGB DBP significantly increased (on the right side from 68.73±8.61 to 73.53±11.10, p=0.015; on the left side from 70.66±13.01 to 77.93±10.40, p=0.003). In the control group no increase in DBP was observed. No side-specific differences were found, except a significant reduction in the maximum velocity of myocardial contraction during the systole with left-sided SGB. CONCLUSIONS: Even with our methods we could not prevent the simultaneous occurrence of a partial parasympatholytic effect. For this reason, the SGB has only minor hemodynamic effects, which is desirable as it enhances the safety of the SGB.

Long-term results of therapeutic local anesthesia (neural therapy) in 280 referred refractory chronic pain patients.

BACKGROUND: Can the application of local anesthetics (Neural Therapy, NT) alone durably improve pain symptoms in referred patients with chronic and refractory pain? If the application of local anesthetics does lead to an improvement that far exceeds the duration of action of local anesthetics, we will postulate that a vicious circle of pain in the reflex arcs has been disrupted (hypothesis). METHODS: Case series design. We exclusively used procaine or lidocaine. The inclusion criteria were severe pain and chronic duration of more than three months, pain unresponsive to conventional medical measures, written referral from physicians or doctors of chiropractic explicitly to NT. Patients with improvement of pain who started on additional therapy during the study period for a reason other than pain were excluded in order to avoid a potential bias. Treatment success was measured after one year follow-up using the outcome measures of pain and analgesics intake. RESULTS: 280 chronic pain patients were included; the most common reason for referral was back pain. The average number of consultations per patient was 9.2 in the first year (median 8.0). After one year, in 60 patients pain was unchanged, 52 patients reported a slight improvement, 126 were considerably better, and 41 pain-free. At the same time, 74.1% of the patients who took analgesics before starting NT needed less or no more analgesics at all. No adverse effects or complications were observed. CONCLUSIONS: The good long-term results of the targeted therapeutic local anesthesia (NT) in the most problematic group of chronic pain patients (unresponsive to all evidence based conventional treatment options) indicate that a vicious circle has been broken. The specific contribution of the intervention to these results cannot be determined. The low costs of local anesthetics, the small number of consultations needed, the reduced intake of analgesics, and the lack of adverse effects also suggest the practicality and cost-effectiveness of this kind of treatment. Controlled trials to evaluate the true effect of NT are needed.

Photon upconverting nanoparticles for luminescent sensing of temperature.

Photon upconverting nanoparticles convert near-infrared into visible light (anti-Stokes emission), which strongly reduces the background of autofluorescence and light scattering in biological materials. Hexagonal NaYF(4) nanocrystals doped with Yb(3+) as the sensitizer and Er(3+)/Ho(3+)/Tm(3+) as the activator display at least two emission lines that respond differently to temperature changes. The ratio of the main emission line intensities enables a self-referenced optical readout of the temperature in the physiologically relevant range from 20 to 45 °C. Upconverting nanoparticles of the type NaYF(4):Yb, Er covered by an inactive shell of NaYF(4) are bright and allow for resolving temperature differences of less than 0.5 °C in the physiological range. The optical readout of this nanoparticle-based thermometer offers many options for imaging the two-dimensional distribution of temperature.

Referenced dual pressure- and temperature-sensitive paint for digital color camera read out.

The first fluorescent material for the referenced simultaneous RGB (red green blue) imaging of barometric pressure (oxygen partial pressure) and temperature is presented. This sensitive coating consists of two platinum(II) complexes as indicators and a reference dye, each of which is incorporated in appropriate polymer nanoparticles. These particles are dispersed in a polyurethane hydrogel and spread onto a solid support. The emission of the (oxygen) pressure indicator, PtTFPP, matches the red channel of a RGB color camera, whilst the emission of the temperature indicator [Pt(II) (Br-thq)(acac)] matches the green channel. The reference dye, 9,10-diphenylanthracene, emits in the blue channel. In contrast to other dual-sensitive materials, this new coating allows for the simultaneous imaging of both indicator signals, as well as the reference signal, in one RGB color picture without having to separate the signals with additional optical filters. All of these dyes are excitable with a 405 nm light-emitting diode (LED). With this new composite material, barometric pressure can be determined with a resolution of 22 mbar; the temperature can be determined with a resolution of 4.3 °C.

Dissociated neural processing for decisions in managers and non-managers.

Functional neuroimaging studies of decision-making so far mainly focused on decisions under uncertainty or negotiation with other persons. Dual process theory assumes that, in such situations, decision making relies on either a rapid intuitive, automated or a slower rational processing system. However, it still remains elusive how personality factors or professional requirements might modulate the decision process and the underlying neural mechanisms. Since decision making is a key task of managers, we hypothesized that managers, facing higher pressure for frequent and rapid decisions than non-managers, prefer the heuristic, automated decision strategy in contrast to non-managers. Such different strategies may, in turn, rely on different neural systems. We tested managers and non-managers in a functional magnetic resonance imaging study using a forced-choice paradigm on word-pairs. Managers showed subcortical activation in the head of the caudate nucleus, and reduced hemodynamic response within the cortex. In contrast, non-managers revealed the opposite pattern. With the head of the caudate nucleus being an initiating component for process automation, these results supported the initial hypothesis, hinting at automation during decisions in managers. More generally, the findings reveal how different professional requirements might modulate cognitive decision processing.

Long time monitoring of the respiratory activity of isolated mitochondria.

We have investigated the ability of optical oxygen sensors incorporated in a microplate to determine the respiratory activity of cell fractions. Different cell fractions were monitored, in particular to evaluate the long term functionality of isolated mitochondria. It is possible to continuously sense respiratory activity of isolated mitochondria over time. We found that they are functional for three hours but stop respiring at a critical limit of 20% air saturation in the system. Furthermore, inhibition and enhancement of respiratory activity were detected. In conclusion, oxygen sensors are a powerful tool to evaluate the functionality of isolated mitochondria.

Oxygen and temperature sensitivity of blue to green to yellow light-emitting Pt(II) complexes.

The synthesis and photophysical properties of a series of yellow-green to blue-green emitting heteroleptic, cyclometalated Pt(II)(acac) complexes based on substituted phenylpyridine and tetrahydroquinoline ligands is reported. The luminescence intensities and lifetimes of these compounds were also studied in poly(styrene) films with respect to their responses to oxygen and temperature. Particularly, due to the insensitivity to oxygen quenching, these complexes are promising candidates as inert reference dyes in optical sensors. On the other hand, the Pt(II) complex with 2-(4-bromophenyl)-5,6,7,8-tetrahydroquinoline as C^N ligand, displays a strong temperature quenching effect. The distinct response to temperature was additionally calibrated after incorporation in poly(vinylidene chloride-co-acrylonitrile) serving as oxygen-blocking matrix copolymer. The resulting yellow-green-emitting temperature sensor signifies an interesting alternative to the available mostly red emitting temperature-sensitive probes.

Targeted luminescent near-infrared polymer-nanoprobes for in vivo imaging of tumor hypoxia.

Polystyrene nanoparticles (PS-NPs) were doped with an oxygen-sensitive near-infrared (NIR)-emissive palladium meso-tetraphenylporphyrin and an inert reference dye which are both excitable at 635 nm. The nanosensors were characterized with special emphasis on fundamental parameters such as absolute photoluminescence quantum yield and fluorescence lifetime. The PS-NPs were employed for ratiometric dual-wavelength and lifetime-based photoluminescent oxygen sensing. They were efficiently taken up by cultured murine alveolar macrophages, yielding a characteristic and reversible change in ratiometric response with decreasing oxygen concentration. This correlated with the cellular hypoxic status verified by analysis of hypoxia inducible factor-1α (HIF-1α) accumulation. In addition, the surface of PS-NPs was functionalized with polyethylene glycol (PEG) and the monoclonal antibody herceptin, and their binding to HER2/neu-overexpressing tumor cells was confirmed in vitro. First experiments with tumor-bearing mouse revealed a distinctive ratiometric response within the tumor upon hypoxic condition induced by animal sacrifice. These results demonstrate the potential of these referenced NIR nanosensors for in vitro and in vivo imaging that present a new generation of optical probes for oncology.

Complementary therapy systems and their integrative evaluation.

Complementary and alternative medicine (CAM) is becoming an integral part of modern medicine. Complementary and alternative medicine therapy systems include natural medicinal products, nonpharmacological treatments, and counselling on health and lifestyle issues. Complementary and alternative medicine concepts are often elaborate, transcending biophysical models and employing the principles of salutogenesis. Evaluations of CAM therapy systems need to be integrative and cover the dimensions of: (1) therapeutic professionalism; (2) patient perspective and public demand; (3) conceptuality; (4) safety, effectiveness, and costs. Complex research strategies are required, which reverse the phases of conventional drug assessment. The predominant use of randomized trials would introduce structural bias and create an artificial picture. Important are evaluations of the whole system in real-world conditions, and surveys on component evaluations. Systemic CAM assessments should consist of a broad array of high-quality research methods: well-conducted randomized and nonrandomized studies, cohort studies, qualitative research, high-quality case reports and case series, studies on patient perspective, safety analyses, economic analyses, etc. Good clinical judgement, a core epistemic element of medicine based on nonstochastic principles, should also be integrated and could reflect routine patient care.

Upconverting nanoparticles for nanoscale thermometry.

Upconverting materials are capable of absorbing near-infrared light and converting it into short-wavelength luminescence. The efficiency of this remarkable effect is highly temperature dependent and thus can be used for temperature determination (thermometry) on a nanometer scale. All the upconverting materials discovered so far display several (mainly two) narrow emission bands, each of which has its own temperature dependence. The ratio of the intensity of two of these bands provides a referenced signal for optical sensing of temperature, for example inside cells.

Moral concepts set decision strategies to abstract values.

Persons have different value preferences. Neuroimaging studies where value-based decisions in actual conflict situations were investigated suggest an important role of prefrontal and cingulate brain regions. General preferences, however, reflect a superordinate moral concept independent of actual situations as proposed in psychological and socioeconomic research. Here, the specific brain response would be influenced by abstract value systems and moral concepts. The neurobiological mechanisms underlying such responses are largely unknown. Using functional magnetic resonance imaging (fMRI) with a forced-choice paradigm on word pairs representing abstract values, we show that the brain handles such decisions depending on the person's superordinate moral concept. Persons with a predominant collectivistic (altruistic) value system applied a "balancing and weighing" strategy, recruiting brain regions of rostral inferior and intraparietal, and midcingulate and frontal cortex. Conversely, subjects with mainly individualistic (egocentric) value preferences applied a "fight-and-flight" strategy by recruiting the left amygdala. Finally, if subjects experience a value conflict when rejecting an alternative congruent to their own predominant value preference, comparable brain regions are activated as found in actual moral dilemma situations, i.e., midcingulate and dorsolateral prefrontal cortex. Our results demonstrate that superordinate moral concepts influence the strategy and the neural mechanisms in decision processes, independent of actual situations, showing that decisions are based on general neural principles. These findings provide a novel perspective to future sociological and economic research as well as to the analysis of social relations by focusing on abstract value systems as triggers of specific brain responses.

Multiple fluorescent chemical sensing and imaging.

Optical sensors, unlike most others, enable multiple sensing of (bio)chemical species by making use of probes whose signals can be differentiated by spectral and/or temporal resolution. Multiple sensors are of substantial interest for continuous monitoring of chemical parameters in complex samples such as blood, bioreactor fluids, in the chemical industry, aerodynamic research, and when monitoring food quality control, to mention typical examples. Moreover, such sensors enable non-invasive, non-toxic and online detection. We discuss in this critical review the state of the art in terms of spectroscopic principles, materials (mainly indicator probes and polymers), and give selected examples for dual and triple sensors along with a look into the future (109 references).

Dual sensing of pO(2) and temperature using a water-based and sprayable fluorescent paint.

Core-shell particles (CSPs) composed of a polystyrene core and a poly(vinyl pyrrolidone) shell were dyed with a luminescent platinum(ii) porphyrin probe for oxygen. In parallel, microparticles were dyed with a luminescent iridium(ii) complex acting as a probe for temperature. The particles were deposited (by spraying) on a surface to enable continuous imaging of the distribution of oxygen (and thus of barometric pressure) and temperature. Unlike most previous paints of this kind, a binder polymer is not needed and water can be used as a dispersant. This makes the paint environmentally friendly and reduces costs in terms of occupational health, clean-up, and disposal. Both indicator probes in the sensor paint can be excited at 405 nm using LEDs or diode lasers, whilst their emission maxima are spectrally separated by about 130 nm. Thus, two independent optical signals are obtained that allow for fluorescent imaging of barometric pressure (in fact oxygen partial pressure) and of temperature, and also to correct the oxygen signal for effects of temperature. The paint was calibrated at air pressures ranging from 50 mbar to 2000 mbar and at temperatures between 1 degrees C and 50 degrees C.