Anti-Inflammatory Characteristics of Local Anesthetics: Inhibition of TNF-α Secretion of Lipopolysaccharide-Stimulated Leucocytes in Human Blood Samples.

Background. Local anesthetics (LAs) have potent anti-inflammatory properties. Inflammatory down-regulation is crucial in diseases with overactive immune reactions, such as acute respiratory distress syndrome (ARDS) and chronic inflammation. We investigated the influence of four LAs, procaine, lidocaine, mepivacaine, and bupivacaine, on the reduction of tumor necrosis factor-alpha (TNF-α) secretion in lipopolysaccharide (LPS)-activated human leucocytes. Methods. Blood samples of 28 individuals were stimulated with LPS. The reduction of TNF-α production by each of the four LAs added (0.5 mg/mL) was measured and correlated with biometric variables. A response was defined as reduction to <85% of initial levels. Results. All four LAs down-regulated the TNF-α secretion in 44−61%: Bupivacaine (44.4%), lidocaine (61.5%), mepivacaine (44.4%), and procaine (50% of the individuals, "responders"). The TNF-α secretion was reduced to 67.4, 68.0, 63.6, and 67.1% of the initial values in responders. The effects in both patients and healthy persons were the same. Interindividual responses to LAs were not correlated with the duration or type of complaints, basal TNF-α serum level, sex, BMI, or age of responders. Conclusions. Four clinically relevant LAs (amid-LA and ester-LA) attenuate the inflammatory response provoked by LPS. They are potential candidates for drug repositioning in treating overactive immune reactions and chronic inflammation.

Therapy With Local Anesthetics to Treat Vulvodynia. A Pilot Study.

INTRODUCTION: Vulvodynia (chronic vulvar pain) is a sexually debilitating disorder with a prevalence of ∼10%. AIM: To investigate the effectiveness of therapy with local anesthetics (TLA) in women with severe vulvodynia, we conducted a prospective, non-controlled observational study. METHODS: 45 patients with severe chronic vulvodynia (primary and secondary vulvodynia, 0-10 numeric analogue scale (NAS) ≥6, median 7.9, duration ≥6 months, median 65.2 months) in an outpatient practice in Germany were treated with TLA in 3-12 sessions using procaine 1% as local anesthetic. Effectiveness was analyzed with Wilcoxon signed rank tests and Wilcoxon rank sum tests. OUTCOMES: Therapeutic success as a reduction of pain to ≤4 NAS lasting for ≥6 months after end of therapy. RESULTS: TLA successfully reduced vulvodynia in 36 of 45 patients (80 %, responders). The NAS reduction was from 7.9 to 2.4 (P < .001). Even patients denominated as non-responders experienced a significant reduction in NAS (P = .03). In responders, long-term success was observed for 6.8-125 months (median 24.1 months). No adverse events occurred. CLINICAL TRANSLATION: A promising new treatment for a hard-to-treat chronic female pain disorder. STRENGTHS AND LIMITATIONS: Limitation: Monocentric, non-controlled observational design; Strength: the high number of patients treated. CONCLUSION: The high success rate of TLA in this investigation offers new perspectives on the etiology of vulvodynia as a complex pain syndrome affecting several nerves of the pelvic floor, and also provides early insight into the effectiveness of TLA in women with vulvodynia. Weinschenk S, Benrath J, Kessler E, et al. Therapy With Local Anesthetics to Treat Vulvodynia. A Pilot Study. Sex Med 2022;10:100482.

Membrane-Mediated Activity of Local Anesthetics.

The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels, causing anesthesia. However, there is a growing body of research showing that LAs act on a wide range of receptors and channel proteins far beyond simple analgesia. The current concept of ligand recognition may no longer explain the multitude of protein targets influenced by LAs. We hypothesize that LAs can cause anesthesia without directly binding to the receptor proteins just by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels based on LAs' amphiphilicity. It is possible that LAs act in one of the following ways: They 1) dissolve raft-like membrane microdomains, 2) impede nerve impulse propagation by lowering the lipid phase transition temperature, or 3) modulate the lateral pressure profile of the lipid bilayer. This could also explain the numerous additional effects of LAs besides anesthesia. Furthermore, the concepts of membrane-mediated activity and binding to ion channels do not have to exclude each other. If we were to consider LA as the middle part of a continuum between unspecific membrane-mediated activity on one end and highly specific ligand binding on the other end, we could describe LA as the link between the unspecific action of general anesthetics and toxins with their highly specific receptor binding. This comprehensive membrane-mediated model offers a fresh perspective to clinical and pharmaceutical research and therapeutic applications of local anesthetics. SIGNIFICANCE STATEMENT: Local anesthetics, according to the World Health Organization, belong to the most important drugs available to mankind. Their rediscovery as therapeutics and not only anesthetics marks a milestone in global pain therapy. The membrane-mediated mechanism of action proposed in this review can explain their puzzling variety of target proteins and their thus far inexplicable therapeutic effects. The new concept presented here places LAs on a continuum of structures and molecular mechanisms in between small general anesthetics and the more complex molecular toxins.

Uterine contractility changes in a perfused swine uterus model induced by local anesthetics procaine, lidocaine, and ropivacaine.

BACKGROUND: Local anesthetics (LAs) are increasingly used as therapeutics due to their multiple molecular effects. They may be potential agents also in gynecology and reproductive medicine. The objective of this study was to investigate the contractility response of the perfused swine uterus to different concentrations of the LAs procaine, lidocaine, and ropivacaine. METHODS AND FINDINGS: In an extracorporeal perfusion model with fresh swine uteri, effects of administered boli of these three LAs in concentrations of 0.1 mg/mL, 0.5 mg/mL and 1.0 mg/mL on uterine contractility and peristalsis were assessed using an intrauterine double-chip micro-catheter. A dose-dependent increase in intrauterine pressure (IUP) in the isthmus and corpus uteri was observed after the administration of the ester-LA procaine 0.1, 0.5, and 1.0%, which was not seen with lower concentrations, or buffer solution. An increase-decrease curve was found after increasing concentrations of the amide-LA lidocaine and ropivacaine, with an IUP plateau with 0.1 and 0.5%, and a decrease with 1% (p<0.01). All reactions were seen in both the isthmus and corpus uteri. The difference of the contractility pattern between ester- and amide-LA at 1% concentration was significant. CONCLUSION: LAs dose-dependently modulate contractility in non-pregnant swine uteri. The amid-LAs lidocaine and ropivacaine reduce contractility in higher concentrations and may be used as therapeutics in disorders with increased uterine contractility, as dysmenorrhoea, endometriosis, and infertility. The multiple molecular effects of LAs may explain these effects. This in-vitro pilot study in vitro provides initial data for designing further studies to transfer the results onto humans.

["Critical discussion should be encouraged!" - a qualitative analysis of medical students' evaluation of a complementary medicine course]. / "Kritische Diskussion sollte mehr gefördert werden!"­ Eine qualitative Auswertung der Lehrevaluation von Medizinstudierenden zur komplementärmedizinischen Lehre.

BACKGROUND: In 2002, the new version of the German Medical Licensure Act integrated Naturopathy and Complementary Medicine into the cross-sectoral unit 12 "Rehabilitation, Physical Medicine and Naturopathy" (QB12) of the medical undergraduate course. At the University of Heidelberg, Complementary Medicine (CAM) is an obligatory clinical subject of the medical undergraduate curriculum and is delivered in the form of lectures and small group work. As a central educational objective, medical students should be able to explain the principles of classical Naturopathy and the most commonly used CAM procedures. The aim was to explore the attitudes, learning needs and interests of medical students with regard to Naturopathy and CAM, and thus establish the teaching requirements. METHODS: The lectures and internships were evaluated using a faculty-based teaching evaluation form. The free-text of the evaluation forms between winter semester 2011/2012 and summer semester 2013 were assessed using Mayring qualitative content analysis. RESULTS: The free-texts were divided into three deductive main categories (Attitudes, Learning Needs and Interests) and further subcategories. A central topic was the polarization of views in medical students regarding CAM; it ranged from lively resistance to great enthusiasm. Strikingly, comments often showed that students had significant reservations with respect to CAM and would require further evidence from the teachers in order to embrace this concept. This was particularly prominent in the use of non-pharmaceutical methods. DISCUSSION: Our results show that evidence-based teaching, combined with practical experience, contributes positively to the critical appraisal of CAM amongst medical students. These findings can serve as the basis for planning, implementation and realization of CAM teaching within mainstream undergraduate medical education.

Local Anesthetics, Procaine, Lidocaine, and Mepivacaine Show Vasodilatation but No Type 1 Allergy: A Double-Blind, Placebo-Controlled Study.

BACKGROUND: Therapy with local anesthetics (LAs), also known as neural therapy, is used in integrative medicine because of its anti-inflammatory properties. Ester-linked LAs are often avoided because of their alleged high allergenicity. Little data supports this assumption and hence the importance of our investigation on type-1 allergies against ester- and amide-linked LAs. We performed a prospective, double-blinded, placebo-controlled observational study. METHODS: 177 patients received 340 intracutaneous injections with 1% procaine, 0.5% lidocaine, 1% mepivacaine, or saline solution. Every patient received two different tests on each forearm. Reactions were monitored for 15 minutes. RESULTS: No type-1 allergy was observed. The mean erythema diameter of the wheals after 10 minutes was procaine 8.0 ± 6.4 mm, mepivacaine 7.6 ± 6.3 mm, lidocaine 4.4 ± 4.8 mm, and NaCl 3.7 ± 3.2 mm. The wheal diameter of all substances showed a crescendo-decrescendo phenomenon. The procaine and mepivacaine wheals were significantly larger than those of lidocaine and NaCl. No general signs of hypersensitivity were observed. Diameter and intensity were independent of the injection site, order of injection, age, gender, and body mass index. CONCLUSION: This study shows no higher type-1 allergenicity of the ester-linked LA procaine, compared to the amide-linked LAs lidocaine and mepivacaine, and supports its use in therapy and short-track surgery.

Inter-Rater Reliability of Neck Reflex Points in Women with Chronic Neck Pain.

BACKGROUND: Neck reflex points (NRP) are tender soft tissue areas of the cervical region that display reflectory changes in response to chronic inflammations of correlated regions in the visceral cranium. Six bilateral areas, NRP C0, C1, C2, C3, C4 and C7, are detectable by palpating the lateral neck. We investigated the inter-rater reliability of NRP to assess their potential clinical relevance. METHODS: 32 consecutive patients with chronic neck pain were examined for NRP tenderness by an experienced physician and an inexperienced medical student in a blinded design. A detailed description of the palpation technique is included in this section. Absence of pain was defined as pain index (PI) = 0, slight tenderness = 1, and marked pain = 2. Findings were evaluated either by pair-wise Cohen's kappa (ĸ) or by percentage of agreement (PA). RESULTS: Examiners identified 40% and 41% of positive NRP, respectively (PI > 0, physician: 155, student: 157) with a slight preference for the left side (1.2:1). The number of patients identified with >6 positive NRP by the examiners was similar (13 vs. 12 patients). ĸ values ranged from 0.52 to 0.95. The overall kappa was ĸ = 0.80 for the left and ĸ = 0.74 for the right side. PA varied from 78.1% to 96.9% with strongest agreement at NRP C0, NRP C2, and NRP C7. Inter-rater agreement was independent of patients' age, gender, body mass index and examiner's experience. CONCLUSION: The high reproducibility suggests the clinical relevance of NRP in women.

Heart rate variability (HRV) in deep breathing tests and 5-min short-term recordings: agreement of ear photoplethysmography with ECG measurements, in 343 subjects.

PURPOSE: We analyzed heart rate variability (HRV) taken by ECG and photoplethysmography (PPG) to assess their agreement. We also analyzed the sensitivity and specificity of PPG to identify subjects with low HRV as an example of its potential use for clinical applications. METHODS: The HRV parameters: mean heart rate (HR), amplitude, and ratio of heart rate oscillation (E-I difference, E/I ratio), RMSSD, SDNN, and Power LF, were measured during 1-min deep breathing tests (DBT) in 343 individuals, followed by a 5-min short-term HRV (s-HRV), where the HRV parameters: HR, SD1, SD2, SDNN, Stress Index, Power HF, Power LF, Power VLF, and Total Power, were determined as well. Parameters were compared through correlation analysis and agreement analysis by Bland-Altman plots. RESULTS: PPG derived parameters HR and SD2 in s-HRV showed better agreement than SD1, Power HF, and stress index, whereas in DBT HR, E/I ratio and SDNN were superior to Power LF and RMSSD. DBT yielded stronger agreement than s-HRV. A slight overestimation of PPG HRV over HCG HRV was found. HR, Total Power, and SD2 in the s-HRV, HR, Power LF, and SDNN in the DBT showed high sensitivity and specificity to detect individuals with poor HRV. Cutoff percentiles are given for the future development of PPG-based devices. CONCLUSION: HRV measured by PPG shows good agreement with ECG HRV when appropriate parameters are used, and PPG-based devices can be employed as an easy screening tool to detect individuals with poor HRV, especially in the 1-min DBT test.

Injections of Local Anesthetics into the Pharyngeal Region Reduce Trapezius Muscle Tenderness.

BACKGROUND: Neck pain is a frequent reason for seeking medical advice. Neuroanatomical findings suggest a close connection between the pharynx and the trapezius region. Irritation of the pharynx may induce tenderness of this area. Specific tender points, called neck reflex points (NRPs), can be identified here with high reproducibility. We hypothesized that therapeutic local anesthesia (TLA; or neural therapy, NT) in the pharyngeal region can reduce tenderness in patients with therapy-resistant neck pain. PATIENTS AND METHODS: 17 consecutive female patients with chronic cervical pain and positive trapezius NRPs received bilateral injections of 0.5 ml 1% procaine into the palatine velum. The NRPs were assessed using a 3-level pain index (PI = 0, 1, or 2) before and 3-5 min after each injection. RESULTS: We found a significant reduction in tenderness of the NRP of the trapezius region (NRP C7) immediately after TLA/NT. 30 positive NRPs were found before therapy and only 13 after therapy (p < 0.01). The average PI of the NRP C7 was 1.24 ± 0.77 before and 0.35 ± 0.59 after therapy (right side), and 1.34 ± 0.59 before and 0.59 ± 0.69 after therapy (left side). The pre- and post-therapy PI values were significantly different on both the right and left sides of the trapezius region (p < 0.01). No adverse effects were observed. CONCLUSIONS: Pharyngeal irritation may induce and maintain therapy-resistant cervical pain in patients with chronic pharyngeal disease. These patients could benefit from remote TLA/NT injections in the pharyngeal region.

New perineal injection technique for pudendal nerve infiltration in diagnostic and therapeutic procedures.

PURPOSE: Pudendal nerve injection is used as a diagnostic procedure in the vulvar region and for therapeutic purposes, such as in vulvodynia. Here, we provide a new, easy-to-perform perineal injection technique. PATIENTS AND METHODS: We analyzed 105 perineal injections into the pudendal nerve with a local anesthetic (LA), procaine in 20 patients. A 0.4 × 40 mm needle was handled using a stop-and-go technique while monitoring the patient's discomfort. The needle was placed 1-2 cm laterally to the dorsal introitus. After aspiration, a small amount of LA was applied. After subcutaneous anesthesia, the needle was further advanced step-by-step. Thus, 5 ml could be applied with little discomfort to the patient. Anesthesia in the pudendal target region was the primary endpoint of our analysis. RESULTS: In 93 of 105 injections (88.6 %), complete perineal anesthesia was achieved with a single injection. 12 injections were repeated. These injections were excluded from the analysis. Severity of injection pain, on visual analog scale (VAS) from 0 to 100, was 26.8 (95 % CI 7.2-46.4). Age (ß = 0.33, p < 0.01) and the number of previous injections (ß = 0.35, p < 0.01) inversely correlated with injection pain. Injection pain and anesthesia were not affected by BMI, the number and the side of previous injections, or order of injection. A reversible vasovagal reaction was common, but no serious adverse effects occurred. CONCLUSION: Perineal pudendal injection is an effective and safe technique for anesthesia in diagnostic (vulva biopsy) and therapeutic indications (pudendal neuralgia), and regional anesthesia in perinatal settings.

Successful therapy of vulvodynia with local anesthetics: a case report.

BACKGROUND: Vulvodynia often occurs with unexplained vulvar pain and hyperesthesia, sexual dysfunction, and psychological disability, lacking an organic or microbiological substrate. CASE REPORT: A 25-year-old woman with generalized, unprovoked vulvodynia for 12 years was treated repeatedly with procaine 1% for 14 sessions after she had previously had numerous unsatisfying multidisciplinary treatments. We observed a decrease in pain scores on the visual analogue scale (VAS) from initially 8-9 to presently 0-2. Injection sites were: Head's zones and trigger points of the lower abdomen, regional hypogastric ganglia, bilateral maxillary sinus, and scars of the lower jaw. No major adverse events were observed. Injections to remote sites improved symptoms more strongly than local or regional therapy. After a 3-year follow-up the patient is free of symptoms. CONCLUSION: Therapy with local anesthetics (TLA, neural therapy) can be a useful additional therapy in complicated cases of vulvodynia. Further studies on the underlying mechanism of injections into remote foci (interference field, stoerfeld) and the effectiveness of TLA in chronic pain syndromes should be performed.