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.

The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels. The concept of ligand recognition, however, does not explain the multitude of protein targets influenced by LAs. Here we review alternative functional models based on the indirect lipid-mediated effects of LAs on membrane proteins. Based on their amphiphilicity, LAs specifically immerse themselves into the bilayer membranes. LAs could cause anesthesia without having to directly bind to the receptor proteins by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels. This could explain the numerous additional effects of LA besides anesthesia. It is conceivable that LAs act in one of the following ways: they (a) dissolve raft-like membrane micro-domains, (b) lower the lipid phase transition temperature and thereby affect nerve impulse propagation, or (c) modulate the lateral pressure profile of the lipid bilayer. Note that the two different concepts of membrane-mediated activity and binding to ion channels do not exclude each other. In fact, LA molecules can be regarded as the middle part of a continuum, ranging from entirely unspecific interactions of general anesthetics that act via dissolution in membranes, towards toxins with an exceptional affinity to highly specific binding sites. This comprehensive membrane-mediated model, describing a continuum of actions, offers a fresh perspective to clinical and pharmaceutical research and applications of local anesthetics. Significance Statement Local anesthetics belong to the most important drugs available to mankind. Their re-discovery as therapeutics, 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 as yet inexplicable therapeutic effects. The new concept presented here resolves these conundrums, by placing LAs into a continuum of structures and molecular mechanisms, namely in-between small general anesthetics and the more complex molecular toxins.

SummaryBackground: 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.

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.