tACS entrains neural activity while somatosensory input is blocked.

Transcranial alternating current stimulation (tACS) modulates brain activity by passing electrical current through electrodes that are attached to the scalp. Because it is safe and noninvasive, tACS holds great promise as a tool for basic research and clinical treatment. However, little is known about how tACS ultimately influences neural activity. One hypothesis is that tACS affects neural responses directly, by producing electrical fields that interact with the brain's endogenous electrical activity. By controlling the shape and location of these electric fields, one could target brain regions associated with particular behaviors or symptoms. However, an alternative hypothesis is that tACS affects neural activity indirectly, via peripheral sensory afferents. In particular, it has often been hypothesized that tACS acts on sensory fibers in the skin, which in turn provide rhythmic input to central neurons. In this case, there would be little possibility of targeted brain stimulation, as the regions modulated by tACS would depend entirely on the somatosensory pathways originating in the skin around the stimulating electrodes. Here, we directly test these competing hypotheses by recording single-unit activity in the hippocampus and visual cortex of alert monkeys receiving tACS. We find that tACS entrains neuronal activity in both regions, so that cells fire synchronously with the stimulation. Blocking somatosensory input with a topical anesthetic does not significantly alter these neural entrainment effects. These data are therefore consistent with the direct stimulation hypothesis and suggest that peripheral somatosensory stimulation is not required for tACS to entrain neurons.

Pharmacological interventions for the management of pain and discomfort during lumbar puncture in newborn infants.

BACKGROUND: Lumbar puncture (LP) is a common invasive procedure, most frequently performed to diagnose infection. Physicians perform LP in newborn infants with the help of an assistant using a strict aseptic technique; it is important to monitor the infant during all the steps of the procedure. Without adequate analgesia, LP can cause considerable pain and discomfort. As newborns have increased sensitivity to pain, it is crucial to adequately manage the procedural pain of LP in this population. OBJECTIVES: To assess the benefits and harms, including pain, discomfort, and success rate, of any pharmacological intervention during lumbar puncture in newborn infants, compared to placebo, no intervention, non-pharmacological interventions, or other pharmacological interventions. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, and three trial registries in December 2022. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs comparing drugs used for pain management, sedation, or both, during LP. We considered the following drugs suitable for inclusion. • Topical anesthetics (e.g. eutectic mixture of local anesthetics [EMLA], lidocaine) • Opioids (e.g. morphine, fentanyl) • Alpha-2 agonists (e.g. clonidine, dexmedetomidine) • N-Methyl-D-aspartate (NMDA) receptor antagonists (e.g. ketamine) • Other analgesics (e.g. paracetamol) • Sedatives (e.g. benzodiazepines such as midazolam) DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) or standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CIs). Our main outcomes were successful LP on first attempt, total number of LP attempts, episodes of bradycardia, pain assessed with validated scales, episodes of desaturation, number of episodes of apnea, and number of infants with one or more episodes of apnea. We used the GRADE approach to evaluate the certainty of the evidence. MAIN RESULTS: We included three studies (two RCTs and one quasi-RCT) that enrolled 206 newborns. One study included only term infants. All studies assessed topical treatment versus placebo or no intervention. The topical anesthetics were lidocaine 4%, lidocaine 1%, and EMLA. We identified no completed studies on opioids, non-steroidal anti-inflammatory drugs, alpha-2 agonists, NMDA receptor antagonists, other analgesics, sedatives, or head-to-head comparisons (drug A versus drug B). Based on very low-certainty evidence from one quasi-RCT of 100 LPs in 76 infants, we are unsure if topical anesthetics (lidocaine), compared to no anesthesia, has an effect on the following outcomes. • Successful LP on first attempt (first-attempts success in 48% of LPs in the lidocaine group and 42% of LPs in the control group) • Number of attempts per LP (mean 1.9 attempts, [standard error of the mean 0.2] in the lidocaine group, and mean 2.1 attempts [standard error of the mean 2.1] in the control group) • Episodes of bradycardia (0% of LPs in the lidocaine group and 4% of LPs in the control group) • Episodes of desaturation (0% of LPs in the lidocaine group and 8% of LPs in the control group) • Occurrence of apnea (RR 3.24, 95% CI 0.14 to 77.79; risk difference [RD] 0.02, 95% CI -0.03 to 0.08). Topical anesthetics compared to placebo may reduce pain assessed with the Neonatal Facial Coding System (NFCS) score (SMD -1.00 standard deviation (SD), 95% CI -1.47 to -0.53; I² = 98%; 2 RCTs, 112 infants; low-certainty evidence). No studies in this comparison reported total number of episodes of apnea. We identified three ongoing studies, which will assess the effects of EMLA, lidocaine, and fentanyl. Three studies are awaiting classification. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effect of topical anesthetics (lidocaine) compared to no anesthesia on successful lumbar puncture on first attempt, the number of attempts per lumbar puncture, episodes of bradycardia, episodes of desaturation, and occurrence of apnea. Compared to placebo, topical anesthetics (lidocaine or EMLA) may reduce pain assessed with the NFCS score. One ongoing study will assess the effects of systemic treatment.

Assessing the modulation of cutaneous sensory fiber excitability using a fast perception threshold tracking technique.

INTRODUCTION: Topical application of lidocaine-and-prilocaine (LP) cream attenuates the functionality of small cutaneous nerve fibers. The aim of this human study was to measure the underlying excitability modulation of small cutaneous nerve fibers using a novel and fast perception threshold tracking (PTT) technique. METHODS: Small sensory fibers were selectively blocked by 120-minute topical application of LP and confirmed by quantitative sensory testing. Excitability changes of small (activated by a specially designed pin electrode) and large (patch electrode) nerve fibers were assessed as the strength-duration relation and threshold electrotonus. RESULTS: The excitability assessed by the strength-duration relation and threshold electrotonus was significantly modulated for the small afferents (P < 0.05, Wilcoxon's test) but not the large afferents. DISCUSSION: This novel PTT technique was able to assess inhibition of membrane properties of small cutaneous fibers, suggesting the usefulness of the technique as a diagnostic method for assessing impairment of small fibers, as seen in many types of polyneuropathies.

Acute pain responses in dairy calves undergoing cornual nerve blocks with or without topical anesthetic.

Dairy calves are routinely administered medicines, vaccines, and anesthesia via injection. Although injections are painful, little is known about methods to alleviate this pain. The aim of this study was to determine whether lidocaine-prilocaine cream, a topical anesthetic, reduced calves' pain response to a subcutaneous injection around the cornual nerve. Calves were assigned 1 of 2 treatments: lidocaine-prilocaine cream at the sites of injection (n = 10) or no cream (n = 9). Thirty minutes after treatment, calves received a subcutaneous injection of 2% buffered lidocaine hydrochloride around the left and right cornual nerves. Contrary to our hypothesis, calves that received anesthetic cream beforehand displayed more escape behaviors during the injections than control calves. Both treatments had similarly low amounts of head-related behaviors afterward. Maximum eye temperature did not differ between the calves that received anesthetic cream and control calves, although eye temperature increased over time for both treatments. Heart rate increased during the 30 s following the first injection in both treatments. There were no treatment differences for any heart rate measures over the 5-min period after the first injection (mean heart rate, root mean square of successive differences, high-frequency power, and the ratio of low-frequency power to high-frequency power). These results suggest that cornual nerve blocks with buffered lidocaine are painful and that a lidocaine-prilocaine cream was not only ineffective in reducing this pain but that it may also worsen it.

The effects of lidocaine-prilocaine cream on responses to intravenous catheter placement in cats sedated with dexmedetomidine and either methadone or nalbuphine.

OBJECTIVE: To compare the reaction to cephalic intravenous (IV) catheter placement with or without lidocaine-prilocaine cream in cats sedated with dexmedetomidine and methadone or nalbuphine. STUDY DESIGN: Prospective, randomized, blind study. ANIMALS: A group of 24 female mixed breed cats. METHODS: Cats were randomly allocated to one of the two sedation protocols: dexmedetomidine (0.01 mg kg-1) and methadone (0.3 mg kg-1; DEXMET) or dexmedetomidine (0.01 mg kg-1) and nalbuphine (0.3 mg kg-1; DEXNALB). Sedation was scored 30 minutes later using a visual analog scale. Subsequently, a 2 × 3.5 cm area of the antebrachium over the cephalic vein was clipped, and half the cats within each protocol were randomly assigned for topical lidocaine-prilocaine cream (treatment), whereas no cream was applied to other cats (control). After 20 minutes, an attempt was made to place a 24 gauge catheter into the cephalic vein and the reaction of the cats to this procedure was scored using a numeric scale 0-3. Sedation and catheterization reaction scores were compared between sedation protocols and whether cats were administered lidocaine-prilocaine cream or not using the Friedman test followed by the Bonferroni procedure. A p value < 0.05 was considered significant. RESULTS: Sedation scores were not different between sedation protocols or between treatment and control cats within each protocol. All cats administered lidocaine-prilocaine cream showed no reaction to IV catheter placement. Among the control cats, no response was observed in one cat in DEXNALB. Catheterization reaction score was lower in the treatment cats in both the sedation protocols when compared with their respective controls. CONCLUSIONS AND CLINICAL RELEVANCE: Lidocaine-prilocaine cream applied for 20 minutes abolished the reaction to catheterization in cats sedated with dexmedetomidine and nalbuphine or methadone. Facilitation of IV catheter placement occurred within 20 minutes of lidocaine-prilocaine application.

Real-life use of the eutectic mixture lidocaine/prilocaine spray in men with premature ejaculation.

Topical anaesthetics are considered a first-line therapy option in men with premature ejaculation (PE). A cross-sectional retrospective analysis was performed to evaluate the real-life use of the eutectic mixture of prilocaine/lidocaine spray (FORTACIN™) in a cohort of 198 white-European men who had been consecutively and prospectively seen at a single tertiary-referral andrology centre for self-reported PE and naive for previous PE treatments. Descriptive statistics was used to describe the whole cohort and the paired t-test was applied to investigate potential differences throughout a 12-month follow-up (baseline, 1, 3, 6 and 12 months). Overall, mean (SD) age was 37 (6.5) years. Of all, lifelong, acquired and subjective PE were reported in 101 (51%), 59 (29.8%) and 38 (19.2%) patients at baseline, respectively. FORTACIN™ use increased up to 6 months, with 184 (92.9%) and 128 (66.4%) men who had tried and regularly used the compound, respectively. At 12-month follow-up, 53 (26.8%) men reported a regular use of the compound. Mean Premature Ejaculation Diagnostic Tool score significantly decreased at 6 and 12 months compared to baseline (all p < 0.05). Conversely, mean IELT significantly improved at 6-month follow-up compared to baseline (all p ≤ 0.04). Overall, FORTACIN™ emerged to be a safe and effective treatment option in PE patients of various types, with almost one fourth of patients still under treatment after 12 months. Timing and dosing of the drug can deserve to be adjusted according to patient's needs and their sexual ecology.

Evaluation of eutectic lidocaine/prilocaine cream for jugular blood sampling in cats.

OBJECTIVES: The study aimed to evaluate the efficacy of a eutectic lidocaine/prilocaine cream (EMLA cream; Astra Pharmaceuticals) in reducing pain and reaction to venepuncture during jugular blood sampling in cats after a 30-min topical application time. METHODS: The study was a prospective, blind, controlled clinical trial. Eighteen healthy client-owned cats were randomly allocated to two study groups. All cats were clipped on the left jugular groove region and then, depending on the study group, either the placebo (liquid paraffin) or EMLA cream was applied to the region. The area was then kept protected for the next 30 mins. Except for the operator who administered the product, all operators were blinded to the study groups. Blood sampling was performed by an experienced operator and a stress score was assigned to each cat according to the reactions observed during the venepuncture. Also, the procedure was classified as being 'easy' or 'difficult' by the same operator. RESULTS: A significantly reduced stress score was observed in cats that received the EMLA cream compared with those belonging to the placebo group (P = 0.048); withdrawal movements were observed in 1/9 cats treated with the EMLA cream vs 7/9 cats of the placebo group (P = 0.015). The jugular venepuncture was defined as easy in 1/9 cats that received the placebo and in 8/9 cats in the EMLA group (P = 0.015). CONCLUSIONS AND RELEVANCE: The present study provides evidence for the efficacy of the EMLA cream after a 30-min application time for jugular venepuncture in cats, together with significantly reduced stress for patients. Therefore, this study supports the routine use of EMLA cream as good practice to enhance the welfare of cats and to simplify venepuncture procedures.

Hybrid nanofilms as topical anesthetics for pain-free procedures in dentistry.

Topical anesthetics are widely applied in order to relieve the discomfort and anxiety caused by needle insertion and other painful superficial interventions at the oral cavity. So far, there are no commercially available effective topical anesthetic formulations for that purpose, and the most of developments are related to hydrophilic and low mucoadhesive forms. Therefore, we have prepared different hybrid nanofilms composed of biopolymer matrices (chitosan, pectin, and chitosan-pectin) blended with nanostructured lipid carriers (NLC) loading the eutectic mixture of 5% lidocaine-prilocaine (LDC-PLC), in order to fulfill this gap in the market. These dual systems were processed as hybrid nanofilms by the solvent/casting method, and its mucoadhesive, structural and mechanical properties were detailed. The most appropriate hybrid nanofilm combined the advantages of both pectin (PCT) and NLC components. The resultant material presented sustained LDC-PLC release profile for more than 8 h; permeation across porcine buccal mucosa almost twice higher than control and non-cytotoxicity against 3T3 and HACAT cell lines. Then, the in vivo efficacy of PCT/NLC formulation was compared to biopolymer film and commercial drug, exhibiting the longest-lasting anesthetic effect (> 7 h), assessed by tail flick test in mice. These pectin-based hybrid nanofilms open perspectives for clinical trials and applications beyond Dentistry.

Transcutaneous anaesthetic nano-enabled hydrogels for eyelid surgery.

Local anaesthetics are administered as a diffuse superficial slow injection in blepharoplasty. Current transcutaneous local anaesthetic formulations are not licensed for use on the face due to safety concerns. Here we report for the first time the permeation of local anaesthetics (lidocaine, bupivacaine loaded SNEDDS and their hydrogels) across human eyelid and mouse skin as a novel and ocular safe formulation for eyelid surgery. SNEDDS were loaded with high levels of anaesthetics and incorporated within carbomer hydrogels to yield nano-enabled gels. Lidocaine hydrogels have a significantly reduced lag time compared to EMLA, while they enhance lidocaine flux across human eyelid skin by 5.2 fold. Ex vivo tape stripping experiments indicated localisation of anaesthetics within the stratum corneum and dermis. Initial histopathological studies have shown no apparent signs of skin irritation. These results highlight the potential clinical capability of nano-enabled anaesthetic hydrogels as a non-invasive anaesthetic procedure for eyelid surgery.

Nanohybrid hydrogels designed for transbuccal anesthesia.

BACKGROUND: Local anesthesia in dentistry is by far the most terrifying procedure for patients, causing treatment interruption. None of the commercially available topical formulations is effective in eliminating the pain and phobia associated to the needle insertion and injection. MATERIALS AND METHODS: In this work we prepared a nanostructured lipid-biopolymer hydrogel for the sustained delivery of lidocaine-prilocaine (LDC-PLC) for transbuccal pre-anesthesia. The lipid was composed of optimized nanostructured lipid carriers (NLC) loaded with 5% LDC-PLC (NLC/LDC-PLC). The biopolymer counterpart was selected among alginate, xanthan (XAN), and chitosan matrices. The XAN-NLC hydrogel presented the most uniform aspect and pseudoplastic rheological profile, as required for topical use; therefore, it was selected for subsequent analyses. Accelerated stability tests under critical conditions (40°C; 75% relative humidity) were conducted for 6 months, in terms of drug content (mg/g), weight loss (%), and pH. RESULTS: In vitro LDC-PLC release profile through Franz diffusion cells revealed a bimodal kinetics with a burst effect followed by the sustained release of both anesthetics, for 24 hours. Structural analyses (fourier transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy) gave details on the molecular organization of the hybrid hydrogel, confirming the synergic interaction between the components. Safety and efficacy were evaluated through in vitro cell viability (3T3, HaCat, and VERO cells) and in vivo antinociceptive (tail-flick, in mice) tests, respectively. In comparison to a control hydrogel and the eutectic mixture of 5% LDC-PLC cream (EMLA®), the XAN-NLC/LDC-PLC hybrid hydrogel doubled and quadrupled the anesthetic effect (8 hours), respectively. CONCLUSION: Considering such exciting results, this multifaceted nanohybrid system is now ready to be further tested in clinical trials.