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Study Objective: To simulate bupivacaine pharmacokinetics in scenarios of labor epidural analgesia (LEA) extended for intrapartum cesarean delivery (CD) with epidural or intrathecal boluses, followed by transversus abdominis plane (TAP) block with liposomal bupivacaine (LB) for postcesarean analgesia., Design: Bupivacaine plasma concentrations were simulated using a 2-compartment distribution model fit to previous study data., Setting: Virtual pharmacokinetic simulations., Patients: Virtual individuals (1000, each scenario) had uniform weight (80 kg) but varying absorption parameters., Interventions: The 6 scenarios varied in LEA infusion duration (6 or 24 h), local anesthetic used for bolus to extend LEA (epidural lidocaine or intrathecal bupivacaine), TAP block regimen, and time between bolus and TAP block., Measurements: Scenario outcomes included geometric mean (GM) peak bupivacaine plasma concentration (C max ) with 95% prediction interval (PI), median (range) C max , and number of virtual individuals (per 1000) with C max reaching estimated toxicity thresholds (neurotoxicity: 2000 μg/L; cardiotoxicity: 4000 μg/L)., Main Results: In simulated scenarios of LEA infusion for 24 h with an epidural bolus of lidocaine 400 mg for CD followed 1 h later by TAP block, the GM C max for the scenarios with TAP blocks including either LB 266 mg plus bupivacaine hydrochloride 52 mg or bupivacaine hydrochloride 104 mg was 1860 (95% PI, 1107-3124) and 1851 (95% PI, 1085-3157) μg/L, respectively. Among 1000 virtual individuals for each scenario, 404 and 401 had C max reaching 2000 μg/L, respectively; 1 and 0 had C max reaching 4000 μg/L, respectively. For other scenarios, GM C max remained <1000 μg/L., Conclusions: Across 6 different simulations of TAP blocks for intrapartum CD analgesia, LEA with bupivacaine (with or without boluses for extension and including a conservative modeling of lidocaine without epinephrine), followed by TAP block with LB and/or bupivacaine hydrochloride 0, 1, or 2 h after CD, is unlikely to result in bupivacaine plasma concentrations reaching local anesthetic systemic toxicity thresholds in healthy patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel Katz reports equipment, drugs, or supplies was provided by Pacira BioSciences Inc. Jia Song reports financial support was provided by Pacira BioSciences Inc. Matthew Carangelo reports financial support was provided by Pacira BioSciences Inc. Roy Winston reports financial support was provided by Pacira BioSciences Inc. Timothy Bergsma reports financial support was provided by Pacira BioSciences Inc. Ruth Landau reports financial support was provided by Pacira BioSciences Inc. Daniel Katz reports a relationship with Pacira BioSciences Inc. that includes: non-financial support. Jia Song reports a relationship with Pacira BioSciences Inc. that includes: employment and equity or stocks. Matthew Carangelo reports a relationship with Pacira BioSciences Inc. that includes: employment and equity or stocks. Roy Winston reports a relationship with Pacira BioSciences Inc. that includes: employment and equity or stocks. Ruth Landau reports a relationship with Pacira BioSciences Inc. that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Local anesthetics (LA), as part of multimodal analgesia, have garnered significant interest for their role in delaying the initiation of opioid therapy, reducing postoperative opioid usage, and mitigating both hospitalization duration and related expenses. Despite numerous endeavors to extend the duration of local anesthetic effects, achieving truly satisfactory long-acting analgesia remains elusive. Drawing upon prior investigations, vesicular phospholipid gels (VPGs) emerge as promising candidates for extended-release modalities in small-molecule drug delivery systems. Therefore, we tried to use the amphiphilicity of phospholipids to co-encapsulate levobupivacaine hydrochloride and meloxicam, two drugs with different hydrophilicity, to obtain a long-term synergistic analgesic effect. Initially, the physicochemical attributes of the formulation were characterized, followed by an examination of its in vitro release kinetics, substantiating the viability of extending the release duration of the dual drugs. Sequentially, in vivo investigations encompassing pharmacokinetic profiling and assessment of analgesic efficacy were undertaken, revealing a prolonged release duration of up to 120 h and attainment of optimal postoperative analgesia. Subsequently, inquiries into the mechanism underlying synergistic analgesic effects and safety evaluations pertinent to the delivery strategy were pursued. In summation, we successfully developed a promising formulation to achieve long-acting analgesia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: Pharmacokinetics of local anesthetics are one of the main determinants of success and safety of regional anesthesia and comprise local and systemic distribution phases. This review aims to summarize the latest research findings on this topic in the context of various regional blocks performed for different surgeries and patient populations., Recent Findings: Research into local kinetics and systemic absorption of local anesthetics has chiefly been focused on novel fascial plane blocks, especially the erector spinae plane block, as these are increasingly adopted for regional anesthesia and pain management. As their clinical efficacy is very dependent on injection of large volumes of local anesthetic, doses over typically recommended limits are often administered., Summary: Fascial plane blocks are the regional anesthesia techniques in need of the most pharmacokinetic characterization, not only to better understand their complex mechanisms of action but also to avoid harm from excessive doses of local anesthetics. Further mapping of risk factors for systemic toxicity from administration in different block sites is crucial. Extremes of age and pregnancy are vulnerable patient populations but in whom regional anesthesia, including novel techniques, has been performed with few complications., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intravenous lidocaine is increasingly used as an analgesic adjunct during general anaesthesia. Lidocaine is highly protein-bound and changes to binding can alter drug efficacy or toxicity. We aimed to measure the effect of various propofol and lidocaine plasma concentration combinations on the protein binding and concentration of lidocaine in vitro., Methods: Known targeted concentrations of propofol and lidocaine were added to drug-free human plasma in vitro. Samples were prepared and analysed in various clinically relevant concentration combinations; propofol at 0, 2, 4 and 6 µg/mL, and lidocaine at 1, 3 and 5 µg/mL. The total and unbound concentrations of lidocaine were measured by ultra-high performance liquid chromatography-mass spectrometry and percentage protein binding was determined. Data were presented as mean and standard deviation (SD) and differences between groups analysed., Results: The overall mean protein binding of lidocaine was 68.8% (SD 5.5, range 57.5-80.9%). Beta regression analysis revealed no statistically significant difference in lidocaine percentage binding across a range of propofol and lidocaine concentration combinations., Conclusion: Propofol did not alter the unbound and free pharmacologically active proportion of lidocaine at different clinically targeted concentrations of propofol and lidocaine in plasma in vitro. The percentage of plasma protein binding of lidocaine in this study was consistent with previously published results., (Copyright © 2024 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Study Objective: HR18034, composed of the ropivacaine encapsulated in multi-lamellar, concentric circular structure liposomes as the major component and a small amount of free ropivacaine, has performed well in animal experiments and phase I clinical trials. This trial was to investigate the efficacy, safety, pharmacokinetic profile and the minimum effective dose of HR18034 for postoperative analgesia after hemorrhoidectomy compared with ropivacaine., Design: A multicenter, randomized, double-blind trial., Setting: 19 medical centers in China., Patients: 85 patients undergoing hemorrhoidectomy between October 2022 to November 2022., Interventions: Patients were randomly divided into HR 18034 190 mg group, 285 mg group, 380 mg group and ropivacaine 75 mg group, receiving single local anesthetic perianal injection for postoperative analgesia., Measurements: The primary outcome was the area under the resting state NRS score -time curve within 72 h after injection. The second outcomes included the proportion of patients without pain, the proportion of patients not requiring rescue analgesia, cumulative morphine consumption for rescue analgesia, etc. Safety was evaluated by adverse events incidence and plasma ropivacaine concentrations were measured to explore the pharmacokinetic characteristics of HR18034., Main Results: The areas under the NRS score (at rest and moving states)-time curve were significantly lower in HR 18034 380 mg group than ropivacaine 75 mg at 24 h, 48 h, and 72 h after administration. However, this superiority was not observed in HR18034 190 mg group and 285 mg group. There was no difference in cumulative morphine consumption for rescue analgesia between HR 18034 groups and ropivacaine group., Conclusions: HR 18034 380 mg showed superior analgesic efficacy and equivalent safety compared to ropivacaine 75 mg after hemorrhoidectomy, thus preliminarily determined as minimum effective dose., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2023. Published by Elsevier Inc.)

It remains unclear whether dosage adjustment of intravenous lidocaine is necessary during general anesthesia for elderly patients over 75 years old. This study aimed to investigate the effects of age on the pharmacokinetics (PK) and safety of intravenous lidocaine in patients undergoing general anesthesia. A total of 599 plasma samples were collected from 76 general anesthesia patients across three age groups: 18-64, 65-74, and ≥ 75 years. Lidocaine was administered intravenously at a dose of 1.5 mg/kg for the 18-64 and 65-74 years groups, while the dose was adjusted to 1.0 mg/kg for the ≥ 75 years group. The plasma concentrations of lidocaine and its active metabolites were measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were analyzed using a noncompartmental analysis. The results revealed no significant age-related differences in the PK of lidocaine and its metabolites. Among the three age groups, over 90 % of patient achieved a lidocaine concentration within a safe and effective range when the dosage was normalized to 1.5 mg/kg. In conclusion, age-based dosage adjustment was unnecessary for intravenous lidocaine in patients below 86 years undergoing general anesthesia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background: Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic drug products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established., Objective: To evaluate the ability of a clinical dOFM study to assess BE of topical products containing two moderately lipophilic drugs that have only minor differences in chemical and physical properties., Methods: The study included 20 healthy subjects. Four application sites on each thigh were treated with fixed dose lidocaine/prilocaine combination products, and dermal drug concentrations were monitored with two dOFM probes per application site for 12 h. A reference cream was compared to itself and to an approved generic cream (both serving as positive controls for BE), and to a gel (negative control). BE was established based on AUC 0to12h and C max using the scaled-average-BE approach. Systemic exposure of both drugs was assessed throughout the study., Results: BE was successfully demonstrated for the positive controls, and not for the negative control, for both drugs. The systemic exposure of both drugs was negligible., Conclusions: dOFM accurately demonstrated BE between bioequivalent topical creams, sensitively discriminated between different formulations and differentiated the cutaneous PK of both study drugs, even though they differ only slightly in chemical and physical properties. These results support the utility of dOFM as a cutaneous PK-based BE approach for topical lipophilic drugs, including lidocaine and prilocaine., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To determine (1) the dose of liposomal bupivacaine (LB) to eliminate grade 2 of 5 lameness, the (2) duration of analgesia of LB versus bupivacaine hydrochloride (BH), and (3) LB pharmacokinetics versus BH., Methods: A reversible lameness model was validated in conditioned Thoroughbred horses (n = 12), aged 3 to 10 years. A dose-response trial compared subjective and objective lameness following abaxial sesamoid block with 25 mg BH/nerve or 30, 60, or 133 mg LB/nerve (n = 3/group). The LB dose that eliminated lameness and reduced lameness for the longest was used for blinded, randomized, crossover pharmacokinetic/pharmacodynamic trials (n = 12/group). Data were analyzed using a paired t test or Wilcoxon signed-rank test, P < .05., Results: The 133-mg/nerve dose of LB eliminated lameness in 3 of 3 horses in the dose-response trial, and lameness returned at 6, 36, and 72 hours. In the pharmacokinetic/pharmacodynamic trials, time to return of lameness greater than or equal to starting lameness was longer for LB compared to BH on subjective (LB, 12 hours, 4 to 24 hours; BH, 4 hours, 4 to 12 hours) and objective (LB, 12 hours, 4 to 24 hours; BH, 4 hours, 2 to 6 hours) evaluations. The terminal half-life was not different between formulations (LB, 17.8 hours ± 10.1; BH, 12.4 hours ± 6.3); however, LB had increased area under the concentration-versus-time curve from time 0 to infinity (LB, 388 ng·h/mL ± 117; BH, 63 ng·h/mL ± 18) and mean residence time (LB, 17.6 hours ± 2.4; BH, 3.9 hours ± 1.6)., Conclusions: Liposomal bupivacaine analgesia duration was greater than BH, but the median time until lameness returned was only 12 hours. Bupivacaine is quantifiable in serum and urine beyond loss of clinical effect., Clinical Relevance: A single, high-dose injection of LB is not effective for providing perineural analgesia over several days. Bupivacaine is detectable after the effect of the drug has worn off.

Nanostructured lipid carriers (NLC) have emerged as innovative drug delivery systems, offering distinct advantages over other lipid-based carriers, such as liposomes and solid lipid nanoparticles. Benzocaine (BZC), the oldest topical local anesthetic in use, undergoes metabolism by pseudocholinesterase, leading to the formation of p -aminobenzoic acid, a causative agent for allergic reactions associated with prolonged BZC usage. In order to mitigate adverse effects and enhance bioavailability, BZC was encapsulated within NLC. Utilizing a 2 3 factorial design, formulations comprising cetyl palmitate (solid lipid), propylene glycol monocaprylate (liquid lipid), and Pluronic F68 as surfactants were systematically prepared, with variations in the solid/liquid lipid mass ratios (60:40-80:20%), total lipid contents (15-25%), and BZC concentrations (1-3%). The optimized formulation underwent characterization by dynamic light scattering, differential scanning calorimetry, Raman imaging, X-ray diffraction, small-angle neutron scattering, nanotracking analysis, and transmission electron microscopy (TEM)/cryo-TEM, providing insights into the nanoparticle structure and the incorporation of BZC into its lipid matrix. NLC BZC exhibited a noteworthy encapsulation efficiency (%EE = 96%) and a 1 year stability when stored at 25 °C. In vitro kinetic studies and in vivo antinociceptive tests conducted in mice revealed that NLC BZC effectively sustained drug release for over 20 h and prolonged the anesthetic effect of BZC for up to 18 h. We therefore propose the use of NLC BZC to diminish the effective anesthetic concentration of benzocaine (from 20 to 3% or less), thus minimizing allergic reactions that follow the topical administration of this anesthetic and, potentially, paving the way for new routes of BZC administration in pain management.

Aim: Management of procedural pain in burn care is challenging. Lidocaine-prilocaine cream 5%, eutectic mixture of local anesthetics (EMLA®), is a widely used, effective local anesthetic cream approved for normal intact skin, genital mucosa for superficial surgical procedures, and debridement of chronic leg ulcers. This comprehensive review aimed to determine the safety, analgesic efficacy, and effects of EMLA on burn pathophysiology to provide evidence-based clinical recommendations for introducing the topical anesthetic into burn care., Methods: The PRISMA guidelines were followed for conducting a systematic PubMed search to include all relevant preclinical and clinical studies, according to pre-specified eligibility criteria., Results: Fifteen studies were included in a qualitative synthesis, among which nine were human and six were animal studies. To date, safety and pharmacokinetic data on EMLA application in burns have been limited. Nevertheless, human studies indicated that EMLA is safe and provides adequate procedural-pain relief in adults when applied to smaller burns. Caution should be exercised when using EMLA in younger children, as systemic toxicity, pertaining to prilocaine-induced methemoglobinemia, has been reported owing to overdosing (high doses applied over large burn areas). Furthermore, animal studies demonstrate the potential beneficial effects of EMLA on burn pathophysiology such as anti-inflammatory, decreased capillary permeability to plasma proteins and edema formation, and improved tissue perfusion, which are factors that may impact burn wound progression., Conclusion: Current data on EMLA use in the management of procedural pain in small burns are sparse but suggest that EMLA is safe and effective in adults. Further clinical pharmacokinetic studies are warranted, especially for application on larger burn areas., (Copyright © 2024. Published by Elsevier Ltd.)

Study Objective: To investigate the timing of peak blood concentrations and potential toxicity when using a combination of plain and liposomal bupivacaine for thoracic fascial plane blocks., Design: Pharmacokinetic analysis., Setting: Operating room., Patients: Eighteen adult patients undergoing robotically-assisted mitral valve surgery., Interventions: Ultrasound-guided pecto-serratus and serratus anterior plane blocks using a mixture of 0.5% bupivacaine HCl up to 2.5 mg/kg and liposomal bupivacaine up to 266 mg., Measurements: Arterial plasma bupivacaine concentration., Main Results: Samples from 13 participants were analyzed. There was substantial inter-patient variability in plasma concentrations. A geometric mean maximum bupivacaine concentration was 1492 ng/ml (range 660 to 4650 ng/ml) at median time of 30 min after injection. In 4/13 (31%) patients, plasma bupivacaine concentrations exceeded our predefined 2000 ng/ml toxic threshold. A second much smaller peak was observed about 32 h after the injection. No obvious signs of local anesthetic toxicity were observed., Conclusions: Combined injection of plain and liposomal bupivacaine for pecto-serratus/serratus anterior plane blocks produced a biphasic pattern, with the highest arterial plasma concentrations observed within 30 min. Maximum concentrations exceeded the potential toxic threshold in nearly a third of patients, but without clinical evidence of toxicity. Clinicians should not assume that routine combinations of plain and liposomal bupivacaine for thoracic fascial plane blocks are inherently safe., Competing Interests: Declaration of competing interest Daniel I Sessler - is a consultant for Pacira Pharmaceuticals. Other authors have no conflicts of interest to declare. DIS is a consultant for Pacira Pharmaceuticals. The Division of Multi-specialty Anesthesiology conducts other research funded by Pacira, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pain, a complex and debilitating condition affecting millions globally, is a significant concern, especially in the context of post-operative recovery. This comprehensive review explores the complexity of pain and its global impact, emphasizing the modulation of voltage-gated sodium channels (VGSC or NaV channels) as a promising avenue for pain management with the aim of reducing reliance on opioids. The article delves into the role of specific NaV isoforms, particularly NaV 1.7, NaV 1.8, and NaV 1.9, in pain process and discusses the development of sodium channel blockers to target these isoforms precisely. Traditional local anesthetics and selective NaV isoform inhibitors, despite showing varying efficacy in pain management, face challenges in systemic distribution and potential side effects. The review highlights the potential of nanomedicine in improving the delivery of local anesthetics, toxins and selective NaV isoform inhibitors for a targeted and sustained release at the site of pain. This innovative strategy seeks to improve drug bioavailability, minimize systemic exposure, and optimize therapeutic outcomes, holding significant promise for secure pain management and enhancing the quality of life for individuals recovering from surgical procedures or suffering from chronic pain., (© 2024. Controlled Release Society.)

Lidocaine is generally recognized and preferred for local anaesthesia, but in addition, studies have described additional benefits of lidocaine in cancer therapy, inflammation reduction, and wound healing. These properties contribute to its increasing importance in dermatological applications, and not only in pain relief but also in other potential therapeutic outcomes. Therefore, the purpose of our study was to enhance lidocaine delivery through the skin. A stable nanostructured lipid carrier (NLC), as a passive permeation enhancer, was developed using a 2 3 full factorial design. The nanosystems were characterized by crystallinity behaviour, particle size, zeta potential, encapsulation efficiency measurements, and one of them was selected for further investigation. Then, NLC gel was formulated for dermal application and compared to a traditional dermal ointment in terms of physicochemical (rheological behaviour) and biopharmaceutical (qualitative Franz diffusion and quantitative Raman investigations) properties. The study also examined the use of 3D printed solid microneedles as active permeation enhancers for these systems, offering a minimally invasive approach to enhance transdermal drug delivery. By actively facilitating drug permeation through the skin, microneedles can complement the passive transport achieved by NLCs, thereby providing an innovative and synergistic approach to improving lidocaine delivery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Szilvia Berko reports article publishing charges was provided by University of Szeged (FundRef, Grant No. 6938). Ferhan Ayaydin reports financial support and equipment, drugs, or supplies were provided by EUs Horizon 2020 Research and Innovation Program (SGA No. 739593). Szilvia Berko reports financial support and equipment, drugs, or supplies were provided by TKP2021-EGA-32 has been implemented with the support provided by the Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: A novel external oblique intercostal block (EOIB) might have analgesic effects on T6-10 and be indicated for laparoscopic gastrectomy. However, EOIB effects on postoperative pain are unknown. We aim to generate evidence to support such EOIB application. We will compare the efficacy of EOIB and wound infiltration (WI) in a single-center, single-blind, randomized controlled trial., Methods: We will assess plasma concentrations of levobupivacaine after EOIB, its pharmacokinetics, and the pinprick test in patients randomly assigned to receive EOIB or WI before laparoscopic or robot-assisted gastric distal or total gastrectomy. The EOIB and WI will start after general anesthesia induction with 20 and 40 mL of 0.25% levobupivacaine per side, respectively, before skin closure. The outcomes will be numeric rating scale (NRS) scores at 12 h postoperatively (primary) and postoperative NRS scores at 2, 24, and 48 h; fentanyl application; QoR-15 scores on postoperative days 1, 2, and 7; and World Health Organization Disability Assessment Schedule 2.0 scores at 3 months (secondary)., Conclusions: We hope that our study will provide evidence to support EOIB application in laparoscopic surgery. Plasma concentrations will help determine levobupivacaine pharmacokinetics, which if similar to conventional nerve blocks, will indicate EOIB's safety.

Ropivacaine hydrochloride (RPL) is a local anesthetic agent that has been widely used for the treatment of pain during or after surgery. However, this drug is only available in parenteral dosage form and may contribute to the infiltration of RPL into the plasma, causing some undesirable side effects. Intradermal delivery of RPL using dissolving microneedles may become a promising strategy to deliver such drugs into the skin. This research aimed to develop RPL-loaded dissolving microneedles (DMN-RPLs) as a proof of the concept of intradermal delivery of a local anesthetic. The DMN-RPLs were fabricated using either centrifugation or air-pressurized chamber methods. Several polymers, such as poly(vinyl pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), and sodium hyaluronate (SH), were utilized for manufacturing the DMN-RPLs. The prepared DMN-RPLs were assessed for their thermal properties, chemical bonds, mechanical strength, insertion ability, skin-dissolution study, and drug content. Furthermore, in-skin deposition and dermatokinetic studies were also performed. The results showed that F9 (30 % w/w PVP-4 % w/w SH) and F10 (30 % w/w PVP-5 % w/w PVA) containing 5 % w/w of RPL were the most promising formulations, as shown by their needle height reduction (<10 %) and insertion depth (∼400 μm). Both formulations were also able to deliver more than 60 % of the RPL contained in the DMNs into the epidermis, dermis, and receiver compartment. This study, for the first time, has provided a proof concept to deliver RPL as a local anesthetic using DMNs and the intradermal route, aiming to minimize pain and discomfort during administration and improve the patient's experience., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Little is known about the pharmacodynamic characteristics of liposomal bupivacaine. Hypothesizing that they would not identify pharmacodynamic differences from plain bupivacaine during the initial period after administration, but would find better long-term pharmacodynamic characteristics, the authors designed a randomized, controlled, triple-blinded, single-center study in volunteers., Methods: Volunteers aged 18 to 55 yr (body mass index, 18 to 35 kg/m2) received two ulnar nerve blocks under ultrasound guidance. Using a crossover design with a washout phase of 36 days or more, one block was performed with liposomal and one with plain bupivacaine. Which came first was determined by randomization. Sensory data were collected by pinprick testing and motor data by thumb adduction, either way in comparison with the contralateral arm. Endpoints included success, time to onset, and duration of blockade. Residual efficacy was assessed by the volunteers keeping a diary. Statistical analysis included Wilcoxon signed-rank and exact McNemar's tests, as well as a generalized estimation equation model., Results: Successful sensory blockade was noted in 8 of 25 volunteers (32%) after liposomal and in 25 of 25 (100%) after plain bupivacaine (P < 0.0001). Significant differences emerged for time to onset, defined as 0% response to pinpricking in four of five hypothenar supply areas (P < 0.0001), and for time from onset to 80% or 20% in one of five areas (P < 0.001; P < 0.001). Carryover effects due to the randomized sequencing were unlikely (estimate, -0.6286; sequence effect, 0.8772; P = 0.474). Self-assessment greater than 3.5 days did reveal, for liposomal bupivacaine only, intermittent but unpredictable episodes of residual sensory blockade., Conclusions: The results show that liposomal bupivacaine is not a suitable "sole" drug for intraoperative regional anesthesia. Findings of its limited long-term efficacy add to existing evidence that a moderate effect, at best, should be expected on postoperative pain therapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Background: The establishment of optimal dosing regimens for intravenous (IV) lidocaine in the perioperative setting, aiming to balance effective pain relief with minimisation of potential side effects, is a topic of ongoing debate. This discussion stems from the significant variability in lidocaine's pharmacokinetic (PK) parameters and its relatively narrow safety margin. Population pharmacokinetic (popPK) modelling has emerged as a valuable tool for understanding the factors contributing to this observed variability in drug kinetics., Objectives: This systematic review compiles the existing knowledge on lidocaine's PK properties and published popPK models, with a focus on significant covariates., Methods: A systematic search on Cochrane CENTRAL, Medline, and EMBASE was performed from inception to June 2023. Original clinical studies that administered IV lidocaine to adults and performed PK analyses using a nonlinear mixed effects modelling approach were included. The quality of the included studies was assessed by compliance with the Clinical Pharmacokinetics (ClinPK) statement checklist., Results: Seven studies were included, which involved a diverse adult population, including both volunteers and patients with various comorbidities. Lidocaine PK was primarily characterised by a two- or three-compartment model. The volume of distribution at steady state ranged from 66 to 194 L, and the total clearance ranged from 22 to 49 L/h. Despite adjusting for significant covariates like heart failure status, alpha-1-acid glycoprotein, duration of lidocaine infusion, and body weight, each study revealed substantial variability in PK parameters. The potential impact of hepatic or renal function biomarkers on these PK parameters calls for further investigation. Incomplete reporting of key aspects of developed models may hinder the models' reliability and clinical application., Conclusion: The findings emphasise the importance of tailoring drug dosage to ensure the safe and effective use of intravenous lidocaine. Optimal design methodologies may be incorporated for a more efficient identification of important covariates. Utilising contemporary model evaluation methods like visual predictive checks and bootstrapping would enhance the robustness of popPK models and the reliability of their predictions. This comprehensive review advances our understanding of lidocaine's pharmacokinetics and lays the groundwork for further research in this critical area of perioperative pain management. Review protocol registered on 25 August 2023 in PROSPERO (CRD42023441113). This work was supported by the Fundamental Research Grant Scheme, the Ministry of Higher Education, Malaysia (FRGS/1/2020/SKK01/UM/02/2)., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra-high-performance liquid chromatography-tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) C max was 11.4 ± 6.0 ng/mL and mean t max was 11.3 ± 4.7 min. Mean t 1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500-4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects., (© 2024 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Objectives: Pecto-intercostal fascial block (PIFB) and rectus sheath block (RSB) have been combined to offer better analgesia for cardiac surgery patients, but safety of the analgesic protocol with a large volume of ropivacaine is uncertain., Methods: This is a prospective observational study at Peking University People's Hospital to investigate the pharmacokinetic profile of ropivacaine after combined regional blocks. Patients undergoing elective cardiac surgery by a median sternotomy were enrolled to receive bilateral PIFB and RSB with 70 mL 0.3% ropivacaine (total dose 210 mg). Blood was sampled at 5, 10, 15, 30, 60, 90 and 120 mins after blocks. Total blood concentration of ropivacaine for patients were measured., Results: Ten patients were enrolled and analyzed. The peak total ropivacaine concentration varied from 0.67 to 2.42 µg/mL. Time to reach the peak values mainly located between 10 and 30 mins after the performance. No patients had ropivacaine concentration values above toxic threshold (4.3 µg/mL), and there were no systemic toxicity symptoms during the perioperative period., Conclusions: PIFB combined with RSB in a general injection of 70 mL 0.3% ropivacaine does not give rise to toxic levels, and it is an effective and safe analgesic protocol for cardiac surgery patients.

Background: The aim of the present study was to predict the time to onset and duration of action of two local anesthetics (lidocaine and bupivacaine) based on experimental dimensions of a typical nerve and experimental octanol/water partition coefficients., Methods: We began our compilation of experimental data with a numerical solution of the Smoluchowski equation for the transfer of lidocaine and bupivacaine across the axon membrane in the region of the node of Ranvier (axolemma) and across the Schwann cell. The difference between the aqueous and lipid environments of the neuron was simulated by including the coordinate-dependent chemical potential. In the second step, the permeation rates calculated using the diffusion equation were used to solve a system of four ordinary differential equations. This approach allowed us to simulate the cellular environment for a longer time and to compare our model with pharmacokinetic properties (time to onset and duration of action) of local anesthetics from the literature. The behavior of local anesthetics under physiological conditions and in case of local acidosis was also simulated., Results: We demonstrated that local anesthetics cross the axolemma in a time span of less than 1 μs. The time to onset of action, controlled by diffusion from the epineurium to an axon with a typical distance of 500 μm, was 167 s and 186 s for lidocaine and bupivacaine, respectively. The calculated half-life, which is a measure of the duration of action, was 41 min and 328 min for lidocaine and bupivacaine, respectively., Conclusions: Duration of action is controlled by the storage capacity of lipophilic compartments around the axon, which is higher for bupivacaine but lower in local acidosis. For the latter case, the literature, including textbooks, provides a misinterpretation, namely that protonated species cannot penetrate the membrane., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Differences in neonatal pharmacokinetics are known to cause systemic accumulation of levobupivacaine with adverse effects during epidural analgesia. Therefore, it is not recommended to surpass 48 hours of administration in neonates. Free and total levobupivacaine levels are considered as predictors of toxicity., Objective: The aim of the LEVON pilot study was to detect the accumulation of levobupivacaine during epidural analgesia exceeding 48 hours in neonates., Methods: Ten neonates received a loading dose of levobupivacaine (1.25 mg/kg) followed by a continuous infusion (0.2 mg/kg/hour) epidurally. Free and total levobupivacaine concentrations were measured 0.5, 1, 6, 12, 36, 72 and 144 hours after the start of infusion. Cumulative doses of levobupivacaine, pain scores and clinical signs of toxicity were used for assessing efficacy and safety., Results: The median concentrations of total levobupivacaine were 586.0, 563.0, 837.5, 957.0, 1930.0, 708.5 and 357.5 ng/ml. The median concentrations of free levobupivacaine were 4.0, 3.6, 5.5, 3.6, 5.5, 0.8 and 0.0 ng/ml. Three patients reached concerning concentrations of total levobupivacaine. Levels of free levobupivacaine remained low. No signs of toxicity were observed., Conclusion: Caudal epidural analgesia with levobupivacaine lasting longer than 48 hours appears to be safe providing that free levobupivacaine levels are below the presumed threshold for toxicity (Tab. 1, Fig. 1, Ref. 29). Text in PDF www.elis.sk Keywords: free levobupivacaine, total levobupivacaine, neonate, caudal continuous epidural analgesia, postoperative pain.

Local anesthetics are used clinically for the control of postoperative pain management. This study aimed to develop chitosan (CS) with genipin (GP) hydrogels as the hydrophilic lipid shell loaded poly(ε-caprolactone) (PC) nanocapsules as the hydrophobic polymeric core composites (CS-GP/PC) to deliver bupivacaine (BPV) for the prolongation of anesthesia and pain relief. The swelling ratio, in vitro degradation, and rheological properties enhancement of CS-GP/PC polymeric hydrogel. The incorporation of PC nanocapsules into CS-GP hydrogels was confirmed by SEM, FTIR, and XRD analysis. Scanning electron microscopy results demonstrated that the CS-GP hydrogels and CS-GP/PC polymeric hydrogels have a porous structure, the pore dimensions being non-uniform with diameters between 25 and 300 μm. The in vitro drug release profile of CS-GP/PC polymeric hydrogel has been achieved 99.2 ± 1.12% of BPV drug release in 36 h. Cellular viability was evaluated using the CCK-8 test on 3T3 fibroblast cells revealed that the obtained CS-GP/PC polymeric hydrogel with BPV exhibited no obvious cytotoxicity. The CS-GP/PC polymeric hydrogel loaded with BPV showed significant improvement in pain response compared to the control group animals for at least 7 days. When compared with BPV solution, CS-GP hydrogel and CS-GP/PC polymeric hydrogel improved the skin permeation of BPV 3-fold and 5-fold in 24 h, respectively. In vitro and in vivo results pointed out PC nanocapsules loaded CS-GP hydrogel can act as effective drug carriers, thus prolonging and enhancing the anesthetic effect of BPV. Histopathological results demonstrated the excellent biodegradability and biocompatibility of the BPV-loaded CS-GP/PC polymeric hydrogel system on 7, 14, and 21 days without neurotoxicity.HIGHLIGHTSPreparation and characterization of CS-GP/PC polymeric hydrogel system.BPV-loaded CS-GP/PC exhibited prolonged in vitro release in PBS solution.Cytotoxicity of BPV-loaded CS-GP/PC polymeric hydrogel against fibroblast (3T3) cells.Development of CS-GP/PC a promising skin drug-delivery system for local anesthetic BPV.

Various techniques have been explored to prolong the duration and improve the efficacy of local anaesthetic nerve blocks. Some of these involve mixing local anaesthetics or adding adjuncts. We did a literature review of studies published between 01 May 2011 and 01 May 2021 that studied specific combinations of local anaesthetics and adjuncts. The rationale behind mixing long- and short-acting local anaesthetics to hasten onset and extend duration is flawed on pharmacokinetic principles. Most local anaesthetic adjuncts are not licensed for use in this manner and the consequences of untested admixtures and adjuncts range from making the solution ineffective to potential harm. Pharmaceutical compatibility needs to be established before administration. The compatibility of drugs from the same class cannot be inferred and each admixture requires individual review. Precipitation on mixing (steroids, non-steroidal anti-inflammatory drugs) and subsequent embolisation can lead to serious adverse events, although these are rare. The additive itself or its preservative can have neurotoxic (adrenaline, midazolam) and/or chondrotoxic properties (non-steroidal anti-inflammatory drugs). The prolongation of block may occur at the expense of motor block quality (ketamine) or block onset (magnesium). Adverse effects for some adjuncts appear to be dose-dependent and recommendations concerning optimal dosing are lacking. An important confounding factor is whether studies used systemic administration of the adjunct as a control to accurately identify an additional benefit of perineural administration. The challenge of how best to prolong block duration while minimising adverse events remains a topic of interest with further research required., (© 2021 Association of Anaesthetists.)

Many strategies have been developed to overcome the stratum corneum (SC) barrier, including functionalized nanostructures. Chemical penetration enhancers (CPEs) and cell-penetrating peptides (CPP) were applied to decorate nanostructured lipid carriers (NLC) for topical anesthetic and pain relief. A novel pyrenebutyrate (PB-PEG-DSPE) compound was synthesized by the amide action of the carboxylic acid group of PB with the amido groups of DSPE-PEG. PB-PEG-DSPE has a hydrophobic group, hydrophilic group, and lipid group. The lipid group can be inserted into NLC to form PB functional NLC. In order to improve the penetrability, TAT and PB multi-decorated NLC were designed for the delivery of lidocaine hydrochloride (LID) (TAT/PB LID NLC). The therapeutic effects of NLC in terms of in vitro skin penetration and in vivo in animal models were further studied. The size of TAT/PB LID NLC tested by DLS was 153.6 ± 4.3 nm. However, the size of undecorated LID NLC was 115.3 ± 3.6 nm. The PDI values of NLC vary from 0.13 ± 0.01 to 0.16 ± 0.03. Zeta potentials of NLC were negative, between -20.7 and -29.3 mV. TAT/PB LID NLC (851.2 ± 25.3 µg/cm 2 ) showed remarkably better percutaneous penetration ability than PB LID NLC (610.7 ± 22.1 µg/cm 2 ), TAT LID NLC (551.9 ± 21.8 µg/cm 2 ) ( p  < .05) and non-modified LID NLC (428.2 ± 21.4 µg/cm 2 ). TAT/PB LID NLC exhibited the most prominent anesthetic effect than single ligand decorated or undecorated LID NLC in vivo . The resulting TAT/PB LID NLC exhibited good skin penetration and anesthetic efficiency, which could be applied as a promising anesthesia system.

Background: The spread of spinal anesthesia was influenced by many factors, and the effect of body height on spinal anesthesia is still arguable. This study aimed to explore the impact of height on the spread of spinal anesthesia and the stress response in parturients., Methods: A total of ninety-seven parturients were allocated into two groups according to their height: the shorter group (body height was shorter than 158 cm) and taller group (body height was taller than 165 cm). Spinal anesthesia was performed with the same amount of 12 mg plain ropivacaine in mothers of different heights. The primary outcome of the study was the success or failure of the spinal anesthesia. The secondary outcomes of the study were stress response, time to T6 sensory level, the incidence of hypotension, the satisfaction of abdominal muscle relaxation and patient VAS scores., Results: The rate of successful spinal anesthesia in the shorter group was significantly higher than that in the taller group (p = 0.02). The increase of maternal cortisol level in the shorter group was lower than that in the taller group at skin closure (p = 0.001). The incidence of hypotension (p = 0.013), time to T6 sensory block (p = 0.005), the quality of abdominal muscle relaxation (p <  0.001), and VAS values in stretching abdominal muscles and uterine exteriorization (p <  0.001) in the shorter group were significantly different from those in the taller group. Multivariate analysis showed that vertebral column length (p <  0.001), abdominal girth (p = 0.022), amniotic fluid index (p = 0.022) were significantly associated with successful spinal anesthesia., Conclusions: It's difficult to use a single factor to predict the spread of spinal anesthesia. Patient's vertebral column length, amniotic fluid index and abdominal girth were the high determinant factors for predicting the spread of spinal anesthesia., Trials Registration: ChiCTR-ROC-17012030 ( Chictr.org.cn ), registered on 18/07/2017., (© 2021. The Author(s).)

Alpinia galanga oil (AGO) has an anesthetic activity but its water insoluble property limits its clinical applications. The aim of the present study was to develop a self-nanoemulsifying drug delivery system of AGO (SNEDDS-AGO) to avoid the use of organic solvent and investigate AGO transportation pathway and anesthetic activity. Three optimized formulations from a contour plots of droplet size; SNEDDS-AGO-1, SNEDDS-AGO-2, and SNEDDS-AGO-3, composed of AGO, Miglyol 812, Cremophor RH 40, Capmul MCM EP, and ethanol at the ratios of 40:10:35:10:5, 40:20:15:20:5, and 60:10:15:10:5, respectively were selected as they possessed different droplet size of 62 ± 0.5, 107 ± 2.8, and 207 ± 4.3 nm, respectively. It was found that the droplet size played an important role in fish anesthesia. SNEDDS-AGO-3 showed the longest anesthetic induction time (270 sec) (p < 0.03). Transportation pathway and skin permeation of SNEDDS-AGO-2 were investigated using nile red labelled AGO and detected by fluorescence microscope. AGO was found mostly in brain, gills, and skin suggesting that the transportation pathway of AGO in zebrafish is passing through the gills and skin to the brain. SNEDDS-AGO formulations showed significantly higher permeation through the skin than AGO ethanolic solution. In conclusion, SNEDDS is a promising delivery system of AGO., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Liposomal bupivacaine (LB) is a long-acting formulation of bupivacaine. The safety and efficacy of LB has been demonstrated across surgical procedures. However, pharmacokinetic (PK) parameters and safety of LB in the Chinese population have not been assessed., Methods: In this single-arm, single center, phase 1, open-label study, PK and safety of local infiltration with LB 266 mg were assessed in healthy Chinese adults. Eligible participants were aged 18 to 55 years with biologic parents and grandparents of Chinese ethnicity, in generally good health (i.e., no clinically significant abnormalities), and with a body mass index (BMI) 19.0 to 24.0 kg/m 2 (inclusive) and body weight ≥ 50 kg., Results: Participants (N = 20) were predominantly men (80 %); mean age was 32 years; and mean BMI was 21.8 kg/m 2 . After LB administration, mean plasma levels of bupivacaine rapidly increased during the first hour and continued to increase through 24 h; plasma levels then gradually decreased through 108 h followed by a monoexponential decrease through 312 h. Geometric mean maximum plasma concentration was 170.9 ng/mL; the highest plasma bupivacaine concentration detected in any participant was 374.0 ng/mL. Twenty-two treatment-emergent adverse events were reported (mild, n = 21; moderate, n = 1)., Conclusions: After single-dose administration of LB, PK measures were similar to a previously reported profile in US adults. The highest observed peak plasma concentration of bupivacaine was several-fold below the plasma concentration threshold accepted as being associated with neurotoxicity or cardiotoxicity (2000-4000 ng/mL). These data support that LB is well tolerated and safe in individuals of Chinese descent., Trial Registration: NCT04158102 (ClinicalTrials.gov identifier), Date of registration: November 5, 2019., (© 2021. The Author(s).)

Suspension-based matrix transdermal delivery systems (TDSs) are specialized systems that maintain a continuous driving force for drug delivery over prolonged wear. The pressure-sensitive adhesive (PSA) is the most critical constituent of such systems. Our study aimed to determine the effect of different mixing methods on the performance of silicone PSA-based suspension TDSs. Lidocaine suspension TDSs were prepared using conventional slow rotary mixing, high-speed homogenization, bead-mill homogenization, vortex shaking, and by an unguator. Resultant TDSs were tested for tack, shear, and peel properties and correlated to coat weight, content uniformity, microstructure, and in vitro permeation across dermatomed human skin. Every mixing method tested caused a significant reduction in peel. However, bead-mill homogenization resulted in significant loss of all adhesive properties tested, while unguator-mixed TDSs retained most properties. Good linear correlation (R 2 = 1.000) between the shear properties of the TDSs with the average cumulative amount of lidocaine permeated after 24 h was observed, with no significant difference between percutaneous delivery from slow rotary-mixed systems (1334 ± 59.21 μg/cm 2 ) and unguator-mixed systems (1147 ± 108.3 μg/cm 2 ). However, significantly lower delivery from bead-mill homogenized systems (821.1 ± 28.00 μg/cm 2 ) was noted. While many factors affect TDS performance, careful consideration must also be given to the processing parameters during development as they have been shown to affect the resultant system's therapeutic efficacy. Extensive mixing with bead-mill homogenization demonstrated crystallization of drug, loss in adhesive properties, coat weight, and film thickness, with reduced transdermal delivery of lidocaine from the prepared system.

Background: Ropivacaine is commonly used in local infiltration anaesthesia (LIA) as pain management after total knee arthroplasty (TKA). Although considered safe, no studies evaluated the pharmacokinetics of high-dose ropivacaine infiltration in simultaneous bilateral TKA., Methods: We studied 13 patients undergoing unilateral and 15 undergoing bilateral TKA. Standard LIA technique was used with ropivacaine 0.2%, 200 ml (400 mg) injected peri-articularly in each knee. Free and total plasma concentrations of ropivacaine were measured within 24 h using liquid chromatography-mass spectrometry. A population pharmacokinetic model was built using non-linear mixed-effects models., Results: Peak free ropivacaine concentration was 0.030 (0.017-0.071) μg ml -1 (mean [99% confidence interval]) vs 0.095 (0.047-0.208) μg ml -1 , and peak total ropivacaine concentration was 0.756 (0.065-1.222) μg ml -1 vs 1.695 (0.077-3.005) μg ml -1 for unilateral and bilateral TKA, respectively. The pharmacokinetics was ascribed a one-compartment model with first-order absorption. The main identified covariates were protein binding, allometrically scaled body weight on clearance and volume, and unilateral or bilateral surgery on volume., Conclusions: This is the first study to investigate the pharmacokinetics of free and total ropivacaine after unilateral and bilateral TKA. A population model was successfully built and peak free ropivacaine concentration stayed below previously proposed toxic thresholds in patients undergoing unilateral and bilateral TKA receiving LIA with high-dose ropivacaine., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04702282., Competing Interests: Declarations of interest The authors declare that they have no conflicts of interest., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Currently, the influences of free terminal groups (hydroxyl, carboxyl and ester) of PLGA on encapsulating active pharmaceutical ingredient are relatively ambiguous even though PLGA types were defined as critical quality attributes in vast majority of design of experiment process. In this study, emulsion method combined with premix membrane emulsification technique has been used to encapsulate ropivacaine (RVC), a small molecule local anesthetic in clinical. Based on the narrow particle size distribution, the influences and mechanisms of the terminal groups on properties of ropivacaine loaded microspheres have been investigated in detail. It was found that microspheres prepared by PLGA with hydroxyl or ester groups exhibited lower encapsulation efficiency but faster in vitro release rate than that of carboxyl groups. In the meanwhile, on microcosmic level analysis by quartz crystal microbalance with dissipation, atomic force microscope and confocal laser scanning microscopy, we attributed this distinction to the specific interaction between ropivacaine and different terminal groups. Subsequently, the reaction activation centers were verified by density functional simulation calculation and frontier molecular orbital theory at molecular level. Additionally, pharmacokinetics and pharmacodynamic research of infiltration anesthesia model were performed to compare sustained release ability, duration and intensity of the anesthetic effect in vivo. Finally, potential safety and toxicity were evaluated by the biochemical analysis. This study not only provides a novel mechanism of drug encapsulation process but also potential flexible selections in terms of various anesthesia indications in clinical., (Copyright © 2021. Published by Elsevier B.V.)

Hyperbaric 2% prilocaine is increasingly used for spinal anesthesia. It is the only local anesthetic metabolized to o-toluidine, a human bladder carcinogen. Increase of o-toluidine hemoglobin adducts, a marker of o-toluidine ability to modify the DNA structure, was described following subcutaneous injection. In this prospective cohort study we aimed to assess and quantify o-toluidine hemoglobin adducts and urinary o-toluidine after a single intrathecal dose of hyperbaric prilocaine.10 patients undergoing surgery received 50 mg of hyperbaric prilocaine intrathecally. Blood and urine samples were collected before injection and up to 24 h later (Hospital Braine l'Alleud-Waterloo, Braine l'Alleud, Belgium). Urinary o-toluidine and o-toluidine hemoglobin adducts were measured by tandem mass-spectrometry after gas-chromatographic separation (Institute of the Ruhr-Universität, Bochum Germany). The trial was registered to ClinicalTrials.gov (NCT03642301; 22-08-2018)Intrathecal administration of 50 mg of hyperbaric prilocaine leads to a significant increase of o-toluidine hemoglobin adducts (0.1 ± 0.02-11.9 ± 1.9 ng/g Hb after 24 h, p = 0.001). Peak of urinary o-toluidine was observed after 8 h (0.1 ± 0.1-460.5 ± 352.8 µg/L, p = 0.001) and declined to 98 ± 66.8 µg/L after 24 h (mean ± SD)Single intrathecal administration of hyperbaric prilocaine leads to a systemic burden with o-toluidine and o-toluidine hemoglobin adducts. O-toluidine-induced modifications of DNA should be examined and intrathecal hyperbaric prilocaine should not be proposed to patients chronically exposed to o-toluidine.Clinical trial number and registry URL NCT03642301.

Background: This prospective, randomised, observer-blinded study has been conducted in patients undergoing procedures of the lower extremities to evaluate the time to complete block resolution of 2-chloroprocaine 1% at three intrathecal doses (30, 40 and 50 mg)., Methods: After informed consent, we enrolled 45 male and female patients, aged 18-65 years, ASA score I-II, BMI 18-32 kg/m 2 , undergoing elective lower limb procedures lasting ≤40 min and with a requested dermatomeric level of sensory block ≥ T12. The patients were randomised in a 1:1:1 ratio to receive Chloroprocaine HCl 1% at one of the three different intrathecal doses (Group 30 = 30 mg, Group 40 = 40 mg or Group 50 = 50 mg). The progression and regression of both sensory and motor blocks were evaluated blindly. Urine and venous blood samples were collected for pharmacokinetic analysis., Results: Times to regression of spinal blocks were 1.76 ± 0.35 h, 2.13 ± 0.46 h and 2.23 ± 0.38 h, in Group 30, 40 and 50 respectively: the 30 mg dose showed a significantly faster resolution of spinal block than the 40 mg (p = 0.034) and the 50 mg (p = 0.006). Time to readiness for surgery was significantly reduced with the dose of 50 mg when compared to dose of 30 mg (p = 0.0259)., Conclusions: The doses of 50 mg and 40 mg yielded a longer resolution of spinal block than the dose of 30 mg. Nevertheless, the dose of 30 mg resulted in a higher secondary failure rate., Trial Registration: Registration of clinical trial: clinicaltrials.gov ( NCT02481505 ).

Lidocaine has not been associated with cancer in humans despite 8 decades of therapeutic use. Its metabolite, 2,6-xylidine, is a rat carcinogen, believed to induce genotoxicity via N-hydroxylation and DNA adduct formation, a non-threshold mechanism of action. To better understand this dichotomy, we review literature pertaining to metabolic activation and genotoxicity of 2,6-xylidine, identifying that it appears resistant to N-hydroxylation and instead metabolises almost exclusively to DMAP (an aminophenol). At high exposures (sufficient to saturate phase 2 metabolism), this may undergo metabolic threshold-dependent activation to a quinone-imine with potential to redox cycle producing ROS, inducing cytotoxicity and genotoxicity. A new rat study found no evidence of genotoxicity in vivo based on micronuclei in bone marrow, comets in nasal tissue or female liver, despite high level exposure to 2,6-xylidine (including metabolites). In male liver, weak dose-related comet increases, within the historical control range, were associated with metabolic overload and acute systemic toxicity. Benchmark dose analysis confirmed a non-linear dose response. The weight of evidence indicates 2,6-xylidine is a non-direct acting (metabolic threshold-dependent) genotoxin, and is not genotoxic in vivo in rats in the absence of acute systemic toxic effects, which occur at levels 35 × beyond lidocaine-related exposure in humans., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography-mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated., (© 2020 John Wiley & Sons Ltd.)

Background: Intercostal nerve blocks with liposomal bupivacaine are commonly used for thoracic surgery pain management. However, dose scheduling is difficult because the pharmacokinetics of a single-dose intercostal injection of liposomal bupivacaine has never been investigated. The primary aim of this study was to assess the median time to peak plasma concentration (Tmax) following a surgeon-administered, single-dose infiltration of 266 mg of liposomal bupivacaine as a posterior multilevel intercostal nerve block in patients undergoing posterolateral thoracotomy., Methods: We chose a sample size of 15 adults for this prospective observational study. Intercostal injection of liposomal bupivacaine was considered time 0. Serum samples were taken at the following times: 5, 15, and 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours. The presence of sensory blockade, rescue pain medication, and pain level were recorded after the patient was able to answer questions., Results: Forty patients were screened, and 15 patients were enrolled in the study. Median (interquartile range [IQR]) Tmax was 24 (12) hours (confidence interval [CI], 19.5-28.5 hours) with a range of 15 minutes to 48 hours. The median (IQR) peak plasma concentration (Cmax) was 0.6 (0.3) μg/mL (CI, 00.45-0.74 μg/mL) in a range of 0.3-1.2. The serum bupivacaine concentration was undetectable (<0.2 μg/mL) at 96 hours in all patients. There was significant variability in reported pain scores and rescue opioid medication across the 15 patients. More than 50% of patients had return of normal chest wall sensation at 48 hours. All patients had resolution of nerve blockade at 96 hours. No patients developed local anesthetic toxicity., Conclusions: This study of the pharmacokinetics of liposomal bupivacaine following multilevel intercostal nerve blockade demonstrates significant variability and delay in systemic absorption of the drug. Peak serum concentration occurred at 48 hours or sooner in all patients. The serum bupivacaine concentration always remained well below the described toxicity threshold (2 μg/mL) during the 96-hour study period.

Background: Surgical procedure usually causes serious postoperative pain and poor postoperative pain management negatively affects quality of life, function and recovery time. We aimed to investigate the role of wound infiltration with ropivacaine as an adjuvant to patient controlled analgesia (PCA) in postoperative pain control for patients undergoing transforaminal lumbar interbody fusion., Methods: One hundred twelve patients undergoing lumbar fusion were retrospectively reviewed and divided into two groups (ropivacaine and control groups) according to whether received wound infiltration with ropivacaine or not. Visual Analogue Scale (VAS) score, analgesics consumption, number of patients requiring rescue analgesic, hospital duration and incidence of complications were recorded. Surgical trauma was assessed using operation time, intraoperative blood loss and incision length., Results: The amount of sufentanil consumption in ropivacaine group at 4 h postoperatively was lower than that of control group (24.5 ± 6.0 μg vs 32.1 ± 7.0 μg, P < 0.001) and similar results were observed at 8, 12, 24, 48 and 72 h postoperatively(P < 0.001). Fewer patients required rescue analgesia within 4 to 8 h postoperatively in ropivacaine group (10/60 vs 19/52, P = 0.017). Length of postoperative hospital durations were shorter in patients receiving ropivacaine infiltration compared to control cohorts (6.9 ± 0.9 days vs 7.4 ± 0.9 days, P = 0.015). The incidence of PONV in ropivacaine group was lower than that in control group (40.4% vs 18.3%, P = 0.01). However, VAS scores were similar in two groups at each follow-up points postoperatively, and no difference was observed(P > 0.05)., Conclusion: Wound infiltration with ropivacaine effectively reduces postoperative opioid consumption and PONV and may be a useful adjuvant to PCA to improve recovery for patients undergoing lumbar spine surgery.

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT 1A , α 2 -receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na + currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A hybrid micelle based mobile phase was used to develop and validate a liquid chromatographic method for the separation and quantification of two local anesthetics namely; lidocaine hydrochloride (LID), and bupivacaine hydrochloride (BPV) in presence of the frequently co administered vasopressors phenyl ephrine (PHR) and ephedrine (EPH). Optimization of chromatographic separation conditions was performed applying experimental one factor at a time tool, and design of experiment, where the retention behavior of all analytes using both optimization protocols was in accordance. Chromatographic separation was carried on a C8 column operating at 40 °C at a flow rate of 1.5 mL/min. using a mobile phase consisting of 0.18 M sodium dodecyl sulphate, 10% acetonitrile, containing 0.3% triethyl amine and adjusted to pH 7 using 2 M ortho phosphoric acid, adopting UV detection at 230 nm. The proposed method was fully validated and applied to both in vitro and in vivo analysis of rat blood samples. The pharmacokinetics of both LID and BPV was followed when they were solitary injected or when co administered with either PHR or EPH. Moreover, the in vitro spiked experiment was also subjected to documented bio-analytical validation procedures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In clinical practice, lidocaine is used as local anesthetic for the management of post-operative pain. The commercial formulation including gels, injections and ointments showed short duration of action (1 to 2 h). In this paper, the efforts have being made to develop tailored lidocaine-microemulsion (o/w), which on penetration in the skin layer cause micro-depots formation due to destabilization of the microemulsion system. To identify the microemulsion region, pseudo ternary diagrams were constructed using Capmul MCM as oil, Pluronic F68 as tri-block surfactant, polyethylene glycol 200 as co-surfactant at 1:4 and 1:6 ratios (S:Co-S). The selected 5%w/v lidocaine loaded microemulsion [Ld-ME-2(1:4)] was stable in thermodynamic test and during shelf life period (3 months). In ex vivo permeability study, the lidocaine release from Ld-ME-2(1:4) microemulsion was sustained in comparison to the marketed lidocaine ointment. The skin irritation study confirmed the safety of lidocaine loaded microemulsion. Tail flick test showed improved and sustain local anaesthetic effect in comparison to the market ointment. The improved efficacy of microemulsion system, was due to high penetration in the skin layer due to local precipitation of lidocaine from microemulsion. The findings suggest that the tailored microemulsion could be a potential strategy to prolong the local anaesthesia.

Microemulsion is the preferred vehicle for local anesthetics; however, the toxicity and irritation associated with a quantity use of surfactants (S) and co-surfactants (CS), i.e., medium- or short-chain alcohols, restrict its commercial application. In this study, efforts have been made to enlarge the CS-free microemulsion area by mixing olive oil (OL) with α-linolenic acid (ALA) and linoleic acid (LA), and by using vitamin E succinate (VES) as an auxiliary oil. Through Box-Behnken design and the optimization of nondominated sorting genetic algorithm II, the optimal microemulsion formulation (M E0 ) with a large steady-state simultaneous permeation rate (J s ) and skin retention was screened as 3.23% OL, 0.45% ALA, 1.81% LA, 0.91% VES, 13.60% S, 5% lidocaine and water. Three percent ethanol was screened as a permeability enhancer for the hydrogel of M E0 , which showed a statistical increase in J s and skin retention through the abdominal skin of guinea pigs. The optimized formulation had desirable characterization, good stability and negligible irritation. The large J s and skin retention were well reflected in the pinprick test, wherein intensity of anesthetic effect and duration of action were increased significantly over the commercial cream. The developed CS-free microemulsion hydrogel with low S could be a promising strategy for the topical delivery of lidocaine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Local anaesthetics (LAs) are commonly used in surgery, especially in dentistry. They cause a transitory inhibition of nerve signal due to the blockade of the voltage-gated sodium channels. LAs are administrated alone or with vasoconstriction agents, such as adrenaline. Toxicity of LAs is associated to neurological and cardiovascular alterations. Tachycardia, arrhythmia, tremors, tonic-clonic seizure and respiratory depression (at high doses) are the main symptoms of intoxication by LAs. Lidocaine, articaine and mepivacaine are among the most used anaesthetics. This study aimed to fully validated a new method for the simultaneous detection of articaine and mepivacaine in whole blood. Sample treatment consisted in a liquid-liquid extraction with phosphate buffer (pH 8, 0.1 M) and ethyl-acetate. Analysis was performed by liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode (transitions: articaine, 285→8658 m/z; mepivacaine, 247→9870 m/z; lidocaine - internal standard -, 235→8658 m/z). The method proved to be highly sensitive with limit of quantifications for articaine and mepivacaine of 0.8 and 0.1 ng/mL, respectively. Accuracy and precision were always within the acceptance criteria. The new procedure was also successfully applied to a preliminary pharmacokinetics study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To evaluate bupivacaine concentrations in maternal plasma and transfer into breast milk in women undergoing liposomal bupivacaine infiltration in the transversus abdominis plane after cesarean birth., Methods: Prospective cohort study of healthy pregnant women who underwent cesarean birth at term followed by a transversus abdominis plane block using 52 mg bupivacaine hydrochloride 0.25% (20 mL) and 266 mg liposomal bupivacaine 1.3% (20 mL). Simultaneous blood and milk samples were collected in a staggered fashion, three to four samples per patient at the following timepoints after block administration: 2, 6, 12, 24, 48, 72, and 96 hours. Quantification of bupivacaine was performed by liquid chromatography-tandem mass spectrometry. Neonatal drug exposure was modeled by calculating milk/plasma area under the curve (AUC) ratios, neonatal dosage, and relative neonatal dosage of bupivacaine at each sampling time., Results: Thirty patients were enrolled. Concentrations in breast milk peaked at 6 hours (mean 58 ng/mL), followed by constant and steady decline to low levels at 96 hours (mean 5.2 ng/mL). Maternal plasma concentrations had two peaks, first at 6 hours (mean 155.9 ng/mL) and then at 48 hours (mean 225.8 ng/mL), followed by steady decline. Milk/plasma AUC0-t ratios ranged between AUC0-2 of 0.45 (80% CI 0.38-0.52) and AUC0-96 of 0.15 (80% CI 0.14-0.17). Neonatal dosage ranged between a mean of 355.9 ng/kg at 0-2 hours and a mean of 15,155.4 ng/kg at 0-96 hours. Relative neonatal dosage was less than 1% at all time intervals. No serious adverse reactions occurred in any neonate., Conclusion: Bupivacaine is excreted in breast milk after local infiltration of liposomal bupivacaine and bupivacaine hydrochloride mixture into transversus abdominis plane blocks after cesarean birth. Relative neonatal dosages of less than 1% (less than 10% is considered to be unlikely to be of clinical concern) suggest minimal risks for breastfeeding healthy, term neonates after the administration of this combination of local anesthetics to mothers., Clinical Trial Registration: ClinicalTrials.gov, NCT03526419.

Background: Levobupivacaine is commonly used during transversus abdominis plane (TAP) block in pediatric patients. However, the dosing regimen is still empirical, and the pharmacokinetic properties of levobupivacaine are not considered. Here, the pharmacokinetics of levobupivacaine during an ultrasound-guided TAP block were evaluated to optimize dosing regimen, regarding the between-subject variability (BSV) and the volume of levobupivacaine injected., Method: The clinical trial (prospective, randomized, double-blind study protocol) was conducted in 40 children aged 1-5 years, who were scheduled for inguinal surgery. Each patient received 0.4 mg/kg of levobupivacaine with a volume of local anesthesia solution adjusted to 0.2 mL/kg of 0.2% or 0.4 mL/kg of 0.1% levobupivacaine. Blood samples were collected at 5, 15, 20, 25, 30, 45, 60, and 75 minutes after the block injection. The population pharmacokinetic analysis was performed using the NONMEM software., Results: From the pharmacokinetic parameters obtained, median Cmax, tmax,, and area under the concentration versus time curve were 0.315 mg/L, 17 minutes, and 41 mg/L·min, respectively. BSV of clearance was explained by weight. At the dose regimen of 0.4 mg/kg, none of the infants showed signs of toxicity, but in 13 patients, TAP block failed. After analysis, BSV for absorption rate constant, distribution volume, and clearance were 81%, 47%, and 41%, respectively. Residual unexplained variability was estimated to be 14%., Conclusions: For improved efficiency in the pediatric population, the dose of levobupivacaine should be greater than 0.4 mg/kg. Children's weight should be considered to anticipate any risk of toxicity.

Levobupivacaine is a long-acting amide local anaesthetic used in analgesia and anaesthesia. Like other local anaesthetic drugs, levobupivacaine exhibits effects on motor and sensory nerves by inhibiting the opening of voltage-gated sodium channels, and hence propagation of neuronal action potentials. Levobupivacaine is the S(-) stereoisomer of dextrobupivacaine, although both are used commercially in the racemic form bupivacaine. A favourable safety and drug effect profile for levobupivacaine has led to widespread use. Levobupivacaine is generally well tolerated but dose adjustment is important in populations such as paediatrics and the elderly. The pharmacokinetic properties of levobupivacaine are similar to that of bupivacaine; both extensively metabolised in the liver, and excreted in the urine and faeces. In vitro, animal model and human studies confirm a lower risk of cardiac and central nervous system toxicity with levobupivacaine compared with bupivacaine. Clinical trials of relative potency are impaired by the variability in chosen endpoints for sensory and motor function blockade, but clinically significant differences in potency are minor, with most clinical trials showing similar duration and quality of anaesthesia between levo- and racemic bupivacaine. In practice, levobupivacaine is most commonly used in regional anaesthesia, neuraxial anaesthesia and local infiltration analgesia. This review includes an appraisal of evidence from clinical trials of the pharmacokinetic and pharmacodynamic properties of levobupivacaine.

Pain management in veterinary patients is a crucial component of appropriate patient care. Multimodal analgesia that includes both systemically and locally/regionally administered drugs is generally the most effective approach to providing pain relief. Local anaesthetic drugs used in local and regional blockade are unique in that they can completely block the transmission of pain (in conscious patients) or nociceptive (in anaesthetized patients) signals, thereby providing profound analgesia. In addition, local and regional administration of drugs, when compared with systemic bolus administration, generally results in a lower incidence of dose-related adverse effects. Due to the potential to provide profound analgesia and the high safety margin (when used correctly) of this drug class, local anaesthetics are recommended as part of the analgesic protocol in the majority of patients undergoing surgical procedures or suffering traumatic injuries. This manuscript, Part 1 of a two-part instalment, emphasizes the importance of using local and regional anaesthesia as a component of multimodal analgesia, provides a review of the basic pharmacokinetics/pharmacodynamics of local anaesthetic drugs in general, lists information on commonly used local anaesthetic drugs for local and regional blockade in dogs and cats, and briefly introduces the novel liposome-encapsulated bupivacaine (NOCITA®). Part 2 is a review of local and regional anaesthetic techniques used in dogs and cats (Grubb & Lobprise, 2020)., (© 2020 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

Finding an ideal anesthetic agent for postoperative pain control, with long action and low side effects, is still a challenge. Local anesthetics have potential for such application if their time of action is improved. This work introduces a new hybrid formulation formed by the association of a nanostructured lipid carrier with a biopolymeric system to encapsulate bupivacaine (BVC). The hybrid formulation was physicochemical and structurally characterized by DLS, TEM, DSC, XRD and FTIR-ATR, and it remained stable for 12 months at room temperature. In vivo analgesia and imaging tests showed that the hybrid system was able to modulate the release, and to increase the concentration of BVC at the site of action, by forming a nanogel in situ. Such nanogel improved over 5 times (>24 h) the anesthesia duration, when compared to free BVC at clinical (0.5%) doses. Therefore, this novel in situ-forming nanogel shows great potential to be used in postsurgical pain control, improving the action of BVC, without losing its versatility of (infiltrative) application., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Lidocaine, as the only local anesthetic approved for intravenous administration in the clinic, can relieve neuropathic pain, hyperalgesia, and complex regional pain syndrome. Intravenous injection of lidocaine during surgery is considered as an effective strategy to control postoperative pain, but the mechanism of its analgesic effect has not been fully elucidated. This paper intends to review recent studies on the mechanism of the analgesic effect of lidocaine. To the end, we conducted an electronic search of the PubMed database. The search period was from 5 years before June 2019. Lidocaine was used as the search term. A total of 659 documents were obtained, we included 17 articles. These articles combined with the 34 articles found by hand searching made up the 51 articles that were ultimately included. We reviewed the analgesic mechanism of lidocaine in the central nervous system.

Objective: To evaluate selected effects of midazolam or lidocaine administered prior to etomidate for co-induction of anesthesia in healthy dogs., Study Design: Prospective crossover experimental study., Animals: A group of 12 healthy adult female Beagle dogs., Methods: Dogs were premedicated with intravenous (IV) butorphanol (0.3 mg kg -1 ), and anesthesia was induced with etomidate following midazolam (0.3 mg kg -1 ), lidocaine (2 mg kg -1 ) or physiologic saline (1 mL) IV. Heart rate (HR), arterial blood pressure, respiratory rate (f R ) and intraocular pressure (IOP) were recorded following butorphanol, after co-induction administration, after etomidate administration and immediately following intubation. Baseline IOP values were also obtained prior to sedation. Etomidate dose requirements and the presence of myoclonus, as well as coughing or gagging during intubation were recorded. Serum cortisol concentrations were measured prior to premedication and 6 hours following etomidate administration., Results: Blood pressure, f R and IOP were similar among treatments. Blood pressure decreased in all treatments following etomidate administration and generally returned to sedated values following intubation. HR increased following intubation with midazolam and lidocaine but remained stable in the saline treatment. The dose of etomidate (median, interquartile range, range) required for intubation was lower following midazolam (2.2, 2.1-2.6, 1.7-4.1 mg kg -1 ) compared with lidocaine (2.7, 2.4-3.6, 2.2-5.1 mg kg -1 , p = 0.012) or saline (3.0, 2.8-3.8, 1.9-5.1 mg kg -1 , p = 0.015). Coughing or gagging was less frequent with midazolam compared with saline. Myoclonus was not observed. Changes in serum cortisol concentrations were not different among treatments., Conclusions and Clinical Relevance: Midazolam administration reduced etomidate dose requirements and improved intubation conditions compared with lidocaine or saline treatments. Neither co-induction agent caused clinically relevant differences in measured cardiopulmonary function, IOP or cortisol concentrations compared with saline in healthy dogs. Apnea was noted in all treatments following the induction of anesthesia and preoxygenation is recommended., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)