RESUMEN
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.
Asunto(s)
Anestésicos Locales , Preparaciones de Acción Retardada , Liberación de Fármacos , Levobupivacaína , Meloxicam , Dolor Postoperatorio , Dolor Postoperatorio/tratamiento farmacológico , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/química , Animales , Meloxicam/administración & dosificación , Meloxicam/farmacocinética , Masculino , Levobupivacaína/administración & dosificación , Fosfolípidos/química , Fosfolípidos/administración & dosificación , Ratas Sprague-Dawley , Bupivacaína/administración & dosificación , Bupivacaína/farmacocinética , Bupivacaína/química , Bupivacaína/análogos & derivados , Analgésicos/administración & dosificación , Analgésicos/química , Analgésicos/farmacocinética , Geles , Sinergismo FarmacológicoRESUMEN
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.
Asunto(s)
Administración Intravenosa , Anestesia General , Anestésicos Locales , Lidocaína , Humanos , Lidocaína/administración & dosificación , Lidocaína/farmacocinética , Lidocaína/sangre , Anciano , Persona de Mediana Edad , Anestesia General/métodos , Masculino , Adulto , Femenino , Anciano de 80 o más Años , Adulto Joven , Estudios Prospectivos , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/sangre , Adolescente , Factores de Edad , Relación Dosis-Respuesta a DrogaRESUMEN
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.
Asunto(s)
Anestesia de Conducción , Anestésicos Locales , Bloqueo Nervioso , Humanos , Anestesia de Conducción/métodos , Anestesia de Conducción/efectos adversos , Anestésicos Locales/farmacocinética , Anestésicos Locales/administración & dosificación , Anestésicos Locales/efectos adversos , Bloqueo Nervioso/métodos , Bloqueo Nervioso/efectos adversos , EmbarazoRESUMEN
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.
Asunto(s)
Anestésicos Locales , Quemaduras , Combinación Lidocaína y Prilocaína , Quemaduras/complicaciones , Quemaduras/terapia , Humanos , Combinación Lidocaína y Prilocaína/farmacocinética , Combinación Lidocaína y Prilocaína/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/administración & dosificación , Anestésicos Locales/efectos adversos , Animales , Dolor Asociado a Procedimientos Médicos/etiología , Prilocaína/farmacocinética , Prilocaína/administración & dosificación , Lidocaína/farmacocinética , Lidocaína/administración & dosificaciónRESUMEN
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 23 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. NLCBZC 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 NLCBZC 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 NLCBZC 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.
Asunto(s)
Anestésicos Locales , Benzocaína , Portadores de Fármacos , Lípidos , Benzocaína/administración & dosificación , Benzocaína/química , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Anestésicos Locales/farmacocinética , Anestésicos Locales/farmacología , Portadores de Fármacos/química , Animales , Lípidos/química , Ratones , Nanoestructuras/química , Liberación de Fármacos , Masculino , Nanopartículas/químicaRESUMEN
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.
Asunto(s)
Anestésicos Locales , Hemorreoidectomía , Liposomas , Dolor Postoperatorio , Ropivacaína , Humanos , Ropivacaína/administración & dosificación , Ropivacaína/efectos adversos , Ropivacaína/farmacocinética , Método Doble Ciego , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Masculino , Femenino , Persona de Mediana Edad , Anestésicos Locales/administración & dosificación , Anestésicos Locales/efectos adversos , Anestésicos Locales/farmacocinética , Hemorreoidectomía/efectos adversos , Hemorreoidectomía/métodos , Adulto , Resultado del Tratamiento , Dimensión del Dolor , China , Canal Anal/cirugía , Relación Dosis-Respuesta a DrogaRESUMEN
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.
Asunto(s)
Anestésicos Locales , Gastrectomía , Nervios Intercostales , Laparoscopía , Levobupivacaína , Bloqueo Nervioso , Dolor Postoperatorio , Humanos , Laparoscopía/métodos , Bloqueo Nervioso/métodos , Gastrectomía/métodos , Levobupivacaína/administración & dosificación , Dolor Postoperatorio/prevención & control , Dolor Postoperatorio/tratamiento farmacológico , Método Simple Ciego , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Femenino , Persona de Mediana Edad , Masculino , Anciano , Adulto , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Nanomedicina , Manejo del Dolor , Bloqueadores del Canal de Sodio Activado por Voltaje , Humanos , Bloqueadores del Canal de Sodio Activado por Voltaje/administración & dosificación , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinética , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Manejo del Dolor/métodos , Animales , Canales de Sodio Activados por Voltaje/metabolismo , Anestésicos Locales/administración & dosificación , Anestésicos Locales/uso terapéutico , Anestésicos Locales/farmacocinética , Dolor/tratamiento farmacológicoRESUMEN
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 (â¼400 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.
Asunto(s)
Anestésicos Locales , Sistemas de Liberación de Medicamentos , Agujas , Ropivacaína , Piel , Ropivacaína/administración & dosificación , Ropivacaína/farmacocinética , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/química , Animales , Piel/metabolismo , Administración Cutánea , Liberación de Fármacos , Absorción Cutánea , Povidona/química , Prueba de Estudio Conceptual , Solubilidad , Ácido Hialurónico/química , Ácido Hialurónico/administración & dosificación , Microinyecciones/métodos , Masculino , Ratas Sprague-Dawley , Alcohol Polivinílico/químicaRESUMEN
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 23 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.
Asunto(s)
Administración Cutánea , Anestésicos Locales , Lidocaína , Permeabilidad , Absorción Cutánea , Piel , Lidocaína/administración & dosificación , Lidocaína/farmacocinética , Lidocaína/química , Absorción Cutánea/efectos de los fármacos , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/química , Animales , Piel/metabolismo , Lípidos/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Nanoestructuras/química , Nanoestructuras/administración & dosificación , Porcinos , Agujas , Tamaño de la Partícula , GelesRESUMEN
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 AUC0to12h and Cmax 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.
Asunto(s)
Administración Cutánea , Anestésicos Locales , Absorción Cutánea , Piel , Equivalencia Terapéutica , Humanos , Masculino , Adulto , Anestésicos Locales/farmacocinética , Anestésicos Locales/administración & dosificación , Femenino , Piel/metabolismo , Adulto Joven , Combinación Lidocaína y Prilocaína/farmacocinética , Combinación Lidocaína y Prilocaína/administración & dosificación , Lidocaína/farmacocinética , Lidocaína/administración & dosificación , Crema para la Piel/farmacocinética , Crema para la Piel/administración & dosificación , Prilocaína/farmacocinética , Prilocaína/administración & dosificación , Perfusión/métodosRESUMEN
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).
Asunto(s)
Administración Intravenosa , Anestésicos Locales , Lidocaína , Modelos Biológicos , Humanos , Lidocaína/farmacocinética , Lidocaína/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/administración & dosificación , Adulto , Infusiones IntravenosasRESUMEN
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.
Asunto(s)
Anestésicos Locales , Bupivacaína , Estudios Cruzados , Liposomas , Bloqueo Nervioso , Humanos , Bupivacaína/administración & dosificación , Bupivacaína/farmacocinética , Adulto , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Masculino , Femenino , Bloqueo Nervioso/métodos , Adulto Joven , Persona de Mediana Edad , Adolescente , Método Doble Ciego , Nervio Cubital/efectos de los fármacos , Ultrasonografía Intervencional/métodosRESUMEN
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.
Asunto(s)
Anestésicos Locales , Bupivacaína , Liposomas , Válvula Mitral , Bloqueo Nervioso , Procedimientos Quirúrgicos Robotizados , Ultrasonografía Intervencional , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anestésicos Locales/administración & dosificación , Anestésicos Locales/sangre , Anestésicos Locales/farmacocinética , Bupivacaína/administración & dosificación , Bupivacaína/sangre , Bupivacaína/farmacocinética , Liposomas/administración & dosificación , Válvula Mitral/cirugía , Bloqueo Nervioso/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/efectos adversosRESUMEN
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) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 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.
Asunto(s)
Bupivacaína , Tonsilectomía , Adulto , Humanos , Bupivacaína/farmacocinética , Anestésicos Locales/farmacocinética , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Tonsilectomía/efectos adversos , Tonsilectomía/métodos , Dimensión del DolorRESUMEN
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.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Bloqueo Nervioso , Humanos , Amidas/farmacocinética , Analgésicos , Anestésicos Locales/farmacocinética , Bloqueo Nervioso/métodos , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/prevención & control , Ropivacaína , Estudios ProspectivosRESUMEN
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.
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Bupivacaína , Lidocaína , Bupivacaína/farmacocinética , Lidocaína/farmacocinética , Anestésicos Locales/farmacocinética , Fibras Nerviosas MielínicasRESUMEN
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.
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Analgesia Epidural , Recién Nacido , Humanos , Levobupivacaína , Analgesia Epidural/efectos adversos , Anestésicos Locales/efectos adversos , Anestésicos Locales/farmacocinética , Bupivacaína/efectos adversos , Proyectos Piloto , Dimensión del Dolor , Método Doble Ciego , Dolor PostoperatorioRESUMEN
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.
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Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacología , Bupivacaína/administración & dosificación , Bupivacaína/farmacología , Hidrogeles/química , Administración Tópica , Anestésicos Locales/efectos adversos , Anestésicos Locales/farmacocinética , Animales , Bupivacaína/efectos adversos , Bupivacaína/farmacocinética , Supervivencia Celular/efectos de los fármacos , Química Farmacéutica , Liberación de Fármacos , Estabilidad de Medicamentos , Femenino , Iridoides/química , Nanocápsulas/química , Manejo del Dolor/métodos , Poliésteres/química , Ratas , Ratas Sprague-Dawley , ReologíaRESUMEN
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.