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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.)

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.)

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.

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.)

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.

Objective: To compare the perioperative effects and pharmacoeconomics of peripheral nerve blocks (PNBs) versus fentanyl target-controlled infusion (fTCI) in dogs undergoing tibial plateau levelling osteotomy (TPLO)., Study Design: Randomized clinical study., Animals: A total of 39 dogs undergoing unilateral TPLO., Methods: After acepromazine and methadone, anaesthesia was induced with propofol and maintained with isoflurane. Dogs were allocated to group fTCI [target plasma concentration (TPC) 1 ng mL -1 ] or group PNB (nerve stimulator-guided femoral-sciatic block using 0.2 and 0.1 mL kg -1 of levobupivacaine 0.5%, respectively). If nociceptive response occurred, isoflurane was increased by 0.1%, and TPC was increased by 0.5 ng mL -1 in group fTCI; a fentanyl bolus (1 μg kg -1 ) was administered in group PNB. During the first 24 postoperative hours, methadone (0.2 mg kg -1 ) was administered intramuscularly according to the Short Form Glasgow Composite Pain Scale, or if pain was equal to 5/24 or 4/20 for two consecutive assessments, or if the dog was non-weight bearing. The area under the curve (AUC) of pain scores, cumulative postoperative methadone requirement, food intake and pharmacoeconomic implications were calculated., Results: Incidence of bradycardia (p = 0.025), nociceptive response to surgery (p = 0.041) and AUC of pain scores (p < 0.0001) were greater in group fTCI. Postoperatively, 16/19 (84.2%) and eight/20 (40%) dogs in groups fTCI and PNB, respectively, were given at least one dose of methadone (p = 0.0079). Food intake was greater in group PNB (p = 0.049). Although total cost was not different (p = 0.083), PNB was more cost-effective in dogs weighing >15 kg., Conclusions and Clinical Relevance: Compared with group fTCI, incidence of bradycardia, nociceptive response to surgery, postoperative pain scores, cumulative methadone requirement were lower, and food intake was greater in group PNB, with an economic advantage in dogs weighing >15 kg., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Learning Objectives: After reading this article, the participant should be able to: 1. Describe the fundamental concepts of multimodal analgesia techniques and how they target pain pathophysiology. 2. Effectively educate patients on postoperative pain and safe opioid use. 3. Develop and implement a multimodal postoperative analgesia regimen., Summary: For many years, opioids were the cornerstone of postoperative pain control, contributing to what has become a significant public health concern. This article discusses contemporary approaches to multimodal, opioid-sparing postoperative pain management in the plastic surgical patient.

Background: Intraperitoneal (IP) administration of local anesthetics is used in adults and children for postoperative analgesia after laparoscopic surgery. Population pharmacokinetics (PK) of IP bupivacaine has not been determined in children. Objectives of this study were (1) to develop a population PK model to compare IP bupivacaine administered via manual bolus atomization and micropump nebulization and (2) to assess postoperative morphine requirements after intraoperative administration. We hypothesized similar PK profiles and morphine requirements for both delivery methods., Methods: This was a prospective, sequential, observational study. After institutional review board (IRB) approval and written informed parental consent, 67 children 6 months to 6 years of age undergoing robot-assisted laparoscopic urological surgery received IP bupivacaine at the beginning of surgery. Children received a total dose of 1.25 mg/kg bupivacaine, either diluted in 30-mL normal saline via manual bolus atomization over 30 seconds or undiluted bupivacaine 0.5% via micropump nebulization into carbon dioxide (CO2) insufflation tubing over 10-17.4 minutes. Venous blood samples were obtained at 4 time points between 1 and 120 minutes intraoperatively. Samples were analyzed by liquid chromatography with mass spectrometry. PK parameters were calculated using noncompartmental and compartmental analyses. Nonlinear regression modeling was used to estimate PK parameters (primary outcomes) and Mann-Whitney U test for morphine requirements (secondary outcomes)., Results: Patient characteristics between the 2 delivery methods were comparable. No clinical signs of neurotoxicity or cardiotoxicity were observed. The range of peak plasma concentrations was 0.39-2.44 µg/mL for the manual bolus atomization versus 0.25-1.07 μg/mL for the micropump nebulization. IP bupivacaine PK was described by a 1-compartment model for both delivery methods. Bupivacaine administration by micropump nebulization resulted in a significantly lower Highest Plasma Drug Concentration (Cmax) and shorter time to reach Cmax (Tmax) (P < .001) compared to manual bolus atomization. Lower plasma concentrations with less interpatient variability were observed and predicted by the PK model for the micropump nebulization (P < .001). Adjusting for age, weight, and sex as covariates, Cmax and area under the curve (AUC) were significantly lower with micropump nebulization (P < .001). Regardless of the delivery method, morphine requirements were low at all time points. There were no differences in cumulative postoperative intravenous/oral morphine requirements between manual bolus atomization and micropump nebulization (0.14 vs 0.17 mg/kg; P = .85) measured up to 24 hours postoperatively., Conclusions: IP bupivacaine administration by micropump nebulization demonstrated lower plasma concentrations, less interpatient variability, low risk of toxicity, and similar clinical efficacy compared to manual bolus atomization. This is the first population PK study of IP bupivacaine in children, motivating future randomized controlled trials to determine efficacy.

Background: Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations., Methods: The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer., Results: Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system., Conclusions: All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.

Total joint replacement is a widely used and successful surgical approach. Approximately 7 million US adults are currently living with a hip or knee replacement. However, the surgical procedures for total joint replacement are associated with significant postoperative pain, and current strategies do not adequately address this pain, which leads to patient dissatisfaction, reduced mobility, and increased risk of opioid addiction. We hypothesized that the ultra-high-molecular-weight polyethylene (UHMWPE) bearing surfaces used in total joint prosthetics could provide sustained release of the local anesthetic bupivacaine to provide relief from joint pain for an extended period of time after surgery. In this paper, we describe the production of bupivacaine-loaded UHMWPE (BPE) and measure the in vitro bupivacaine release kinetics of BPE. We found that bupivacaine could be released from BPE at clinically relevant rates for up to several days and that BPE possesses antibacterial effects. Therefore, bupivacaine-loaded UHMWPE is a promising material for joint replacement prostheses, and future studies will evaluate its safety and efficacy in in vivo models. STATEMENT OF SIGNIFICANCE: Total joint replacement is associated with significant pain and risk of infection. In our paper, we introduce bupivacaine-loaded ultra-high-molecular-weight polyethylene (BPE), which releases bupivacaine, a pain-treating drug, at doses comparable to currently used doses. Additionally, BPE inhibits the growth of infection-causing bacteria. Therefore, BPE may be able to reduce both postsurgical pain and risk of infection, potentially treating two of the most prominent complications associated with total joint replacement. To our knowledge, this is the first development of a material that can address both complications, and devices incorporating BPE would represent a significant advancement in joint arthroplasty prosthetics. More generally, the incorporation of therapeutic agents into ultra-high-molecular-weight polyethylene could impact many orthopedic procedures owing to its ubiquity., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Postoperative pain is a common form of acute pain that has been treated commonly by local anesthetics through regional nerve blocking. In this study, a series of experiments were conducted using rats to investigate the pharmacokinetic, distribution, and efficacy of a temperature responsive hydrogel-based drug delivery device (PF-72) containing ropivacaine (0.75%) for extended relief of postoperative pain by allowing the prolonged release of ropivacaine. When the ropivacaine was administered using PF-72, its concentration-time curve (AUC last ) and peak concentration (C max ) were 577.0 h*ng/mL and 271.9 ng/mL, respectively. In contrast when the ropivacaine solution was administered using saline solution, its AUC last and C max were 982.8 h*ng/mL and 423.6 ng/mL, respectively. In the tissue distribution study, the peak concentration and mean area under the curve of the ropivacaine in injection area (target tissue) were found about 2-fold higher in the case of PF-72 compared with the case of conventional ropivacaine solution. These results clearly demonstrate the capability of PF-72 hydrogel to retain the ropivacaine at the injection site for an extended period. Effective extended (at least 24 h) pain relief of ropivacaine administered using PF-72 was found in the pharmacodynamic study of prolonged analgesic effect. The results of this study indicated that local drug delivery by PF-72 hydrogel formulation may be an effective method to achieve extended relief of pain. Other advantages of ropivacaine administration using PF-72 include reduced systemic side effects and high localization of a drug in target tissues., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Regional anesthesia has been advocated as adjunct to a multimodal analgesia regimen. The limited duration of the action of available local anesthetics limits their application. Catheters, perineural or IV adjuvants, or repetition of blocks are modalities available to prolong the analgesic benefit of LRA. All of these approaches have their shortcomings. New extended release local anesthetic formulations may provide time-efficient and longer duration of analgesia with a single injection. Available data on liposomal bupivacaine are promising, and more recently, it has been FDA approved for use in interscalene brachial plexus block but not for other nerve blocks at this time. Several other new formulations and compounds, such as HTX-011, Neosaxitoxin, and SABER-Bupivacaine, are also being developed and tested for their safety and analgesic potential., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The avoidance of post-herniorrhaphy pain can be challenging for hernia repair and has the greatest impact on patient's quality of life, health care utilisation and cost to society. Visceral meshes, functionalised with an efficient drug carrier system - hydroxypropyl beta-cyclodextrin polymer (polyHPβCD) coating, were developed to give a prolonged intraperitoneal analgesic drug release. We attempted to evaluate the in vivo pain-relief efficacy of ropivacaine loaded polyHPβCD functionalised polyester meshes in a rat model of visceral pain induced by colorectal distension (CRD). In vivo safety, pharmacokinetic profile and biodegradation were measured via histological analysis and high-performance liquid chromatography, etc. The results confirmed that the polyHPβCD on the functionalised meshes has a high adsorption capacity of ropivacaine and resulted in a sustained drug release in rats after mesh implantation. This was further reaffirmed by an elevated pain threshold (30%) up to 4 days after implantation in the rat CRD model, compared to 1-2 days for non-adapted meshes. Neither polyHPβCD nor the loaded ropivacaine had a major impact on the inflammatory response. This evidence strongly suggests that polyHPβCD functionalised visceral mesh could be a promising approach for post-operative pain control by improving the intraperitoneal drug delivery and bioavailability., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Lidocaine is an amide local anaesthetic initially used intravenously as an antiarrhythmic agent. At some point it was proposed that intravenous lidocaine (IVL) had an analgesic effect that could be potentially beneficial in perioperative settings. Since these preliminary reports, a large body of evidence confirmed that IVL had anti-inflammatory and opiate-sparing effects, a combination of characteristics leading to an array of effects such as a decrease in postoperative pain and opiate consumption, and a reduction in the duration of digestive ileus. Additional studies demonstrated IVL to possess antithrombotic, antimicrobial and antitumoral effects. Beneficial effects of IVL have been characterized in abdominal surgery but remain controversial in other types of surgeries. Because the quality of evidence was limited, due to inconsistency, imprecision and study quality, recent conclusions from meta-analysis pooling together all types of surgery stated the uncertainty about IVL benefits. Additional indications such as the prevention of propofol-induced injection pain, prevention of hyperalgesia, protection against bronchial reactivity by bronchotracheal relaxation during surgery, and the increase in depth of general anaesthesia have since emerged. IVL is rapidly distributed in the body and metabolized by the liver. With the commonly recommended doses, lidocaine's therapeutic index remains very high and the plasma concentrations stay largely below the cardiotoxic and neurotoxic threshold levels, a notion that may be used by clinicians to draw conclusions on the benefit-risk profile of IVL in comparison to other analgesic strategies. The purpose of this review is to address the pharmacokinetic and pharmacodynamic properties of lidocaine in healthy and pathological conditions.

Background: Transversus abdominis plane block is increasingly used for post-Caesarean section analgesia. Cases of toxicity and the limited pharmacokinetic information during pregnancy motivated this study. The objective of the study was to characterise and compare the pharmacokinetics of levobupivacaine with epinephrine in tranversus abdominis plane block, in post-Caesarean section patients and healthy volunteers., Methods: After approval by the Ethics Committee, we collected data from 12 healthy parturients after elective Caesarean section (Study 1) and data from 11 healthy male volunteers from a previous study (Study 2). Transversus abdominus plane block was performed under ultrasound guidance. The following injectates were used: levobupivacaine 0.25%, 20 ml with epinephrine 5 μg ml -1 (Study 1) per side; 20 ml of the same solution (unilateral block) (study 2). The plasma venous concentration of levobupivacaine was measured serially for 90 min. Pharmacokinetic parameters (volume of distribution, clearance, and absorption half-life) were estimated using a non-linear mixed effects model (NONMEM). Simulation in 1000 patients estimated the maximum concentration and the time to reach it after bilateral transversus abdominis plane block., Results: Venous concentrations were below toxic levels (2.62 mg L -1 ). Levobupivacaine volume of distribution after Caesarean section was higher than in healthy volunteers [172 L (70 kg) -1 (95% confidence interval: 137-207) vs 94.3 L (70 kg) -1 (95% CI: 62-128); P<0.01]. Clearance and absorption half-life were similar. The simulation showed that maximum levobupivacaine concentration is lower and occurs later in postpartum patients (P<0.01). Postoperative analgesia was effective., Conclusions: Postpartum women reached relatively low plasma concentrations of levobupivacaine after transversus abdominal plane block given a volume of distribution 80% higher than volunteers, which could confer a greater margin of safety., Clinical Trial Registration: NCT02852720., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Effective postoperative pain control is essential for the recovery of surgical patients. However, long-term analgesia can seldom be achieved with the existing medications. The injectable implants prepared by biodegradable polyesters can be conveniently used during the surgery and slowly release analgesics near the operative incision for a long period., Method: In this study, we prepared lidocaine hydrochloride (Lido-HCl)-loaded injectable poly(lacticco- glycolic acid) (PLGA) implants for prolonged analgesia. The optimized formulation of this injectable implant sustained drug release for up to 5 days, with a cumulative release of 85.8%±1.9% in the in vitro release experiment., Results: The in vivo release of the implants in rats showed good consistency with the in vitro release. The pharmacokinetics of Lido-HCl implants in the thigh muscle of rats was evaluated, and the AUC0-120 h of the Lido-HCl implant was 11.4 times that of Lido-HCl solution, indicating a good sustained release function of the implant. The pharmacodynamics of Lido-HCl implants was measured by the hot plate test. The Lido-HCl solution blocked the sciatic nerve of rats for less than 4 h, while the Lido-HCl implant efficiently blocked the nerve for approximately 120 h., Conclusion: These results demonstrated that the PLGA-based injectable implant is a suitable carrier for postoperative pain control., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Total knee arthroplasty (TKA) is an operation with moderate to severe postoperative pain. The Fast-Track models employ local infiltration techniques with anaesthetics at high volumes (100-150ml). We proposed a genicular nerve block with low volume of local anaesthetic. The aim of our study is to evaluate the periarticular distribution of these blocks in a fresh cadaver model and to describe the technique in a preliminary group of patients submitted to TKA., Materials and Methods: In the anatomical phase, 4 genicular nerves (superior medial, superior lateral, inferior medial and inferior lateral) were blocked with 4ml of local anaesthetic with iodinated contrast and methylene blue in each (16ml in total). It was performed on a fresh cadaver and the distribution of the injected medium was evaluated by means of a CT-scan and coronal anatomical sections on both knees. The clinical phase included 12 patients scheduled for TKA. Ultrasound-guided block of the 4 genicular nerves was performed preoperatively and their clinical efficacy evaluated by assessing pain after the reversal of the spinal block and at 12h after the block. Pain was measured using the numerical scale and the need for rescue analgesia was evaluated., Results: A wide periarticular distribution of contrast was observed by CT-scan, which was later evaluated in the coronal sections. The distribution followed the joint capsule without entering the joint, both in the femur and in the tibia. The pain after the reversal of the subarachnoid block was 2±1, requiring rescue analgesia in 42% of the patients. At 12h, the pain according to the numerical scale was 4±1, 33% required rescue analgesia., Conclusion: The administration of 4ml of local anaesthetic at the level of the 4 genicular nerves of the knee produces a wide periarticular distribution. Our preliminary data in a series of 12 patients undergoing TKA seems to be clinically effective. Nevertheless, extensive case series and comparative studies with local infiltration techniques with anaesthetics are needed to support these encouraging results., (Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Objectives: A relatively new technique to reduce postoperative pain for total knee arthroplasty is to inject a mixture of 266 mg of liposomal bupivacaine and 125 mg of 0.25% bupivacaine HCl with epinephrine 1:300,000 around the knee joint at the time of surgery. Currently, no publications report serum bupivacaine concentrations over time after periarticular injection of liposomal mixed with free bupivacaine. This information is important to ensure safe serum bupivacaine concentrations are maintained especially when considering supplemental or rescue peripheral nerve blocks., Methods: A total of 40 subjects scheduled for primary unilateral total knee arthroplasty with intraoperative periarticular injection of the liposomal bupivacaine and bupivacaine HCl mixture were included. Total serum bupivacaine concentrations were measured after the last injection at selected time points and calculated by gas chromatography. Quantile regression techniques were used to analyze the data over time. This study is registered with ClinicalTrials.gov (ID NCT02626559)., Results: Peak serum concentration ranged from 0.17 to 1.2 μg/mL and occurred from 10 minutes to 48 hours. Across all time points, the 48-hour interval had the highest mean concentration of total serum bupivacaine at 0.55 μg/mL (SD, 0.27). Quantile regression showed total serum bupivacaine concentrations increased over the 48 hours measured. None of the participants demonstrated signs or symptoms of local anesthetic toxicity., Conclusions: Total serum concentrations of bupivacaine after periarticular administration of liposomal bupivacaine mixed with bupivacaine HCl remained below the described toxicity threshold (2.5 μg/mL) within the first 48 hours, and no patients demonstrated signs or symptoms of toxicity. However, peak serum concentration time was not achieved within the 48-hour interval. Additional studies are needed to describe the course of serum bupivacaine levels after 48 hours and to ascertain the risk of toxicity when combining this method of periarticular injection with peripheral nerve blocks.

Although local anesthesia is commonly applied for pain relief, there are several issues such as its short duration of action and low effectiveness at the areas of inflammation due to the acidic pH. The presence of excessive amount of reactive oxygen species (ROS) is known to induce inflammation and aggravate pain. To resolve these issues, we developed a redox-active injectable gel (RIG) with ROS-scavenging activity. RIG was prepared by mixing polyamine-b-poly(ethylene glycol)-b-polyamine with nitroxide radical moieties as side chains on the polyamine segments (PMNT-b-PEG-b-PMNT) with a polyanion, which formed a flower-type micelle via electrostatic complexation. Lidocaine could be stably incorporated in its core. When the temperature of the solution was increased to 37°C, the PIC-type flower micelle transformed to gel. The continuous release of lidocaine from the gel was observed for more than three days, without remarkable initial burst, which is probably owing to the stable entrapment of lidocaine in the PIC core of the gel. We evaluated the analgesic effect of RIG in carrageenan-induced arthritis mouse model. Results showed that lidocaine-loaded RIG has stronger and longer analgesic effect when administered in inflamed areas. In contrast, while the use of non-complexed lidocaine did not show analgesic effect one day after its administration. Note that no effect was observed when PIC-type flower micelle without ROS-scavenging ability was used. These findings suggest that local anesthetic-loaded RIG can effectively reduce the number of injection times and limit the side effects associated with the use of anti-inflammatory drugs for postoperative pain management., Statement of Significance: 1. We have been working on nanomaterials, which effectively eliminate ROS, avoiding dysfunction of mitochondria in healthy cells. 2. We designed redox injectable gel using polyion complexed flower type micelle, which can eliminates ROS locally. 3. We could prepare local anesthesia-loaded redox injectable gel (lido@RIG). 4. Drug release could be extended by local administration of lido@RIG. 5. Deprotonation of lidocaine improved anesthetic effect because ROS were eliminated locally by RIG. 6. Local inflammation could be also suppressed by lido@RIG., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

We evaluated blood bupivacaine concentrations in children having a single-shot sciatic and continuous femoral blocks after anterior cruciate ligament repair. Dried blood spot samples were analyzed for bupivacaine levels at 0, 5, 15, 30, 60, and 120 minutes and 4, 24, and 48 hours. The highest 99% upper confidence interval limit was 135 ng/mL at the 4-hour evaluation point. The 99% upper confidence interval was below potentially toxic levels (1500 ng/mL) across all sampling times. The risk of local anesthetic toxicity in pediatric patients receiving single-shot sciatic and continuous femoral nerve blocks is very low.

Introduction: Liposomal bupivacaine, a prolonged-release formulation of bupivacaine hydrochloride, is indicated for infiltration into the surgical site for postsurgical analgesia. Results from previous total knee arthroplasty (TKA) studies suggest that analgesic efficacy associated with liposomal bupivacaine may be impacted by variability in infiltration technique. The PILLAR study is designed to assess liposomal bupivacaine efficacy in TKA using a standardized infiltration protocol. Materials and Methods/Design: This phase 4, multicenter, randomized, double-blind, controlled, parallel-group study will compare the safety and efficacy of infiltration with liposomal bupivacaine versus standard bupivacaine for postsurgical pain control in adults undergoing primary unilateral TKA. All subjects will receive a standardized pre-surgical analgesic regimen, and will be randomized to receive either liposomal bupivacaine 266 mg/20 mL (admixed with standard bupivacaine 0.5% 20 mL and expanded to a total volume of 120 mL) or bupivacaine 0.5% 20 mL (expanded to a total volume of 120 mL). The study drug will be infiltrated using six syringes (prefilled with 20 mL of study drug solution) to deliver 1-1.5 mL infusions into prespecified periarticular tissues. All subjects will receive standardized postsurgical analgesia and access to rescue medication. The co-primary efficacy endpoints are area under the curve of visual analog scale pain intensity scores from 12-48 hours postsurgery and total postsurgical opioid consumption from 0-48 hours. Secondary efficacy endpoints include other pain assessments, time to first use of rescue medication, discharge readiness, use of skilled nursing facilities, and hospital length of stay. Safety will be evaluated based on adverse events., Discussion/conclusion: The use of a standardized protocol comparing infiltration of equal volumes of the study drug, designed by experienced investigators to ensure complete coverage of all areas innervating the surgical site while minimizing leakage of study drug, will help define the role of liposomal bupivacaine in the setting of TKA.

The hypothesis was that agents delivered intra-articularly after knee arthroscopy will be diluted by residual arthroscopic fluid. Diagnostic arthroscopy was performed on six cadaver knees. Each procedure was followed by an intra-articular injection of a dye solution. Intra-articular aspirates were gathered from three locations. With significance set at p < .05, the aspirates were compared with the initial dye concentration and with each other. No significant difference was noted among the sites, indicating that no specific knee area was exposed to a higher dye concentration. There was a significant difference in dye concentration of the aspirates when compared with the dye's initial concentration. The concentration of fluid injected intra-articularly after arthroscopy was diluted by 27%. These data indicate that agents injected into the knee postarthroscopy are significantly diluted. In vitro and in vivo experiments evaluating chondrotoxicity of various anesthetic agents may not accurately reflect the actual concentration of the drug within the knee joint unless dilution effects are taken into account.

Introduction: Intraoperative wound infiltration with local anaesthetic is commonly used. Apart from the obvious immediate action it has been supported that a possible down regulation of pain receptors may lead to longer effects. Our aim was to compare the use of local anaesthetic versus placebo in order to assess if indeed there is a late beneficial effect., Methods: We conducted an RCT involving 400 consecutive general surgery patients randomized in 2 groups: Group A = placebo, Group B = wound infiltration with 15 ml of ropivacaine 10%. We recorded the preoperative and postoperative pain for the 1st week as well as the type and quantity of the analgesia used during the study period., Results: No significant difference was found between the groups in all known confounding factors recorded. No significant difference was found in the intensity of postoperative pain. More people of group A required NSAIDs during the first 3 PO days while more people of Group B required stronger painkillers. For those patients who underwent a non urgent operation and especially laparoscopic surgery higher pain score was recorded in the group B from the 3rd PO day onwards., Discussion: Intraoperative local infiltration of the wound with local anaesthetic offers no further benefit for the general surgery apart from that of the immediate PO period. There is no late effect for pain control. Considering that during the immediate postoperative period stronger systematic painkillers are given the intraoperative, infiltration of the wound with the local anaesthetic under study offers no obvious benefit., (Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.)

Background: Epidural infusion of levobupivacaine and ropivacaine provides adequate postoperative pain management by minimizing side effects related to IV opioids and improving patient outcome. The safety profile of different drugs can be better estimated by comparing their pharmacokinetic profiles than by considering their objective side effects. Because levobupivacaine and ropivacaine have different pharmacokinetic properties, our aim was to investigate whether there is a difference in the pharmacokinetic variability of the 2 drugs in a homogeneous population undergoing continuous epidural infusion. This double-blind, multicenter, randomized, controlled trial study was designed to compare the pharmacokinetics of continuous thoracic epidural infusion of levobupivacaine 0.125% or ropivacaine 0.2% for postoperative pain management in adult patients who had undergone major abdominal, urological, or gynecological surgery. This study is focused on the evaluation of the coefficient of variation (CV) to assess the equivalence in the systemic exposure and interindividual variability between levobupivacaine and ropivacaine and, therefore, the possible differences in the predictability of the plasmatic concentrations of the 2 drugs during thoracic epidural infusion., Methods: One hundred eighty-one adults undergoing major abdominal surgery were enrolled in the study. Patients were randomized to receive an epidural infusion of levobupivacaine 0.125% + sufentanil 0.75 μg/mL or of ropivacaine 0.2% + sufentanil 0.75 μg/mL at 5 mL/h for 48 hours. The primary end point of this study was to analyze the variability of plasma concentration of levobupivacaine and ropivacaine via an area under the curve within a range of 15% of the CV during 48 hours of continuous epidural infusion. The CV shows how the concentration values of local anesthetics are scattered around the median concentration value, thus indicating the extent to which plasma concentration is predictable during infusion. Secondary end points were to assess the pharmacologic profile of the local anesthetics used in the study, including an analysis of mean peak plasma concentrations, and also to assess plasma clearance, side effects, pain intensity (measured with a verbal numeric ranging score, i.e., static Numeric Rating Scale [NRS] and dynamic NRS]), and the need for rescue doses., Results: The comparison between the 2 CVs showed no statistical difference: the difference between area under the curve was within the range of 15%. The CV was 0.54 for levobupivacaine and 0.51 for ropivacaine (P = 0.725). The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine. Clearance of ropivacaine decreases with increasing patient age. There were no significant differences in NRS, dynamic NRS scores, the number of rescue doses, or in side effects between groups., Conclusions: Considering the CV, the interindividual variability of plasma concentration for levobupivacaine and ropivacaine is equivalent after thoracic epidural infusion in adults. We found a reduction in clearance of ropivacaine depending on patient age, but this finding could be the result of some limitations of our study. The steady-state concentration was not reached during the 48-hour infusion and the behavior of plasma concentrations of ropivacaine and levobupivacaine during continuous infusions lasting more than 48 hours remains to be investigated, because they could reach toxic levels. Finally, no differences in the clinical efficacy or in the incidence of adverse effects between groups were found for either local anesthetic.

Only limited data are available regarding the infiltration of local anaesthetic for total hip arthroplasty (THA), and no studies were performed for THA using the anterior approach. In this prospective, randomised placebo-controlled study we investigated the effect of both standard and reverse infiltration of local anaesthetic in combination with the anterior approach for THA. The primary endpoint was the mean numeric rating score for pain four hours post-operatively. In addition, we recorded the length of hospital stay, the operating time, the destination of the patient at discharge, the use of pain medication, the occurrence of side effects and pain scores at various times post-operatively. Between November 2012 and January 2014, 75 patients were included in the study. They were randomised into three groups: standard infiltration of local anaesthetic, reversed infiltration of local anaesthetic, and placebo. There was no difference in mean numeric rating score for pain four hours post-operatively (p = 0.87). There were significantly more side effects at one and eight hours post-operatively in the placebo group (p = 0.02; p = 0.03), but this did not influence the mobilisation of the patients. There were no differences in all other outcomes between the groups. We found no clinically relevant effect when the infiltration of local anaesthetic with ropivacaine and epinephrine was used in a multimodal pain protocol for THA using the anterior approach., (©2015 The British Editorial Society of Bone & Joint Surgery.)

Background: The needle tip placed at the level of posterior cord under ultrasound guidance is described as the most effective way to obtain single shot successful block in adults, for forearm and hand surgeries., Objective: The aim of this research was to study the spread of dye (depicting the local anesthetic) through catheters placed along the posterior cord. This was performed with continuous infraclavicular blocks placed under ultrasound guidance in children., Methods: Twenty-four ASA 1 and 2 children, aged 7 months to 8 years old, scheduled for upper limb orthopedic surgeries were included in this prospective descriptive study. They received continuous infraclavicular block under ultrasound guidance. Skin markings were obtained from catheters that were placed below the posterior cord inserted 2-3 cm beyond the tip of the Tuohy needle. A radio-opaque dye was injected into the catheters and 5 min later, the dye spread was evaluated fluoroscopically. Postoperatively, all patients received a continuous infusion of 0.125% bupivacaine for pain relief., Results: All 24 cases showed the presence of the dye along the neurovascular bundle in the infraclavicular region suggesting successful blocks. The mean ± standard deviation of the skin marking for the catheter was 5.61 ± 1.77 cm. Postoperatively, all patients had adequate pain relief with the catheters. One patient had break through pain on day 1 and four catheters were accidentally dislodged on day 2., Conclusion: We conclude that continuous infraclavicular catheters can be accurately and effectively placed along the posterior cord exclusively under ultrasound guidance in infants and small children., (© 2014 John Wiley & Sons Ltd.)

Background: Previous reports have suggested that polymorphism of the opioid receptor A118G affects the efficacy of opioid analgesia. The aim of this study was to investigate whether such polymorphism contributed to variability in epidural mixture (sufentanil plus ropivacaine) requirements through patient-controlled epidural analgesia (PCEA) after cesarean section., Methods: One hundred eighty consenting women undergoing elective cesarean delivery were enrolled in the study. Patients received sufentanil and ropivacaine for pain control after surgery. Sufentanil (50 mcg) diluted with 0.2% ropivacaine in a total volume of 100 mL was administered by PCEA with a background infusion rate of 2 mL/h and a pump program set to deliver 0.5-mL boluses with a lockout time of 15 minutes. The analgesic effect and adverse effects were measured with rating scales. The total consumption of the epidural mixture in the first 24 hours postoperatively was recorded. Blood samples were genotyped to classify patients into 3 groups according to A118G polymorphism., Results: Of 161 patients included in the analysis, 63 were homozygous (AA), 81 were heterozygous (AG), and 17 were homozygous (GG) for the A118G polymorphism. No difference was observed among groups in the consumption of the epidural mixture within the first 24 hours postoperatively (P = 0.3). Satisfaction with analgesia, pain scores, and adverse effects were similar among the groups., Conclusions: The analgesic requirements of patients receiving sufentanil and ropivacaine through PCEA after caesarean section were not associated with A118G polymorphism.

In this study, we determined the plasma concentration of ropivacaine by liquid chromatography-mass spectrometry for 30 hours after local infiltration analgesia in 15 patients with elective hip arthroplasty. The 95% upper prediction bound of maximal unbound plasma concentration of ropivacaine was 0.032 mg/L. Side effects sufficient to stop an IV infusion have been reported at arterial concentrations of 0.34 to 0.85 mg/L. Alpha-1-acid glycoprotein did not correlate with the fraction of unbound ropivacaine during the first 24 hours after local infiltration analgesia. No signs or symptoms of systemic local anesthetic toxicity were observed. The Clopper-Pearson 95% upper confidence limit for adverse signs was 0.218.

Introduction: Although generally considered both safe and effective, local anesthetics are often used in conjunction with opioids postoperatively in part because of the limited duration of drug action of local anesthetics. Much interest exists in extending the duration of local anesthetics' effects, which may reduce the requirement for opioid pain medications that are frequently associated with side effects, including nausea and vomiting, pruritus and respiratory depression., Areas Covered: This article introduces liposomal bupivacaine and SABER®-Bupivacaine, two new formulations of bupivacaine that increase the duration of analgesia postoperatively through two novel slow-release technologies. The pharmacodynamics, pharmacokinetics, efficacy and safety of both preparations of bupivacaine are reviewed. An electronic database search conducted using the Cochrane Central Register of Controlled Trials and MEDLINE/PubMed with the following search terms: 'bupivacaine,' 'liposomal bupivacaine', 'liposome bupivacaine', 'Exparel', 'SABER-Bupivacaine', 'SABER Bupivacaine', and 'SABER' yielded 90 articles (no language or date of publication restrictions were imposed)., Expert Opinion: Clinical trials involving liposomal bupivacaine and SABER-Bupivacaine indicate that both safely prolong analgesia, while decreasing opioid requirements when compared with placebo. However, additional clinical studies are necessary to better determine the efficacy and cost-effectiveness of these long-acting local anesthetic formulations.

Background: Continuous local anesthetic infiltration has been used for pain management after open colorectal surgery. However, its application to patients undergoing laparoscopic colorectal surgery has not been examined. The aim of this prospective, randomized, double-blind, placebo-controlled clinical trial was to study the use of a commercial infiltration device in patients undergoing open or laparoscopic colorectal surgery, along with plasma concentrations of levobupivacaine, its acute-phase binding protein (alpha-1 acid glycoprotein, AAG), and the stress marker, cortisol., Methods: Eligible patients were randomized (2:1) to receive a continuous infiltration of either levobupivacaine or placebo using a commercial device (ON-Q PainBuster) inserted in the preperitoneal layer at the end of surgery. Blood was sampled for determination of levobupivacaine and AAG and cortisol concentrations. Other outcomes measured were pain scores, morbidity and mortality, time to bowel movement, mobilization, and length of hospitalization., Results: In patients having open surgery, the levobupivacaine treatment showed a trend toward reduced total opioid consumption. No patients reported adverse effects attributable to levobupivacaine, despite 11 patients having concentrations at some time(s) during the 96-hour infiltration of up to 5.5 mg/L exceeding a putative toxicity threshold of 2.7 mg/L. AAG concentrations measured postsurgery increased by a mean of 55% (P < 0.001) at 48 hours. Cortisol concentrations also increased significantly by a mean of 191% at 1 hour., Conclusions: Continuous local anesthetic infiltration may be more beneficial in open surgery. The threshold for adverse effects from highly bound local anesthetic drugs established in healthy volunteers is of limited usefulness in clinical scenarios in which AAG concentration increases in response to surgical stress. Hence, there is scope to adopt higher doses to enhance therapeutic benefit.

In the multimodal approach to the management of postoperative pain, local infiltration and regional blocks have been increasingly utilized for pain control. One of the limitations of local anesthetics in the postoperative setting is its relatively short duration of action. Multivesicular liposomes containing bupivacaine have been increasingly utilized for their increased duration of action. Compared with bupivacaine HCl, local infiltration of liposomal bupivacaine has shown to have an increase in duration of action and causes delay in peak plasma concentration. In this article, we attempt to review the clinical literature surrounding liposomal bupivacaine and its evolving role in perioperative analgesia. This new bupivacaine formation may have promising implications in postoperative pain control, resulting in increased patient satisfaction and a decrease in both hospital stay and opioid-induced adverse events (AEs). Although more studies are needed, the preliminary clinical trials suggest that liposomal bupivacaine has predictable pharmacokinetics, a similar side effect profile compared with bupivacaine HCl, and is effective in providing increased postoperative pain control., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to evaluate the analgesic efficacy and safety of rectus sheath block combined with intraperitoneal instillation using two doses of ropivacaine in patients undergoing laparoscopic gynecological surgery., Methods: Altogether 53 consenting women were randomized to receive intraperitoneal infiltration with 0.25% ropivacaine or 0.5% ropivacaine followed by rectus sheath block with 0.375% ropivacaine. The outcomes of clinical safety were measured using plasma concentration of local anesthetics and occurrence of toxic symptoms. The analgesic efficacy was assessed using numerical rating scales for pain and morphine consumption up to 24 hours after surgery., Results: Patients' baseline characteristics, surgical factors, and analgesic outcomes were comparable between the two groups. Although peak plasma concentration of ropivacaine was significantly higher in patients receiving 0.5% ropivacaine, none of analyzed concentrations was above the toxic ones. Besides, no patients showed any symptoms of local anesthetic toxicity., Conclusions: The present study showed that the combination of rectus sheath block with intraperitoneal instillation of ropivacaine was safe and potent enough to relieve pain after laparoscopic surgery.

Aim: The aim of our study was: (i) to investigate whether transversus abdominis plane (TAP) block confers additional analgesic effects to epidural morphine alone; and (ii) to determine plasma levels of local anesthetics after TAP block in post-cesarean women., Material and Methods: The subjects were parturients undergoing cesarean section under combined spinal-epidural anesthesia. Morphine (2 mg) was administered to the epidural space close to the end of surgery. Women who desired TAP block were allocated to the TAP group. Women who did not undergo TAP block were allocated to the control group. In the TAP group, 20 mL of either 0.375% ropivacaine or 0.3% levobupivacaine was infused to both sides of the transversus abdominis plane after surgery. All patients were placed on a patient-controlled i.v. analgesia regimen with morphine after surgery. Time to the first morphine request and amount of morphine consumption within 24 h after surgery were compared in patients with and without TAP block. Plasma concentrations of local anesthetics were determined at 15, 30 and 60 min after TAP block., Results: Forty and 54 patients were allocated to the control and TAP group, respectively. The median time to the first morphine request was longer (555 vs 215 min), and the median cumulative morphine consumption within 24 h was lower (5.3 vs 7.7 mg) in the TAP group than in the control group. The maximum median concentrations of ropivacaine and bupivacaine after TAP block were 784 and 553 ng/mL, respectively., Conclusion: TAP block had additional analgesic effects to epidural morphine alone., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Objective: The purpose of the present study was to investigate the pharmacokinetics and efficacy of ropivacaine in Chinese patients by intra-articular administration after arthroscopic knee surgery, in order to assess the safety and efficacy., Patients and Methods: 21 ASA I-II patients received a single-dose of ropivacaine 150 mg in a 20 ml intra-articular injection at the end of surgery. Plasma samples were collected prior to and after ropivacaine administration. Plasma concentrations of ropivacaine were measured by HPLC. Pharmacokinetic parameters were calculated using noncompartmental analysis. Population pharmacokinetic modeling was performed to yield estimates of clearance, volume of distribution, and absorption rate constant. An analysis of covariates on the pharmacokinetic parameters was also carried out. Pain assessments were made using a verbal rating scale at intervals of 2, 4, 8, 12, 24, 36, 48 and 72 hours after surgery., Results: The results show that the peak plasma concentrations occurred at an average of 0.93 ± 0.56 h (0.25 - 2 h), with a mean of 0.91 ± 0.4 mg/l (range 0.35 - 1.54 mg/l). The peak plasma concentrations and the times to reach the peak plasma concentration exhibited a marked variability among the subjects. All concentrations were well below the estimated toxic threshold (2.2 mg/l). No patient experienced adverse events that may have been related to ropivacaine administration. The intra-articular use of ropivacaine provided excellent control of pain after knee arthroscopy., Conclusion: Ropivacaine 150 mg provided satisfactory postoperative pain relief and can be safely administered by intraarticular injection in Chinese patients after arthroscopic knee surgery and the pharmacokinetic profiles of ropivacaine exhibited marked variability among the subjects. The high variability of pharmacokinetic profiles in this study may be caused by gender and body weight.

Local anaesthetics are often used as part of multimodal pain management techniques to manage postsurgical pain and lessen the need for opioid analgesics; however, the duration of action of traditional formulations of local anaesthetics is short. Liposome bupivacaine is a novel, multivesicular formulation designed for rapid absorption, prolonged release of bupivacaine, and analgesia following a single intra-operative administration into the surgical wound. This article provides a summary of the pharmacokinetic profile of liposome bupivacaine compared with bupivacaine HCl based on data compiled from four randomized, active- and placebo-controlled trials that included pharmacokinetic assessments following single administrations of study drug. Each study evaluated the safety, efficacy and pharmacokinetic profile of liposome bupivacaine in separate surgical populations (patients undergoing inguinal hernia repair, total knee arthroplasty, haemorrhoidectomy or bunionectomy). Pharmacokinetic parameters included maximum plasma drug concentration (C(max)), area under the curve (AUC) for plasma bupivacaine concentration over time extrapolated to infinity (AUC(∞)), time to observed C(max) (t(max)) and terminal elimination half-life of bupivacaine (t(½)). The studies assessed single administrations of liposome bupivacaine at dose levels ranging from 106 to 532 mg or bupivacaine HCl 100 to 150 mg or placebo (0.9 % sodium chloride) given locally via wound infiltration at the end of surgery prior to wound closure. Male and non-pregnant female patients (n = 253) aged ≥18 years, scheduled to undergo surgery as per the specific protocol for each study, were enrolled. Patient characteristics were stratified by liposome bupivacaine doses ≤266 mg and >266 mg, and bupivacaine HCl treatment arms. Pharmacokinetic parameters for liposome bupivacaine doses of 106, 266, 399 and 532 mg were compared. Plasma concentration versus time profiles were quantitatively similar across these four dose levels of liposome bupivacaine, with an initial peak occurring within 1 h after administration followed by a second peak about 12-36 h later. The overall incidence of adverse events was lower in the liposome bupivacaine ≤266-mg group than the liposome bupivacaine >266-mg and bupivacaine HCl groups (100- or 150-mg doses). In summary, liposome bupivacaine was well tolerated across the four studies and varied surgical models, and exhibited bimodal kinetics with rapid uptake observed during the first few hours and prolonged release through 96 h after administration.

Background and Objectives: To minimize acute postoperative pain, a new formulation of slowly released bupivacaine was developed., Methods: Bupivacaine was microencapsulated at 60% (wt/wt) in poly-lactide-co-glycolide polymers and characterized for physicochemical properties and bupivacaine release kinetics. This formulation was injected around the rat sciatic nerve to produce an antinociceptive effect to toe pinch. Mechanical hyperalgesia following lateral plantar paw incision in rats was assessed for 7 to 14 days when the bupivacaine slow-release formulation was placed at the ipsilateral sciatic nerve and compared with the hyperalgesia that developed with various controls., Results: Bupivacaine was released in vitro at a relatively constant rate over a period of ≈ 72 to 96 hours. Complete antinociception, shown as no response to toe pinch, lasted for 23 ± 7 hours, with a half-recovery time of 42 ± 8 hours after sciatic nerve injection of 0.4 mL of the microspheres delivering 34 mg of bupivacaine. Solutions of 0.5% (wt/vol) bupivacaine-HCl (0.1 mL) produced complete antinociception for less than 2 hours and recovery half-times of 2 hours. Postincisional mechanical hyperalgesia, shown by increased withdrawal responses to von Frey filaments, was absent for 24 hours and was lower than control for 96 hours, when the sciatic nerve was blocked by bupivacaine microspheres, whereas the 0.5% bupivacaine solution reduced postincisional pain for only 4 hours., Conclusions: Corresponding to its far greater functional blocking time, the microsphere-bupivacaine formulation was able to significantly reduce postoperative pain below control levels for up to 4 days. These findings of several days of postoperative pain relief, for an injectable formulation containing a single active agent, present an improved and potentially promising therapy to prevent acute pain after surgery.

Introduction: DepoFoam bupivacaine is a novel liposomal formulation of bupivacaine designed to provide prolonged postsurgical analgesia. This dose-ranging study evaluated extent and duration of analgesia following administration of DepoFoam bupivacaine in patients undergoing total knee arthroplasty (TKA)., Methods: Efficacy, safety, and pharmacokinetics of DepoFoam bupivacaine doses of 133, 266, 399, or 532 mg were compared with bupivacaine HCl (150 mg) with epinephrine given as single injections via wound infiltration in TKA patients (N=138). Primary efficacy measure was AUC of pain intensity scores assessed by numeric rating scale with activity (NRS-A) through Day 4 postsurgery. Other assessments included pain intensity at rest (NRS-R), postsurgical opioid consumption, and safety, among others., Results: Mean AUC of NRS-A scores through Day 4 were 20.7, 19.5, 18.8, and 19.1 for the 133-mg, 266-mg, 399-mg, and 532-mg DepoFoam bupivacaine groups vs 20.4 for bupivacaine HCl. With DepoFoam bupivacaine 532-mg, differences in NRS-R scores reached statistical significance (P<0.05) vs bupivacaine HCl on Days 1 and 5 and mean AUC NRS-R scores were significantly lower through Days 2-5; a dose-response trend was demonstrated. Mean rating for blinded care provider's satisfaction with analgesia was significantly higher for DepoFoam bupivacaine 532 mg vs bupivacaine HCl (P ≤ 0.05). Other efficacy measures showed no statistically significant differences., Conclusion: Exposure to bupivacaine increased in a dose-related manner, as reflected by mean and maximum plasma bupivacaine concentrations, and AUC(0-∞). Treatment with DepoFoam bupivacaine 532 mg was associated with statistically significantly greater analgesia while patients were at rest after surgery compared with bupivacaine HCl., (Copyright © 2011. Published by Elsevier B.V.)

A rectus sheath block can provide postoperative analgesia for midline incisions. However, information regarding the pharmacokinetics of local anesthetics used in this block is lacking. In this study, we detail the time course of ropivacaine concentrations after this block. Thirty-nine patients undergoing elective lower abdominal surgery were assigned to 3 groups receiving rectus sheath block with 20 mL of different concentrations of ropivacaine. Peak plasma concentrations were dose dependent, and there were no significant differences in the times to peak plasma concentrations. The present data also suggested a slower absorption kinetics profile for ropivacaine after rectus sheath block than other compartment blocks.

Thirty-one dogs were randomised to receive intermittent wound infusion of bupivacaine or saline after surgery. Wound pressure sensitivity, pain scores, body temperature, heart rate, respiratory rate, analgesic drugs administered, time to walking and time to eating after surgery were recorded. Plasma bupivacaine concentrations were measured. The relative frequency distributions of the non-interventional and interventional pain scores, but not the relative frequency distributions of palpation pain scores or wound pressure sensitivity, were significantly different between groups following surgery. There was a significant difference between groups in the time to eating and in the amount and timing of analgesic drugs administered. Measured plasma bupivacaine concentrations demonstrated systemic absorption of the drug. Bupivacaine infusion into surgical wounds after surgery may improve post-operative recovery, but no effect on wound tenderness was demonstrated in this study., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: DepoFoam bupivacaine (DB) is in development for prolonged postoperative analgesia. Studies were conducted to evaluate the potential local and systemic toxicity and any effect on wound healing after wound infiltration., Methods: The model simulates an inguinal hernia (skin incision ∼2.5 and 5.5 cm). Animals (four/sex/group of each species) received DB 9, 18 or either 25 or 30 mg/kg, bupivacaine solution (B(sol); 7.5 mg/ml, 9 mg/kg) or saline. DB was given at 0.6, 1.2 and 1.0 or 1.2 ml/kg, respectively, and B(sol) or saline at 1.2 ml/kg. Each dose was infiltrated in small fractions on Day 1. End points included histology on Days 3 and 15. Wound healing was recorded on Day 2 through Day 15., Results: There was no adverse effect in either species. Notably, granulomatous inflammation was noted in surgical sites from 8 of 24 rabbits in the DB groups only. Based on the minimal to mild severity on Day 15, this was considered a normal reaction against the liposomes. Except for granulomatous inflammation, there were no differences in overall incidence or severity of histologic changes in the sites dosed to DB, saline or B(sol)., Conclusions: The data reported here are the first demonstration of the safety of DB in toxicology species.

Background and Objectives: Continuous wound infusion of local anesthetics is effective in postoperative pain management and may be useful in major joint arthroplasty, but the optimal technique for postoperative administration of local anesthetics in the wound awaits trials evaluating the optimal type of catheter (single-, few-, or multiholed catheters)., Methods: Sixteen patients undergoing total hip arthroplasty were randomized to intraoperative subfascial placement of a triple-orifice epidural catheter or a 15-cm multiholed catheter. Twenty milliliters of technetium Tc 99m diethylenetriaminepentaacetic acid-labeled saline was injected postoperatively and wound spread for 10 mins was recorded with a double-head gamma camera., Results: Mean (SD) wound spread (cm(2)) was the same with administration through a multiholed catheter versus the epidural catheter in both anterior (89 [15] versus 82 [20], P = 0.4) and lateral (68 [19] versus 60 [11], P = 0.3) projections., Conclusions: Wound spread of a bolus injection through 15-cm multiholed catheters versus triple-orifice epidural catheters is similar with subfascial catheter placement in total hip arthroplasty. Procedure-specific trials are required to evaluate the analgesic efficacy of postoperative administration of local anesthetic in the wound with different types of catheter before general recommendations can be made.

Background and Objective: Local anaesthetics administered intraabdominally have been found to reduce analgesic requirements postoperatively after hysterectomy. This study was designed to assess the optimal dose of local anaesthetics for best pain relief., Methods: Sixty patients undergoing abdominal hysterectomy were randomly divided into three groups to receive 10 ml h infusion of levobupivacaine intraabdominally postoperatively for 48 h in a double-blind manner: group L, 7.5 mg h; group M, 12.5 mg h and group H, 17.5 mg h. Pain intensity was measured using the numeric rating scale, ketobemidone consumption over 48 h was measured with a patient-controlled analgesia pump, recovery parameters, expiratory muscle strength, time to home readiness, plasma concentration of levobupivacaine and health-related quality of life were all measured at defined time points postoperatively., Results: No differences were found between the active groups in pain intensity, recovery parameters or health-related quality of life. Pain intensity was maximal during 0-4 h and during coughing. Expiratory muscle strength decreased significantly during 0-4 h in all active groups, with no differences between the groups. Plasma concentration of levobupivacaine was below known toxic concentrations in humans, and no patient had symptoms of local anaesthetic toxicity. Health-related quality of life showed improved scores at 3 months after the operation compared with preoperative values, but no differences between the groups were found in any of the parameters., Conclusion: Satisfactory analgesia can be achieved with low doses of levobupivacaine administered intraabdominally, except during the early postoperative period. No advantages were seen in this study when higher doses of levobupivacaine were administered as a continuous infusion for postoperative pain relief.

Background: Septorhinoplasty is a traumatic procedure that is associated with epistaxis and postoperative pain. The primary objective of this randomized double-blind controlled trial was to determine whether intranasal 5% lidocaine plus naphazoline decreases postoperative pain and lessens the use of rescue analgesics., Methods: After induction of general anesthesia and laryngeal topical anesthesia with 5% lidocaine, 28 adult patients, scheduled to undergo septorhinoplasty, were randomly assigned to one of two groups, either topical intranasal saline 20 ml (control group) or intranasal 5% lidocaine plus naphazoline solution 0.2 mg ml(-1) (lidocaine group). The perioperative dose of sufentanil, the mean end-tidal concentration of isoflurane, and surgeon satisfaction with the operative field were recorded. In the lidocaine group, plasma lidocaine concentrations were sampled 15, 20, 25, 35, 45, and 55 min after induction of anesthesia. Visual analogue scale pain scores were recorded 30, 60, 90, and 120 min after the patients arrived in the postanesthesia care unit and 24 h after surgery. Consumption of morphine rescue analgesia and the occurrence of any side effects were recorded at the end of the 24-h study period., Results: The intranasal lidocaine-naphazoline application decreased isoflurane requirements [median values: 0.8% (0.7-1.5) vs. 1.2% (0.9-1.8), respectively; P = 0.04] and enhanced surgical conditions. Patients in the lidocaine group experienced less postoperative pain than the control group [1 h after surgery: median values of visual analogue scale: 0 (0-20) vs. 50 (30-80), respectively; P = 0.001], and they required fewer doses of subcutaneous morphine. Total plasma concentrations of lidocaine remained below 4 microg ml(-1) throughout the study period., Conclusions: Intranasal lidocaine plus naphazoline is a simple and efficient technique for decreasing intra- and postoperative pain and for lessening rescue analgesic requirements in the postoperative period after septorhinoplasty. Toxic plasma concentrations of lidocaine were not reached.

Objective: To compare the onset, duration and postoperative pain scores of supraclavicular block with bupivacaine alone and bupivacaine-midazolam combination., Study Design: Randomized controlled clinical trial., Place and Duration of Study: The Postgraduate Medical Institute, Hayatabad Medical Complex, Peshawar, from April 2005 to June 2007., Methodology: A randomized controlled clinical trial was conducted on 50 ASA-I or II adult patients undergoing upper limb surgeries under supraclavicular brachial plexus block. Patients were randomly allocated into two groups of 25 each. Patients in group A were administered 30 ml of 0.5% bupivacaine and those in group B were given 30 ml of 0.5% bupivacaine with midazolam 50 microg x kg-1. Hemodynamic variables (heart rate, noninvasive blood pressure, oxygen saturation), pain scores, rescue analgesic requirements and sedation score were recorded for 24 hours postoperatively, and compared using ANOVA with significance at p <0.05., Results: The onset and duration of sensory and motor block was significantly faster and longer in group B compared to group A (p < 0.001). Pain scores were significantly lower in group B for 24 hours postoperatively (p < 0.001). Demand for rescue analgesic were significantly less in group B. Hemodynamics and sedation scores did not differ between the groups in the studied period., Conclusion: Bupivacaine (0.5%) in combination with Midazolam (50 microg x kg-1) quickened the onset as well as prolonged the duration of sensory and motor blockade of the brachial plexus for upper limb surgery. It improved postoperative analgesia without producing any adverse events compared to plain bupivacaine (0.5%) in equal volume.

Objective: To determine whether ropivacaine infiltration into all layers of the abdominal cesarean wound and spraying of the peritoneum decreases postoperative pain., Methods: A randomized controlled trial of women undergoing cesarean delivery under general anesthetic allocated to receive either 30 mL of 0.75% ropivacaine or 30 mL of saline into the wound, including spraying of the peritoneum. Postoperative pain and need for rescue opioids were assessed., Results: Of the 50 women in the ropivacaine group, 24 (48%) required pethidine or experienced severe pain within 1 hour postoperatively compared with 47 (94%) of 50 women in the control group (relative risk 0.51, 95% CI, 0.38-0.69). The amount of pethidine used in the first hour was reduced in the ropivacaine group (mean difference -58, 95% CI, -73.53 to -42.40). Use of diclofenac and tramadol/paracetamol was also reduced in the ropivacaine group., Conclusion: Ropivacaine wound infiltration and peritoneal spraying during cesarean delivery under general anesthetic reduces severe pain and need for opioids.