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Guo J, Jia Y, Tian L, Kang W, Zhao Y, Yuan S, Sessler DI. Paravertebral analgesia versus wound infiltration in children recovering from cardiac surgery: a randomized controlled trial. Reg Anesth Pain Med 2025:rapm-2025-106506. [PMID: 40368605 DOI: 10.1136/rapm-2025-106506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/23/2025] [Indexed: 05/16/2025]
Abstract
INTRODUCTION Optimal analgesia for thoracotomies remains unclear. Paravertebral blocks are more complex than local anesthetic infiltration but may be more effective. We therefore tested the hypothesis that paravertebral blocks provide better postoperative analgesia than local anesthetic infiltration in children recovering from cardiac surgery thoracotomies. METHODS This was a single-center randomized double-blind trial. We recruited children aged 6-14 years with atrial or ventricular septal defects scheduled for cardiac surgery with cardiopulmonary bypass via thoracotomy were recruited. 100 patients were enrolled and randomized to either postoperative paravertebral blocks (n=50) or local anesthetic wound infiltration (n=50). We recorded opioid consumption during the initial 24 hours after surgery, along with pain scores at 6 hour intervals. Complications including postoperative nausea and vomiting and respiratory failure were also recorded. RESULTS 100 patients (mean 7 years, 43% male) were included in the analysis. The only postoperative opioid used was sufentanil. Total sufentanil consumption in the first 24 hours postsurgery was 0.3±0.4 µg/kg for those receiving paravertebral blocks, significantly lower than the 0.6±0.5 µg/kg for wound infiltration (p=0.002). Faces Pain Scale-Revised pain scores were consistently lower in the paravertebral block group across all measured time points (6, 12, 18, and 24 hours), with the most pronounced difference observed at 6 hours postoperatively (1.7±2.2 vs 3.3±2.2; p<0.001). Postoperative mechanical ventilation time, ICU stay, hospitalization, and incidence of postoperative nausea and vomiting were comparable. CONCLUSION Paravertebral blocks reduced opioid consumption and pain during the first postoperative day in pediatric cardiac thoracotomies but did not accelerate recovery.
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Affiliation(s)
| | | | | | | | | | - Su Yuan
- Fuwai Hospital, Beijing, China
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Bebawy G, Sokar MS, Abdallah OY. Buccal lidocaine mucoadhesive patches for pediatrics' teething pain: overcoming possible hazards of oral gels. Pharm Dev Technol 2024; 29:805-813. [PMID: 39166264 DOI: 10.1080/10837450.2024.2393729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/18/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024]
Abstract
OBJECTIVES The utilization of pharmaceutical products in pediatric medicine, while established for use in adults, often presents uncertainties due to differences in application for children. The FDA discourages the use of local anesthetic gels, notably lidocaine, for teething pain in pediatrics due to concerns regarding potential adverse effects if inadvertently swallowed excessively. Therefore, significant attention is being directed towards modifying available marketed products to make them suitable for pediatric use. Here, we introduce mucoadhesive patches that not only have an adjusted dose of lidocaine but also feature a controlled release profile to manage teething pain with prolonged effect. This design helps to prevent issues related to gel liquefaction and swallowing, thereby reducing the potential hazardous side effects of lidocaine in the pediatric population. METHODS The study involved the development of controlled-release lidocaine HCl-loaded pellets forming a matrix for inclusion in mucoadhesive patches. Characterization was performed to ensure prolonged drug release, particularly during overnight use, aiming to improve pediatric patient compliance and enable precise dosing. KEY FINDINGS The mucoadhesive patches exhibited sustained lidocaine release lasting 24 h, potentially offering overnight relief suitable for pediatric application. The analysis of lidocaine content revealed that the developed patches maintained stable levels compared to doses obtained from commercially available oral gels. This finding implies effective pain control without the need for frequent reapplications, alongside controlled doses that decrease the likelihood of side effects. CONCLUSION The formulated medicated patches demonstrated consistent lidocaine content, effectively controlled drug release, and consequently, reduced the likelihood of undesired side effects when compared to oral gel administration.
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Affiliation(s)
- George Bebawy
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Magda Samir Sokar
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Ossama Y Abdallah
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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Markova L, Cvetko E, Ugwoke CK, Horvat S, Umek N, Stopar Pintarič T. The Influence of Diabetic Peripheral Neuropathy on the Duration of Sciatic Nerve Block with 1.3% Liposomal Bupivacaine and 0.25% Bupivacaine Hydrochloride in a Mouse Model. Pharmaceutics 2022; 14:pharmaceutics14091824. [PMID: 36145571 PMCID: PMC9502724 DOI: 10.3390/pharmaceutics14091824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/05/2022] [Accepted: 08/24/2022] [Indexed: 11/18/2022] Open
Abstract
Little is known regarding the pharmacological properties of extended-release local anesthetics in the setting of diabetic peripheral neuropathy. We investigated and compared the duration of sciatic nerve block following administration of clinically relevant concentrations of liposomal bupivacaine (LB) and bupivacaine hydrochloride (BH) in diabetic mice with peripheral neuropathy. In this prospective, randomized, and double-blind study, twenty-four female C57BL/6J-OlaHsd mice were assigned to a streptozotocin-induced type 1 diabetes group and a control group without diabetes. The presence of peripheral neuropathy was established by assessing the duration of thermal latency of the plantar and tail-flick tests, following which both groups were subdivided into two subgroups in which 35 mg/kg of 1.31% LB and 7 mg/kg of 0.25% BH were respectively administered for sciatic nerve block. The average sensory block duration with BH was 106 min and 117.1 min in the control and diabetic groups, respectively. With LB, the average sensory block duration was 118 min in the control mice, while in mice with diabetic peripheral neuropathy, the average block duration was significantly longer and above the 270 min limit set in our study. Accordingly, sensory block duration was longer with LB compared to BH, and diabetic peripheral neuropathy significantly increased sciatic nerve block duration with LB.
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Affiliation(s)
- Liljana Markova
- Department of Anaesthesiology and Surgical Intensive Therapy, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000 Ljubljana, Slovenia
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
| | - Erika Cvetko
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
| | - Chiedozie Kenneth Ugwoke
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
| | - Simon Horvat
- Department of Animal Science, Biotechnology and Immunology, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230 Domžale, Slovenia
| | - Nejc Umek
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
- Correspondence:
| | - Tatjana Stopar Pintarič
- Department of Anaesthesiology and Surgical Intensive Therapy, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000 Ljubljana, Slovenia
- Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Korytkova Ulica 2, 1000 Ljubljana, Slovenia
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Souza GK, Gallo A, Novicki LH, Neto HR, de Paula E, Marsaioli AJ, Cabeça LF. Inclusion Complex between Local Anesthetic/2-hydroxypropyl-β-cyclodextrin in Stealth Liposome. Molecules 2022; 27:molecules27134170. [PMID: 35807414 PMCID: PMC9267999 DOI: 10.3390/molecules27134170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/16/2022] [Accepted: 06/20/2022] [Indexed: 01/27/2023] Open
Abstract
The drugs delivery system in the treatment of diseases has advantages such as reduced toxicity, increased availability of the drug, etc. Therefore, studies of the supramolecular interactions between local anesthetics (LAs) butamben (BTB) or ropivacaine (RVC) complexed with 2-hydroxypropyl-β-cyclodextrin (HP-βCD) and carried in Stealth liposomal (SL) are performed. 1H-NMR nuclear magnetic resonance (DOSY and STD) were used as the main tools. The displacements observed in the 1H-NMR presented the complexion between LAs and HP-βCD. The diffusion coefficients of free BTB and RVC were 7.70 × 10−10 m2 s−1 and 4.07 × 10−10 m2 s−1, and in the complex with HP-βCD were 1.90 × 10−10 m2 s−1 and 3.64 × 10−10 m2 s−1, respectively, which indicate a strong interaction between the BTB molecule and HP-βCD (98.3% molar fraction and Ka = 72.279 L/mol). With STD-NMR, the encapsulation of the BTB/HP-βCD and RVC/HP-βCD in SL vesicles was proven. Beyond the saturation transfer to the LAs, there is the magnetization transfer to the hydrogens of HP-βCD. BTB and RVC have already been studied in normal liposome systems; however, little is known of their behavior in SL.
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Affiliation(s)
- Gredson Keiff Souza
- Chemistry Institute, State University of Campinas, UNICAMP, Rua Josué de Castro Cidade Universitária, Campinas CEP 13083-970, Brazil; (G.K.S.); (A.J.M.)
| | - André Gallo
- Chemistry Department, Technological Federal University of Parana, UTFPR, Avenida dos Pioneiros, Londrina CEP 86036-370, Brazil; (A.G.); (L.H.N.); (H.R.N.)
| | - Luiza Hauser Novicki
- Chemistry Department, Technological Federal University of Parana, UTFPR, Avenida dos Pioneiros, Londrina CEP 86036-370, Brazil; (A.G.); (L.H.N.); (H.R.N.)
| | - Heitor Rodrigues Neto
- Chemistry Department, Technological Federal University of Parana, UTFPR, Avenida dos Pioneiros, Londrina CEP 86036-370, Brazil; (A.G.); (L.H.N.); (H.R.N.)
| | - Eneida de Paula
- Biology Institute, State University of Campinas, UNICAMP, Rua Josué de Castro Cidade Universitária, Campinas CEP 13083-970, Brazil;
| | - Anita Jocelyne Marsaioli
- Chemistry Institute, State University of Campinas, UNICAMP, Rua Josué de Castro Cidade Universitária, Campinas CEP 13083-970, Brazil; (G.K.S.); (A.J.M.)
| | - Luis Fernando Cabeça
- Chemistry Department, Technological Federal University of Parana, UTFPR, Avenida dos Pioneiros, Londrina CEP 86036-370, Brazil; (A.G.); (L.H.N.); (H.R.N.)
- Correspondence: ; Tel.: +55-43-98040615
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Babaie S, Taghvimi A, Hong JH, Hamishehkar H, An S, Kim KH. Recent advances in pain management based on nanoparticle technologies. J Nanobiotechnology 2022; 20:290. [PMID: 35717383 PMCID: PMC9206757 DOI: 10.1186/s12951-022-01473-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 05/21/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pain is a vital sense that indicates the risk of injury at a particular body part. Successful control of pain is the principal aspect in medical treatment. In recent years, the advances of nanotechnology in pain management have been remarkable. In this review, we focus on literature and published data that reveal various applications of nanotechnology in acute and chronic pain management. METHODS The presented content is based on information collected through pain management publications (227 articles up to April 2021) provided by Web of Science, PubMed, Scopus and Google Scholar services. RESULTS A comprehensive study of the articles revealed that nanotechnology-based drug delivery has provided acceptable results in pain control, limiting the side effects and increasing the efficacy of analgesic drugs. Besides the ability of nanotechnology to deliver drugs, sophisticated nanosystems have been designed to enhance imaging and diagnostics, which help in rapid diagnosis of diseases and have a significant impact on controlling pain. Furthermore, with the development of various tools, nanotechnology can accurately measure pain and use these measurements to display the efficiency of different interventions. CONCLUSIONS Nanotechnology has started a new era in the pain management and many promising results have been achieved in this regard. Nevertheless, there is still no substantial and adequate act of nanotechnology in this field. Therefore, efforts should be directed to broad investigations.
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Affiliation(s)
- Soraya Babaie
- Physical Medicine and Rehabilitation Research Center and Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arezou Taghvimi
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Joo-Hyun Hong
- School of Pharmacy, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea
| | - Hamed Hamishehkar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Seongpil An
- SKKU Advanced Institute of Nanotechnology (SAINT) and Department of Nano Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea.
| | - Ki Hyun Kim
- School of Pharmacy, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea.
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Qi RQ, Liu W, Wang DY, Meng FQ, Wang HY, Qi HY. Development of local anesthetic drug delivery system by administration of organo-silica nanoformulations under ultrasound stimuli: in vitro and in vivo investigations. Drug Deliv 2021; 28:54-62. [PMID: 33342323 PMCID: PMC7751425 DOI: 10.1080/10717544.2020.1856220] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The development of local anesthetic (LA) system is the application of commercial drug for the pain management that indorses the reversible obstructive mechanism of neural transmission through preventing the innervation process in human peripheral nerves. Ropivacaine (RV) is one of the greatest frequently used LA s with the actions of long-lasting and low-toxicity for the post-operative pain management. In this work, we have approached novel design and development of glycosylated chitosan (GCS) encapsulated mesoporous silica nanoparticles (GCS-MONPs)-based nano-scaffold for sustainable distributions and controlled/supported arrival of stacked RV for targeting sites, which can be activated by either outer ultrasound activating to discharge the payload, foundation on-request and dependable analgesia. The structural and morphology analyses result established that prepared nano-formulations have successful molecular interactions and RV loaded spherical morphological structures. The drug release profile of developed nanostructure with ultrasound-activation has been achieved 50% of drug release in 2 h and 90% of drug release was achieved in 12 h, which displays more controlled release when compared to free RV solution. The in vitro cell compatibility analysis exhibited GCS-MONPs with RV has improved neuron cell survival rates when compared to other samples due to its porous surface and suitable biopolymer proportions. The analysis of ex vitro and in vivo pain relief analysis demonstrated treated animal models have high compatibility with GCS-MONPs@RV, which was confirmed by histomorphology. This developed MONPs based formulations with ultrasound-irradiation gives a prospective technique to clinical agony the board through on-request and dependable help with discomfort.
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Affiliation(s)
- Rong-Qin Qi
- Department of Anesthesiology, Jinan Maternal and Child Health Hospital, Jinan, China
| | - Wei Liu
- Department of Anesthesiology, Jinan Maternal and Child Health Hospital, Jinan, China
| | - Duan-Yu Wang
- Department of Anesthesiology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Fan-Qing Meng
- Department of Anesthesiology, Jinan Maternal and Child Health Hospital, Jinan, China
| | - Hong-Ying Wang
- Department of Anesthesiology, Jinan Maternal and Child Health Hospital, Jinan, China
| | - Hai-Yan Qi
- Department of Anesthesiology, Jinan Maternal and Child Health Hospital, Jinan, China
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Hybrid nanofilms as topical anesthetics for pain-free procedures in dentistry. Sci Rep 2020; 10:11341. [PMID: 32647250 PMCID: PMC7347607 DOI: 10.1038/s41598-020-68247-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
Topical anesthetics are widely applied in order to relieve the discomfort and anxiety caused by needle insertion and other painful superficial interventions at the oral cavity. So far, there are no commercially available effective topical anesthetic formulations for that purpose, and the most of developments are related to hydrophilic and low mucoadhesive forms. Therefore, we have prepared different hybrid nanofilms composed of biopolymer matrices (chitosan, pectin, and chitosan-pectin) blended with nanostructured lipid carriers (NLC) loading the eutectic mixture of 5% lidocaine-prilocaine (LDC-PLC), in order to fulfill this gap in the market. These dual systems were processed as hybrid nanofilms by the solvent/casting method, and its mucoadhesive, structural and mechanical properties were detailed. The most appropriate hybrid nanofilm combined the advantages of both pectin (PCT) and NLC components. The resultant material presented sustained LDC-PLC release profile for more than 8 h; permeation across porcine buccal mucosa almost twice higher than control and non-cytotoxicity against 3T3 and HACAT cell lines. Then, the in vivo efficacy of PCT/NLC formulation was compared to biopolymer film and commercial drug, exhibiting the longest-lasting anesthetic effect (> 7 h), assessed by tail flick test in mice. These pectin-based hybrid nanofilms open perspectives for clinical trials and applications beyond Dentistry.
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Palatal needle-free anesthesia for upper molars extraction. A randomized clinical trial. J Craniomaxillofac Surg 2020; 48:815-819. [PMID: 32536538 DOI: 10.1016/j.jcms.2020.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/07/2020] [Accepted: 05/03/2020] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The aim of this study was to compare the ability of liposomal and non-liposomal lidocaine and prilocaine in hydrogel formulations to promote topical anesthesia in palatal mucosa during upper molar extractions. METHODS In this randomized, cross over, triple-blinded clinical trial, a liposomal and a non-liposomal formulation of the eutectic mixture of local anesthetics, 2.5% lidocaine and 2.5% prilocaine, were used to promote palatal anesthesia without the local anesthetic infiltration during bilateral upper molars extractions. RESULTS From the total of 40 patients included in this study, the non-liposomal eutectic lidocaine-prilocaine formulation failed in 40% of cases, unlike the liposomal formulation, which was effective for all patients (Fisher's exact test, p < 0.0001). Furthermore, the liposomal formulation (26.75 ± 7,47 min) induced longer anesthesia duration (t-test, p < 0.0001) than the non-liposomal formulation (16.78 ± 4.75 min). No mucosal ulceration or discomfort was reported for both formulations. CONCLUSION The liposomal formulation was able to induce adequate anesthesia in palatal mucosa during dental extraction, avoiding the local anesthetic infiltration. For the first time, a topical formulation allowed upper molars surgical removal without injection of any local anesthetic agent into palatal mucosa in adults.
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Nascimento Vieira AL, Franz-Montan M, Cabeça LF, de Paula E. Anaesthetic benefits of a ternary drug delivery system (Ropivacaine-in-Cyclodextrin-in-Liposomes): in-vitro and in-vivo evaluation. ACTA ACUST UNITED AC 2019; 72:396-408. [PMID: 31859378 DOI: 10.1111/jphp.13211] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/16/2019] [Indexed: 01/03/2023]
Abstract
OBJECTIVES To evaluate whether a ternary system composed of hydroxypropyl-β-cyclodextrin (HP-βCD) further encapsulated into egg phosphatidylcholine liposomes (LUV) could prolong the action and reduce the toxicity of ropivacaine (RVC). METHODS Dynamic light scattering and NMR were used to characterize the inclusion complex (RVC : HP-βCD), liposomal (RVC : LUV) and ternary (LUV : RVC : HP-βCD) systems containing 0.25% RVC. Their encapsulation efficiency, release kinetics, in-vitro cytotoxicity and in-vivo anaesthetic effect (paw-withdraw tests in mice) were also evaluated. KEY FINDINGS 1 : 1 RVC : HP-βCD inclusion complex was encapsulated in liposomes (220.2 ± 20.3 nm size, polydispersity <0.25, zeta potentials = -31.7 ± 1.4 mV). NMR (diffusion-ordered spectroscopy (DOSY)) revealed stronger anaesthetic binding to LUV : RVC : HP-βCD (Ka = 342 m-1 ) than to RVC : HP-βCD (Ka = 128 m-1 ) or liposomal formulation (Ka = 22 m-1 ). The formulations promoted in-vitro sustained drug release and partially reverted the cytotoxicity of RVC against 3T3 fibroblasts in the profile: LUV : RVC : HP-βCD ≥ RVC : HP-βCD > RVC : LUV. Accordingly, in-vivo sensory block of free RVC (180 min) was prolonged ca. 1.7 times with the ternary system and RVC : HP-βCD (300 min) and 1.3 times with RVC : LUV (240 min). CONCLUSIONS These results confirm the suitability of this double-carrier system in clinical practice, to decrease the toxicity and prolong the anaesthesia time evoked by RVC.
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Affiliation(s)
- Ana Laís Nascimento Vieira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas - Unicamp, Campinas, Brazil
| | - Michelle Franz-Montan
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas - Unicamp, Piracicaba, Brazil
| | - Luís Fernando Cabeça
- Department of Chemistry, Federal Technological University of Paraná, Londrina, Brazil
| | - Eneida de Paula
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas - Unicamp, Campinas, Brazil
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Moraes GS, Santos IBD, Pinto SCS, Pochapski MT, Farago PV, Pilatti GL, Santos FA. Liposomal anesthetic gel for pain control during periodontal therapy in adults: a placebo-controlled RCT. J Appl Oral Sci 2019; 28:e20190025. [PMID: 31778442 PMCID: PMC6882661 DOI: 10.1590/1678-7757-2019-0025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 04/24/2019] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Periodontal therapy usually requires local anesthesia. If effective, a non-invasive, liposomal anesthetic gel could increase the levels of acceptance of patients in relation to periodontal therapy. OBJECTIVE This study investigated the efficacy of liposomal anesthetic gel for pain control during periodontal therapy. METHODOLOGY Forty volunteers with moderate to severe chronic periodontitis were recruited, of which at least three sextants required periodontal therapy. At least one of the selected teeth had one site with a probing depth of ≥4 mm. The volunteers received the following three gels: a placebo, lidocaine/prilocaine (Oraqix®), or a liposomal lidocaine/prilocaine, which were applied to different sextants. Pain frequency was registered during treatment and the volunteers received a digital counter to register any painful or uncomfortable experiences. At the end of each session, the volunteers indicated their pain intensity using rating scales (NRS-101 and VRS-4). The volunteers had their hemodynamic parameters measured by a non-invasive digital monitor. RESULTS Pain frequency/intensity did not show statistical difference between intervention groups. The tested gels did not interfere with the hemodynamic indices. Dental anxiety, suppuration and probing depth could influence pain during periodontal therapy. CONCLUSION Our results suggest limited indications for the use of non-invasive anesthesia when used for scaling and root planing. Intra-pocket anesthetic gel could be a good option for anxious patients, or those who have a fear of needles.
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Affiliation(s)
- Gustavo Simao Moraes
- Universidade Estadual de Ponta Grossa, Departamento de Odontologia, Ponta Grossa, Paraná, Brasil
| | | | | | - Marcia Thais Pochapski
- Universidade Estadual de Ponta Grossa, Departamento de Odontologia, Ponta Grossa, Paraná, Brasil
| | - Paulo Vitor Farago
- Universidade Estadual de Ponta Grossa, Departamento de Ciências Farmacêuticas, Ponta Grossa, Paraná, Brasil
| | - Gibson Luiz Pilatti
- Universidade Estadual de Ponta Grossa, Departamento de Odontologia, Ponta Grossa, Paraná, Brasil
| | - Fabio Andre Santos
- Universidade Estadual de Ponta Grossa, Departamento de Odontologia, Ponta Grossa, Paraná, Brasil
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Liu GL, Bian WC, Zhao P, Sun LH. Delivery of Local Anesthesia: Current Strategies, Safety, and Future Prospects. Curr Drug Metab 2019; 20:533-539. [PMID: 31187706 DOI: 10.2174/1389200220666190610155049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/19/2019] [Accepted: 04/24/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND The systemic administration of anesthesia is associated with severe and undesirable side effects such as sedation, vomiting, nausea, allergies, respiratory problems, and neutrophil dysfunction. With the increase in the procedures of limb surgery, cosmetics, facial, skin, and cancer reconstruction, the demand for local anesthesia has increased multifold during the last one decade. Therefore, novel, safe, and cost-effective methods are being developed to deliver local anesthetics by the surgeons. METHOD To prepare a comprehensive research report on anesthesia, we performed a structured literature search of bibliographic databases for peer-reviewed articles published recently. The studies of different articles were summarized and a deductive qualitative and quantitative data analysis was applied. Subsequently, a comprehensive summary of the analysis was used to frame this review article with ample examples. RESULTS A thorough analysis of the reports suggested that there have been tremendous developments of synthesizing nanoparticle-based local anesthesia drugs. The active targeting ability of nanoparticle-based drug delivery strategy can further help to deliver the desired anesthetic drug locally. It was also found that different local anesthetic drugs are developed into liposome form and show better efficacy in patients receiving anesthesia. CONCLUSION The findings of this review article endorse that safe delivery of anesthesia drugs are essential for the safety of patients. Further, nanotechnology-based strategies are extremely useful for targeted delivery of anesthetic drugs at the required dose without affecting the neighboring tissues.
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Affiliation(s)
- Guo-Liang Liu
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun 130041, China
| | - Wen-Chao Bian
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130041, China
| | - Peng Zhao
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun 130041, China
| | - Li-Hua Sun
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun 130041, China
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Chakravarthy KV, Boehm FJ, Christo PJ. Nanotechnology: A Promising New Paradigm for the Control of Pain. PAIN MEDICINE 2019; 19:232-243. [PMID: 29036629 DOI: 10.1093/pm/pnx131] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Objective The objective of this article is to critically review both preclinical and clinical studies that focus on the use of nanotechnology for both acute and chronic pain management, surveying both diagnostic and therapeutic applications. The article also provides information on nanotechnology for pain practitioners, so that they may better understand how this technology works and how it may be applied to their day-to-day clinical practice. Study Design Narrative review. Methods The Pubmed NCBI and EMBASE databases were utilized to review published reports of in vivo and clinical studies that focus on using nanotechnology for pain management applications in both the acute and chronic pain settings. Results Articles were screened by title, abstract, and full article review. They were then analyzed by specific clinical indications, and appropriate data were presented based on a critical analysis of those articles. Conclusions As the development of nanomedical applications in acute and chronic pain management continues, medical practitioners should consider their growing potential to enhance the care of patients who are consistently living with pain. Current barriers to implementation include manufacturing scale-up for commercial viability, long-term nanoparticle toxicity considerations, and high cost for successful passage through clinical trials. These challenges will need to be overcome with ongoing translational research efforts in collaboration with industry and government bodies such as the Food and Drug Administration (FDA).
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Affiliation(s)
- Krishnan V Chakravarthy
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.,Johns Hopkins Institute for NanoBioTechnology (INBT), Baltimore, Maryland
| | | | - Paul J Christo
- Department of Anesthesiology and Critical Care Medicine, Division of Pain Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
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Hybrid Hydrogel Composed of Polymeric Nanocapsules Co-Loading Lidocaine and Prilocaine for Topical Intraoral Anesthesia. Sci Rep 2018; 8:17972. [PMID: 30568251 PMCID: PMC6299281 DOI: 10.1038/s41598-018-36382-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 11/15/2018] [Indexed: 12/20/2022] Open
Abstract
This study reports the development of nanostructured hydrogels for the sustained release of the eutectic mixture of lidocaine and prilocaine (both at 2.5%) for intraoral topical use. The local anesthetics, free or encapsulated in poly(ε-caprolactone) nanocapsules, were incorporated into CARBOPOL hydrogel. The nanoparticle suspensions were characterized in vitro in terms of particle size, polydispersity, and surface charge, using dynamic light scattering measurements. The nanoparticle concentrations were determined by nanoparticle tracking analysis. Evaluation was made of physicochemical stability, structural features, encapsulation efficiency, and in vitro release kinetics. The CARBOPOL hydrogels were submitted to rheological, accelerated stability, and in vitro release tests, as well as determination of mechanical and mucoadhesive properties, in vitro cytotoxicity towards FGH and HaCaT cells, and in vitro permeation across buccal and palatal mucosa. Anesthetic efficacy was evaluated using Wistar rats. Nanocapsules were successfully developed that presented desirable physicochemical properties and a sustained release profile. The hydrogel formulations were stable for up to 6 months under critical conditions and exhibited non-Newtonian pseudoplastic flows, satisfactory mucoadhesive strength, non-cytotoxicity, and slow permeation across oral mucosa. In vivo assays revealed higher anesthetic efficacy in tail-flick tests, compared to a commercially available product. In conclusion, the proposed hydrogel has potential for provision of effective and longer-lasting superficial anesthesia at oral mucosa during medical and dental procedures. These results open perspectives for future clinical trials.
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Ionic gradient liposomes: Recent advances in the stable entrapment and prolonged released of local anesthetics and anticancer drugs. Biomed Pharmacother 2018; 107:34-43. [DOI: 10.1016/j.biopha.2018.07.138] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 11/18/2022] Open
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Zhou C, Huang J, Yang Q, Li T, Liu J, Qian Z. Gold nanorods-based thermosensitive hydrogel produces selective long-lasting regional anesthesia triggered by photothermal activation of Transient Receptor Potential Vanilloid Type-1 channels. Colloids Surf B Biointerfaces 2018; 171:17-23. [PMID: 30005286 DOI: 10.1016/j.colsurfb.2018.07.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/19/2018] [Accepted: 07/02/2018] [Indexed: 02/05/2023]
Abstract
Long-lasting regional anesthesia and selective sensory block are useful in post-operative analgesia and treatment of pathological pain. Previous studies have demonstrated that activation of TRPV1 (Transient Receptor Potential Vanilloid Type-1) channels facilitated the potency of QX-314 for selective long-lasting regional anesthesia in vivo. Hydrogel is a solid jelly-like material covering a wide range of properties from soft and weak to hard and tough. Gold nanorods are nanoparticles, which can be used for hyperthermia by exposure to near-infrared radiation. We fabricated a gold nanorods and QX-314 containing hydrogel. The molecular weight of hydrogel was adjusted to achieve a targeted phase transition temperature. Gold nanorods with a desired photothermal conversion efficacy and QX-314 were mixed with hydrogel to produce a gold nanorods-QX-314/hydrogel nanocomposite. A rat model of sciatic nerve block was applied to evaluate the regional anesthetic effect of the gold nanorods-QX-314/hydrogel nanocomposite. Upon exposure to near-infrared irradiation, the gold nanorods-QX-314/hydrogel nanocomposite activated TRPV1 channels through photothermal conversion and release of QX-314 at the same time. The gold nanorods and QX-314 loaded hydrogel exhibited a long-lasting regional anesthetic effect with selective sensory function block. Sensory block duration of the nanocomposite was significantly longer than of 1% lidocaine (90.0 ± 12.2 vs. 37.5 ± 12.5 min, P < 0.01). Motor block by the nanocomposite was observed for only 40% of rats with significantly shorter duration than its sensory block (42.5 ± 17.1 vs. 90.0 ± 12.2 min, P < 0.01). The gold nanorods-QX-314/hydrogel nanocomposite can produce a selective long-lasing regional anesthetic effect in a rat model of sciatic nerve block.
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Affiliation(s)
- Cheng Zhou
- Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, and Department of Anesthesiology, West China Hospital of Sichuan University, Sichuan, Chengdu, 610041, PR China
| | - Jianqiong Huang
- Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Sichuan, Chengdu, 610041, PR China
| | - Qian Yang
- School of Pharmacy, College Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Sichuan, Chengdu, 610500, PR China.
| | - Tao Li
- Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, and Department of Anesthesiology, West China Hospital of Sichuan University, Sichuan, Chengdu, 610041, PR China; West China-Washington Mitochondria and Metabolism Center, West China Hospital of Sichuan University, Sichuan, Chengdu, 610041, PR China.
| | - Jin Liu
- Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, and Department of Anesthesiology, West China Hospital of Sichuan University, Sichuan, Chengdu, 610041, PR China
| | - Zhiyong Qian
- State Key Laboratory and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, Sichuan, PR China
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Andreu V, Arruebo M. Current progress and challenges of nanoparticle-based therapeutics in pain management. J Control Release 2017; 269:189-213. [PMID: 29146243 DOI: 10.1016/j.jconrel.2017.11.018] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 11/10/2017] [Accepted: 11/11/2017] [Indexed: 02/07/2023]
Abstract
Pain is a widespread and growing health problem worldwide that exerts a considerable social and economic impact on both patients and healthcare systems and, therefore, on society in general. Although current treatment modalities include a wide variety of pharmacological and non-pharmacological approaches, due to the complexity of pain and individual differences in clinical response these options are not always effective in mitigating and relieving pain. In addition, some pain drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics and opioids show several unfavorable side effects. Therefore, current research advances in this medical field are based on the development of potential treatments to address many of the unmet needs and to overcome the existing limitations in pain management. Nanoparticle drug delivery systems present an exciting opportunity as alternative platforms to improve efficacy and safety of medications currently in use. Herein, we review a broad range of nanoparticle formulations (organic nanostructures and inorganic nanoparticles), which have been developed to encapsulate an array of painkillers, paying special attention to the key advantages that these systems offer, (compared to the use of the free drug), as well as to the more relevant results of preclinical studies in animal models. Additionally, we will briefly discuss the impact of some of these nanoformulations in clinical trials.
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Affiliation(s)
- Vanesa Andreu
- Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain; Aragon Health Research Institute (IIS), Aragón, 50009 Zaragoza, Spain.
| | - Manuel Arruebo
- Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain; Aragon Health Research Institute (IIS), Aragón, 50009 Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029 Madrid, Spain
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Swain A, Nag DS, Sahu S, Samaddar DP. Adjuvants to local anesthetics: Current understanding and future trends. World J Clin Cases 2017; 5:307-323. [PMID: 28868303 PMCID: PMC5561500 DOI: 10.12998/wjcc.v5.i8.307] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 05/03/2017] [Accepted: 05/19/2017] [Indexed: 02/05/2023] Open
Abstract
Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. A large array of opioids ranging from morphine, fentanyl and sufentanyl to hydromorphone, buprenorphine and tramadol has been used with varying success. However, their use has been limited by their adverse effect like respiratory depression, nausea, vomiting and pruritus, especially with its neuraxial use. Epinephrine potentiates the local anesthetics by its antinociceptive properties mediated by alpha-2 adrenoreceptor activation along with its vasoconstrictive properties limiting the systemic absorption of local anesthetics. Alpha 2 adrenoreceptor antagonists like clonidine and dexmedetomidine are one of the most widely used class of local anesthetic adjuvants. Other drugs like steroids (dexamethasone), anti-inflammatory agents (parecoxib and lornoxicam), midazolam, ketamine, magnesium sulfate and neostigmine have also been used with mixed success. The concern regarding the safety profile of these adjuvants is due to its potential neurotoxicity and neurological complications which necessitate further research in this direction. Current research is directed towards a search for agents and techniques which would prolong local anaesthetic action without its deleterious effects. This includes novel approaches like use of charged molecules to produce local anaesthetic action (tonicaine and n butyl tetracaine), new age delivery mechanisms for prolonged bioavailability (liposomal, microspheres and cyclodextrin systems) and further studies with other drugs (adenosine, neuromuscular blockers, dextrans).
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Moradkhani MR, Karimi A, Negahdari B. Nanotechnology application to local anaesthesia (LA). ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:355-360. [PMID: 28395522 DOI: 10.1080/21691401.2017.1313263] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Several advancements have been made on the exact release of local anaesthetics formulation and its efficiency at inducing motor and sensory block for an extended time has been harnessed in clinical practice. The use of sustained release formulations delivers analgesia for a lengthier period of time with one administration, thereby reducing complications that usually arise with administration of conventional analgesia. In addition, controlled release of an anaesthetic drug is said to prevent overdosing, reduced side effects, especially cardiotoxicity, neurotoxicity and tissue lesions. The use of nanotechnology knowledge via liposomal formulation has recorded high successful results in pain control and quick patient recovery.
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Affiliation(s)
- Mahmoud Reza Moradkhani
- a Department of Anesthesiology , Lorestan University of Medical Sciences , Khorramabad , Iran
| | - Arash Karimi
- a Department of Anesthesiology , Lorestan University of Medical Sciences , Khorramabad , Iran
| | - Babak Negahdari
- b Department of Medical Biotechnology , School of Advanced Technologies in Medicine, Tehran University of Medical Sciences , Tehran , Iran
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Franz-Montan M, Ribeiro LNDM, Volpato MC, Cereda CMS, Groppo FC, Tofoli GR, de Araújo DR, Santi P, Padula C, de Paula E. Recent advances and perspectives in topical oral anesthesia. Expert Opin Drug Deliv 2016; 14:673-684. [DOI: 10.1080/17425247.2016.1227784] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Silva CMGD, Fraceto LF, Franz-Montan M, Couto VM, Casadei BR, Cereda CMS, de Paula E. Development of egg PC/cholesterol/α-tocopherol liposomes with ionic gradients to deliver ropivacaine. J Liposome Res 2015; 26:1-10. [DOI: 10.3109/08982104.2015.1022555] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Franz-Montan M, Baroni D, Brunetto G, Sobral VRV, da Silva CMG, Venâncio P, Zago PW, Cereda CMS, Volpato MC, de Araújo DR, de Paula E, Groppo FC. Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans. J Liposome Res 2014; 25:11-9. [PMID: 24807821 DOI: 10.3109/08982104.2014.911315] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To characterize liposomal-lidocaine formulations for topical use on oral mucosa and to compare their in vitro permeation and in vivo anesthetic efficacy with commercially available lidocaine formulations. MATERIALS AND METHODS Large unilamellar liposomes (400 nm) containing lidocaine were prepared using phosphatidylcholine, cholesterol, and α-tocoferol (4:3:0.07, w:w:w) and were characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and in vitro release. In vitro permeation across pig palatal mucosa and in vivo topical anesthetic efficacy on the palatal mucosa in healthy volunteers (double-blinded cross-over, placebo controlled study) were performed. The following formulations were tested: liposome-encapsulated 5% lidocaine (Liposome-Lido5); liposome-encapsulated 2.5% lidocaine (Liposome-Lido2.5); 5% lidocaine ointment (Xylocaina®), and eutectic mixture of lidocaine and prilocaine 2.5% (EMLA®). RESULTS The Liposome-Lido5 and EMLA showed the best in vitro permeation parameters (flux and permeability coefficient) in comparison with Xylocaina and placebo groups, as well as the best in vivo topical anesthetic efficacy. CONCLUSION We successfully developed and characterized a liposome encapsulated 5% lidocaine gel. It could be considered an option to other topical anesthetic agents for oral mucosa.
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Affiliation(s)
- Michelle Franz-Montan
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas - UNICAMP , Piracicaba, São Paulo , Brazil
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Franz-Montan M, Cereda CMS, Gaspari A, da Silva CMG, de Araújo DR, Padula C, Santi P, Narvaes E, Novaes PD, Groppo FC, de Paula E. Liposomal-benzocaine gel formulation: correlation between in vitro assays and in vivo topical anesthesia in volunteers. J Liposome Res 2012; 23:54-60. [PMID: 23245380 DOI: 10.3109/08982104.2012.742536] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The aim of the present study was to characterize a liposome-based benzocaine (BZC) formulation designed for topical use on the oral mucosa and to evaluate its in vitro retention and permeation using the Franz-type diffusion cells through pig esophagus mucosa. To predict the effectiveness of new designed formulations during preclinical studies, a correlation between in vitro assays and in vivo efficacy was performed. Liposomal BZC was characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and morphology. Liposomal BZC (BL10) was incorporated into gel formulation and its performances were compared to plain BZC gel (B10) and the commercially available BZC gel (B20). BL10 and B10 presented higher flux and retention on pig esophagus mucosa with a shorter lag time, when compared to B20. BZC flux was strongly correlated with in vivo anesthetic efficacy, but not with topical anesthesia duration. The retention studies did not correlate with any of the in vivo efficacy parameters. Thus, in vitro permeation study can be useful to predict anesthetic efficacy during preclinical tests, because a correlation between flux and anesthetic efficacy was observed. Therefore, in vitro assays, followed by in vivo efficacy, are necessary to confirm anesthetic performance.
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Affiliation(s)
- Michelle Franz-Montan
- Department of Biochemistry, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
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Relief of palatal injection pain by liposome-encapsulated 2% lignocaine prepared by ultrasonic dental scaler. Br J Oral Maxillofac Surg 2012; 50:784-7. [DOI: 10.1016/j.bjoms.2011.12.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Accepted: 12/21/2011] [Indexed: 11/21/2022]
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Kimi H, Yamashiro M, Hashimoto S. The local pharmacokinetics of ³H-ropivacaine and ¹⁴C-lidocaine after maxillary infiltration anesthesia in rats. Anesth Prog 2012; 59:75-81. [PMID: 22822994 DOI: 10.2344/11-14.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The effects of infiltration anesthesia with ropivacaine on the dental pulp are considered to be weak. This may be partly associated with its permeation into the oral tissue. With the objective of investigating the local pharmacokinetics of ropivacaine and lidocaine following infiltration anesthesia, we injected (3)H-ropivacaine or (14)C-lidocaine to the palatal mucosa in rats, measured distributions of radioactivity in the maxilla, and compared the local pharmacokinetics of these agents. The animals were sacrificed at various times and the maxillas were removed. The palatal mucosa and maxillary nerve were resected, and the bone was divided into 6 portions. We measured radioactivity in each tissue and calculated the level of each local anesthetic (n = 8). Lidocaine diffused to the surrounding tissue immediately after the injection, whereas ropivacaine tended to remain in the palatal mucosa for a longer period. Lidocaine showed a higher affinity for the maxillary bone than ropivacaine. There was a correlation between the distribution level of local anesthetics in the maxillary bone and that in the maxillary nerve. The lower-level effects of infiltration anesthesia with ropivacaine on the dental pulp may be because ropivacaine has a high affinity for soft tissue, and its transfer to bone is slight.
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Franz-Montan M, de Paula E, Groppo F, Ranali J, Volpato M. Efficacy of liposome-encapsulated 0.5% ropivacaine in maxillary dental anaesthesia. Br J Oral Maxillofac Surg 2012; 50:454-8. [DOI: 10.1016/j.bjoms.2011.07.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 07/14/2011] [Indexed: 11/30/2022]
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Franz-Montan M, de Paula E, Groppo FC, Silva AL, Ranali J, Volpato MC. Liposome-encapsulated ropivacaine for intraoral topical anesthesia. ACTA ACUST UNITED AC 2010; 110:800-4. [DOI: 10.1016/j.tripleo.2010.07.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Revised: 07/07/2010] [Accepted: 07/15/2010] [Indexed: 10/18/2022]
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Franz-Montan M, de Paula E, Groppo FC, Silva ALR, Ranali J, Volpato MC. Liposomal delivery system for topical anaesthesia of the palatal mucosa. Br J Oral Maxillofac Surg 2010; 50:60-4. [PMID: 21106282 DOI: 10.1016/j.bjoms.2010.10.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 10/27/2010] [Indexed: 10/18/2022]
Abstract
An effective topical agent to reduce pain during local anaesthesia of the palate is not yet available. The aim of the present study was to evaluate the efficiency of liposome-encapsulated ropivacaine in different concentrations for topical anaesthesia of the palatal mucosa. In this single-blinded, placebo-controlled, crossover study 40 (20 male) healthy volunteers were randomised to be given: liposome-encapsulated 2% ropivacaine, liposome-encapsulated 1% ropivacaine, a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA), and liposomal placebo gel, topically on to the palatal mucosa of the right canine region for 5 min each, at four different sessions. Pain associated with insertion of a 30G needle, and with injection of a local anaesthetic, was rated on a visual analogue scale (VAS). The effect of liposomal ropivacaine 1% and 2% did not differ from that of placebo (p=0.3 and p=0.1, respectively) in reducing pain during insertion of the needle. Lower VAS were obtained with EMLA. In this group VAS were lower in women than men (p=0.007). There was no difference in VAS among groups (p=0.3) as far as injection of the local anaesthetic was concerned. In conclusion, liposomal-encapsulated ropivacaine formulations did not reduce the pain of insertion of a needle into the palatal mucosa. None of the anaesthetic formulations tested, including the positive control (EMLA), were effective in reducing the pain of an injection of local anaesthetic compared with placebo.
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Affiliation(s)
- M Franz-Montan
- Department of Biochemistry, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.
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Franz-Montan M, Silva ALR, Fraceto LF, Volpato MC, Paula ED, Ranali J, Groppo FC. Liposomal encapsulation improves the duration of soft tissue anesthesia but does not induce pulpal anesthesia. J Clin Anesth 2010; 22:313-7. [PMID: 20542419 DOI: 10.1016/j.jclinane.2010.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2008] [Revised: 08/11/2009] [Accepted: 03/22/2010] [Indexed: 11/29/2022]
Abstract
STUDY OBJECTIVE To compare the topical and the pulpal anesthesia efficacy of liposomal and plain benzocaine formulations. DESIGN Double-blinded, randomized crossover study. SETTING University ambulatory dental center. PATIENTS 30 ASA physical status I volunteers. INTERVENTIONS Volunteers received, in three different sessions, topical application of liposome-encapsulated 10% benzocaine (LB10), 10% benzocaine gel (B10), and 20% benzocaine gel (B20) in the right maxillary canine mucobuccal fold. MEASUREMENTS Pain associated with the needle insertion was rated by visual analog scale (VAS) and the duration of topical anesthesia was recorded. Pulpal anesthesia was evaluated using an electric pulp tester. MAIN RESULTS VAS values (median, 1st - 3rd quartiles) were 17 cm (11 - 25), 14 cm (3 - 22), and 21 cm (9 - 21) for B10, LB10, and B20, respectively. No differences were noted among the groups (Friedman test; P = 0.58). Soft tissue anesthesia was also not different. The LB10 [10 (8 - 12) min] showed longer soft tissue anesthesia (Friedman test; P < 0.01) than the other agents [B10 = 8 (5 - 10) min, and B20 = 7 (6 - 9) min]. None of the topical benzocaine formulations tested induced pulpal anesthesia. CONCLUSIONS The encapsulation of benzocaine into liposome increased the duration of soft tissue anesthesia. However, it did not induce pulpal anesthesia.
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Affiliation(s)
- Michelle Franz-Montan
- Department of Physiological Sciences, Piracicaba Dentistry School, State University of Campinas - UNICAMP, 13414-903 Piracicaba, São Paulo, Brazil
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Tofoli GR, Cereda CM, Groppo FC, Volpato MC, Franz-Montan M, Ranali J, de Araújo DR, de Paula E. Efficacy of liposome-encapsulated mepivacaine for infiltrative anesthesia in volunteers. J Liposome Res 2010; 21:88-94. [DOI: 10.3109/08982104.2010.483596] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Wiziack Zago PM, Baroni DB, Groppo FC, de Paula E, Ranali J, Volpato MC. Anesthetic efficacy of liposomal prilocaine in maxillary infiltration anesthesia. J Liposome Res 2010; 21:81-7. [DOI: 10.3109/08982101003754393] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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de Araujo DR, Cereda CMS, Brunetto GB, Vomero VU, Pierucci A, Neto HS, de Oliveira ALR, Fraceto LF, Braga ADFDA, de Paula E. Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine. J Pharm Pharmacol 2010. [DOI: 10.1211/jpp.60.11.0005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Abstract
This study reports an investigation of the pharmacological activity, cytotoxicity and local effects of a liposomal formulation of the novel local anaesthetic ropivacaine (RVC) compared with its plain solution. RVC was encapsulated into large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine, cholesterol and α-tocopherol (4:3:0.07, mole%). Particle size, partition coefficient determination and in-vitro release studies were used to characterize the encapsulation process. Cytotoxicity was evaluated by the tetrazolium reduction test using sciatic nerve Schwann cells in culture. Local anaesthetic activity was assessed by mouse sciatic and rat infraorbital nerve blockades. Histological analysis was performed to verify the myotoxic effects evoked by RVC formulations. Plain (RVCPLAIN) and liposomal RVC (RVCLUV) samples were tested at 0.125%, 0.25% and 0.5% concentrations. Vesicle size distribution showed liposomal populations of 370 and 130 nm (85 and 15%, respectively), without changes after RVC encapsulation. The partition coefficient value was 132 ± 26 and in-vitro release assays revealed a decrease in RVC release rate (1.5 fold, P < 0.001) from liposomes. RVCLUV presented reduced cytotoxicity (P < 0.001) when compared with RVCPLAIN. Treatment with RVCLUV increased the duration (P < 0.001) and intensity of the analgesic effects either on sciatic nerve blockade (1.4–1.6 fold) and infraorbital nerve blockade tests (1.5 fold), in relation to RVCPLAIN. Regarding histological analysis, no morphological tissue changes were detected in the area of injection and sparse inflammatory cells were observed in only one of the animals treated with RVCPLAIN or RVCluv at 0.5%. Despite the differences between these preclinical studies and clinical conditions, we suggest RVCLUV as a potential new formulation, since RVC is a new and safe local anaesthetic agent.
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Affiliation(s)
- Daniele Ribeiro de Araujo
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Cintia Maria Saia Cereda
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Giovanna Bruschini Brunetto
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Viviane Urbini Vomero
- Department of Anatomy, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Amauri Pierucci
- Department of Anatomy, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | - Humberto Santo Neto
- Department of Anatomy, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
| | | | - Leonardo Fernandes Fraceto
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
- Department of Environmental Engineering, State University of São Paulo - UNESP, Sorocaba, SP, Brazil
| | | | - Eneida de Paula
- Department of Biochemistry, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP, Brazil
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Brkovic BMB, Zlatkovic M, Jovanovic D, Stojic D. Maxillary infiltration anaesthesia by ropivacaine for upper third molar surgery. Int J Oral Maxillofac Surg 2009; 39:36-41. [PMID: 20005673 DOI: 10.1016/j.ijom.2009.11.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2008] [Revised: 07/19/2009] [Accepted: 11/17/2009] [Indexed: 11/26/2022]
Abstract
The main purpose of this study was to assess the clinical efficacy and haemodynamic effects of ropivacaine for infiltration anaesthesia in patients undergoing surgical removal of upper third molars. The safety profile of ropivacaine was also studied by investigating the maximal venous plasma concentration of ropivacaine and the reactivity to ropivacaine of isolated human infraorbital arteries. Ropivacaine in concentrations of 0.5, 0.75 and 1% achieved dose-dependent parameters of maxillary infiltration aneasthesia, clinically relevant in concentrations 0.75 and 1%. Postoperative needs for analgesics were observed in 67-100% of patients. Haemodynamic parameters were stable during surgery with significant changes occuring 10 min after surgery. After maxillary infiltration of 2.0 ml 1% ropivacaine, the maximum venous plasma concentration (Cmax) was 82+/-15 microg/l. On isolated human infraorbital artery, ropivacaine (10(-4)M) induced endothelium-independent contraction. This study suggests that 0.75 and 1% ropivacaine offers adequate and safe intraoperative analgesia but not successful postoperative pain control for the surgical removal of upper third molars.
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Affiliation(s)
- B M B Brkovic
- Clinic of Oral Surgery, Faculty of Dentistry, University of Belgrade, Belgrade, Serbia
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Abstract
BACKGROUND Local anesthetic drugs, such as bupivacaine, can cause severe toxicity. Lipid emulsions have been proposed and used clinically for treating such cases. Liposomes may be an alternative for overdose treatment because of their unique structures and surface charges, which allows them to act as high affinity drug "sinks" and remove bupivacaine from solution. METHODS We conducted in vitro experiments with unilamellar and multilamellar anionic, polymer-coated liposomes to determine the amount of bupivacaine bound to liposomes in buffer solutions as a means of assessing the liposome-drug affinity. Binding experiments were also done in human serum to determine the liposomes' ability to compete with serum proteins for binding drug molecules. RESULTS Unilamellar liposomes sequestered 60%-65% and 77%-85% of bupivacaine from buffer at 1.45 and 2.9 mg lipid/mL, respectively. The increased lipid loading increased the drug uptake at all drug concentrations measured (P = 0.001, 0.002, <0.001, and 0.003 for 5, 20, 35, and 50 microM, respectively). Multilamellar liposomes bound more drug per unit mass, with 71%-90% of the total bupivacaine bound at a phospholipid concentration of 1.45 mg lipid/mL. When comparing unilamellar and multilamellar liposomes at 1.45 mg lipid/mL, the multilamellar liposomes were significantly better at 3 of the 4 drug concentrations measured (P = 0.002, 0.001, 0.001, and 0.08 for 5, 20, 35, and 50 microM, respectively). In human serum samples, unilamellar liposomes (2.9 mg lipid/mL) reduced the unbound (free) drug by 36% (P = 0.037), 56% (P = 0.022), 47% (P = 0.042), and 50% (P = 0.018) for bupivacaine concentrations of 5, 20, 35, and 50 microM, respectively. CONCLUSIONS The anionic, pegylated liposomes exhibit high binding for bupivacaine, both in buffer and in human serum. These results suggest that an IV injection of liposomes could be useful for the treatment of bupivacaine toxicity through drug redistribution.
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Affiliation(s)
- Brett A Howell
- Department of Chemical Engineering, University of Florida, Gainesville, Florida 32611, USA
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Current World Literature. Curr Opin Anaesthesiol 2008; 21:684-93. [DOI: 10.1097/aco.0b013e328312c01b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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