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Safety and efficacy concerns of modern strategies of local anesthetics delivery

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Abstract

In the last few decades, several formulations have evolved to realize better efficacy of administered anesthesia. These innovative formulations have facilitated surgeons to perform operations under purely local anesthesia, which provides extra protection and comfort to patients. Ease of delivery of local anesthesia is the need of the current generation, because some of the standard procedures are performed without the use of any sedative agent. Therefore, we are presenting here the various approaches of administration of local anesthetics by the surgeons. To construct a comprehensive report on various methods of anesthesia, we followed a systematic literature search of bibliographic databases of published articles recently in the international journals and publishers of repute. A comprehensive study of several reports of the field indicates that there are significant progresses towards developing novel formulations of anesthesia drugs as well as strategies of delivery. Among formulations, nanoparticle-based delivery approaches, including polymeric, liposomal, and micellar structures, have offered the much needed efficacy with low toxicity. Therefore, several of such techniques are at various stages of clinical trials. Nanotechnology-based delivery approaches have significantly emerged in recent past due to the low systemic toxicity and better efficacy of the nonconventional local anesthetics. The other methods of local anesthesia delivery such as transdermal, magnetophoresis, electrophoresis, and iontophoresis are frequently used due to them being minimally invasive and locally effective. Therefore, the combination of the nanotechnological methods with above mentioned techniques would significantly enhance the overall process of local anesthesia delivery and efficacy.

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References

  • Agarwal A, Gautam S, Gupta D, Singh U (2007) Transdermal diclofenac patch vs eutectic mixture of local anesthetics for venous cannulation pain. Can J Anaesth 54:196–200

    PubMed  Google Scholar 

  • Agarwal R, Iezhitsa I, Agarwal P, Abdul Nasir NA, Razali N, Alyautdin R, Ismail NM (2016) Liposomes in topical ophthalmic drug delivery: an update. Drug Deliv 23:1075–1091

    CAS  PubMed  Google Scholar 

  • Ali I, Saifullah S, Ahmed F, Ullah S, Imkan I, Hussain K, Imran M, Shah MR (2019) Synthesis of long-tail nonionic surfactants and their investigation for vesicle formation, drug entrapment, and biocompatibility. J Liposome Res 13:1–8

    Google Scholar 

  • Badri W, Miladi K, Nazari QA, Greige-Gerges H, Fessi H, Elaissari A (2016) Encapsulation of NSAIDs for inflammation management: overview, progress, challenges and prospects. Int J Pharm 515:757–773

    CAS  PubMed  Google Scholar 

  • Bnyan R, Khan I, Ehtezazi T, Saleem I, Gordon S, O'Neill F, Roberts M (2018) Surfactant effects on lipid-based vesicles properties. J Pharm Sci 107:1237–1246

    CAS  PubMed  Google Scholar 

  • Boogaerts JG, Lafont ND, Declercq AG, Luo HC, Gravet ET, Bianchi JA, Legros FJ (1994) Epidural administration of liposome-associated bupivacaine for the management of postsurgical pain: a first study. J Clin Anesth 6:315–320

    CAS  PubMed  Google Scholar 

  • Bordianu A, Bobirca F (2018) Facial skin cancer surgery under local anesthesia. J Med Life 11:231–237

    PubMed  Google Scholar 

  • Bragagni M, Maestrelli F, Mennini N, Ghelardini C, Mura P (2010) Liposomal formulations of prilocaine: effect of complexation with hydroxypropyl-ss-cyclodextrin on drug anesthetic efficacy. J Liposome Res 20:315–322

    CAS  PubMed  Google Scholar 

  • Cagnie B, Vinck E, Rimbaut S, Vanderstraeten G (2003) Phonophoresis versus topical application of ketoprofen: comparison between tissue and plasma levels. Phys Ther 83:707–712

    PubMed  Google Scholar 

  • Cereda CM, de Araujo DR, Brunetto GB, De Paula E (2004) Liposomal prilocaine: preparation, characterization, and in vivo evaluation. J Pharm Pharm Sci 7:235–240

    CAS  PubMed  Google Scholar 

  • Cereda CM, Brunetto GB, de Araujo DR, de Paula E (2006) Liposomal formulations of prilocaine, lidocaine and mepivacaine prolong analgesic duration. Can J Anaesth 53:1092–1097

    PubMed  Google Scholar 

  • Cereda CM, Tofoli GR, de Brito Junior RB, de Jesus MB, Fraceto LF, Groppo FC, de Araujo DR, de Paula E (2008) Stability and local toxicity evaluation of a liposomal prilocaine formulation. J Liposome Res 18:329–339

    CAS  PubMed  Google Scholar 

  • Cerqueira-Coutinho C, Dos Santos EP, Mansur CR (2016) Niosomes as nano-delivery systems in the pharmaceutical field. Crit Rev Ther Drug Carrier Syst 33:195–212

    PubMed  Google Scholar 

  • Cheng LC, Jiang Y, Xie Y, Qiu LL, Yang Q, Lu HY (2017) Novel amphiphilic folic acid-cholesterol-chitosan micelles for paclitaxel delivery. Oncotarget 8:3315–3326

    PubMed  Google Scholar 

  • Cummings KC 3rd, Napierkowski DE, Parra-Sanchez I, Kurz A, Dalton JE, Brems JJ, Sessler DI (2011) Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Br J Anaesth 107:446–453

    CAS  PubMed  Google Scholar 

  • Dale EL, Kluemper CT, Cowart SJ, Jemison M, Kennedy JW, Gao L, Brzezienski MA, Rehm J (2019) Bupivacaine extended-release liposomal injection versus bupivacaine HCl for early postoperative pain control following wrist operations: a prospective, randomized control trial. J Hand Surg Am

  • Daraee H, Etemadi A, Kouhi M, Alimirzalu S, Akbarzadeh A (2016) Application of liposomes in medicine and drug delivery. Artif Cells Nanomed Biotechnol 44:381–391

    CAS  PubMed  Google Scholar 

  • de Araujo DR, Cereda CM, Brunetto GB, Pinto LM, Santana MH, de Paula E (2004) Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice. Can J Anaesth 51:566–572

    PubMed  Google Scholar 

  • Dubey S, Kalia YN (2010) Non-invasive iontophoretic delivery of enzymatically active ribonuclease A (13.6 kDa) across intact porcine and human skins. J Control Release 145:203–209

    CAS  PubMed  Google Scholar 

  • Franz-Montan M, de Paula E, Groppo FC, Silva AL, Ranali J, Volpato MC (2010) Liposome-encapsulated ropivacaine for intraoral topical anesthesia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110:800–804

    PubMed  Google Scholar 

  • Franz-Montan M, de Paula E, Groppo FC, Silva AL, Ranali J, Volpato MC (2012) Liposomal delivery system for topical anaesthesia of the palatal mucosa. Br J Oral Maxillofac Surg 50:60–64

    CAS  PubMed  Google Scholar 

  • Giannantoni A, Di Stasi SM, Chancellor MB, Costantini E, Porena M (2006) New frontiers in intravesical therapies and drug delivery. Eur Urol 50:1183–1193 (discussion 1193)

    CAS  PubMed  Google Scholar 

  • Gorantla S, Waghule T, Rapalli VK, Singh PP, Dubey SK, Saha RN, Singhvi G (2020) Advanced hydrogels based drug delivery systems for ophthalmic delivery. Recent Pat Drug Deliv Formul 13:291–300

    Google Scholar 

  • Grant SA, Nielsen KC, Greengrass RA, Steele SM, Klein SM (2001) Continuous peripheral nerve block for ambulatory surgery. Reg Anesth Pain Med 26:209–214

    CAS  PubMed  Google Scholar 

  • Grant GJ, Barenholz Y, Bolotin EM, Bansinath M, Turndorf H, Piskoun B, Davidson EM (2004) A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia. Anesthesiology 101:133–137

    CAS  PubMed  Google Scholar 

  • Gratieri T, Kalaria D, Kalia YN (2011) Non-invasive iontophoretic delivery of peptides and proteins across the skin. Expert Opin Drug Deliv 8:645–663

    CAS  PubMed  Google Scholar 

  • Grit M, Crommelin DJ (1993) Chemical stability of liposomes: implications for their physical stability. Chem Phys Lipids 64:3–18

    CAS  PubMed  Google Scholar 

  • Hashim PW, Nia JK, Taliercio M, Goldenberg G (2017) Local anesthetics in cosmetic dermatology. Cutis 99:393–397

    PubMed  Google Scholar 

  • He CX, He ZG, Gao JQ (2010) Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs. Expert Opin Drug Deliv 7:445–460

    CAS  PubMed  Google Scholar 

  • Hewson DW, Worcester F, Sprinks J, Smith MD, Buchanan H, Breedon P, Hardman JG, Bedforth NM (2019) Anaesthetist-controlled versus patient-maintained effect-site targeted propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia (ACCEPTS): study protocol for a parallel-group randomised comparison trial. Trials 20:129

    PubMed  PubMed Central  Google Scholar 

  • Khodabakhsh F, Muyldermans S, Behdani M, Kazemi-Lomedasht F (2020) Liposomal delivery of vascular endothelial growth factor/receptors and their inhibitors. J Drug Target 4:379–385

    Google Scholar 

  • Kim TY, Jung DI, Kim YI, Yang JH, Shin SC (2007) Anesthetic effects of lidocaine hydrochloride gel using low frequency ultrasound of 0.5 MHz. J Pharm Pharm Sci 10:1–8

    CAS  PubMed  Google Scholar 

  • Klein SM, Grant SA, Greengrass RA, Nielsen KC, Speer KP, White W, Warner DS, Steele SM (2000) Interscalene brachial plexus block with a continuous catheter insertion system and a disposable infusion pump. Anesth Analg 91:1473–1478

    CAS  PubMed  Google Scholar 

  • Kogan A, Garti N (2006) Microemulsions as transdermal drug delivery vehicles. Adv Colloid Interface Sci 123–126:369–385

    PubMed  Google Scholar 

  • Kuzma PJ, Kline MD, Calkins MD, Staats PS (1997) Progress in the development of ultra-long-acting local anesthetics. Reg Anesth 22:543–551

    CAS  PubMed  Google Scholar 

  • Le Corre P, Rytting JH, Gajan V, Chevanne F, Le Verge R (1997) In vitro controlled release kinetics of local anaesthetics from poly(D, L-lactide) and poly(lactide-co-glycolide) microspheres. J Microencapsul 14:243–255

    PubMed  Google Scholar 

  • Liu X, Zhao Q (2019) Long-term anesthetic analgesic effects: comparison of tetracaine loaded polymeric nanoparticles, solid lipid nanoparticles, and nanostructured lipid carriers in vitro and in vivo. Biomed Pharmacother 117:109057

    CAS  PubMed  Google Scholar 

  • Maestrelli F, Gonzalez-Rodriguez ML, Rabasco AM, Ghelardini C, Mura P (2010) New, “drug-in cyclodextrin-in deformable liposomes” formulations to improve the therapeutic efficacy of local anaesthetics. Int J Pharm 395:222–231

    CAS  PubMed  Google Scholar 

  • Magarkar A, Dhawan V, Kallinteri P, Viitala T, Elmowafy M, Rog T, Bunker A (2014) Cholesterol level affects surface charge of lipid membranes in saline solution. Sci Rep 4:5005

    CAS  PubMed  PubMed Central  Google Scholar 

  • Malinovsky JM, Le Corre P, Meunier JF, Chevanne F, Pinaud M, Leverge R, Legros F (1999) A dose-response study of epidural liposomal bupivacaine in rabbits. J Control Release 60:111–119

    CAS  PubMed  Google Scholar 

  • Manes S, Martinez AC (2004) Cholesterol domains regulate the actin cytoskeleton at the leading edge of moving cells. Trends Cell Biol 14:275–278

    CAS  PubMed  Google Scholar 

  • Masud S, Wasnich RD, Ruckle JL, Garland WT, Halpern SW, Mee-Lee D, Ashburn MA, Campbell JC (2010) Contribution of a heating element to topical anesthesia patch efficacy prior to vascular access: results from two randomized, double-blind studies. J Pain Symptom Manage 40:510–519

    PubMed  Google Scholar 

  • Mazloomdoost D, Pauls RN, Hennen EN, Yeung JY, Smith BC, Kleeman SD, Crisp CC (2017) Liposomal bupivacaine decreases pain following retropubic sling placement: a randomized placebo-controlled trial. Am J Obstet Gynecol 217:598e1–598e11

    Google Scholar 

  • McCartney CJ, Brull R, Chan VW, Katz J, Abbas S, Graham B, Nova H, Rawson R, Anastakis DJ, von Schroeder H (2004) Early but no long-term benefit of regional compared with general anesthesia for ambulatory hand surgery. Anesthesiology 101:461–467

    PubMed  Google Scholar 

  • McLure HA, Rubin AP (2005) Review of local anaesthetic agents. Minerva Anestesiol 71:59–74

    CAS  PubMed  Google Scholar 

  • Metry AA, Kamal MM, Ragaei MZ, Nakhla GM, Wahba RM (2018) Transdermal ketoprofen patch in comparison to eutectic mixture of local anesthetic cream and subcutaneous lidocaine to control pain due to venous cannulation. Anesth Essays Res 12:914–918

    PubMed  PubMed Central  Google Scholar 

  • Muniz BV, Baratelli D, Di Carla S, Serpe L, da Silva CB, Guilherme VA, Ribeiro LNM, Cereda CMS, de Paula E, Volpato MC, Groppo FC, Fraceto LF, Franz-Montan M (2018) Hybrid hydrogel composed of polymeric nanocapsules co-loading lidocaine and prilocaine for topical intraoral anesthesia. Sci Rep 8:17972

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murthy SN, Sen A, Hui SW (2004) Surfactant-enhanced transdermal delivery by electroporation. J Control Release 98:307–315

    CAS  PubMed  Google Scholar 

  • Murthy SN, Sammeta SM, Bowers C (2010) Magnetophoresis for enhancing transdermal drug delivery: mechanistic studies and patch design. J Control Release 148:197–203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Polat BE, Blankschtein D, Langer R (2010) Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs. Expert Opin Drug Deliv 7:1415–1432

    CAS  PubMed  PubMed Central  Google Scholar 

  • Polat BE, Hart D, Langer R, Blankschtein D (2011) Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J Control Release 152:330–348

    CAS  PubMed  PubMed Central  Google Scholar 

  • Power I (2007) Fentanyl HCl iontophoretic transdermal system (ITS): clinical application of iontophoretic technology in the management of acute postoperative pain. Br J Anaesth 98:4–11

    CAS  PubMed  Google Scholar 

  • Prabhakar A, Ward CT, Watson M, Sanford J, Fiza B, Moll V, Kaye RJ, Morgan Hall O, Cornett EM, Urman RD, Kaye AD (2019) Liposomal bupivacaine and novel local anesthetic formulations. Best Pract Res Clin Anaesthesiol 33:425–432

    PubMed  Google Scholar 

  • Rose JS, Neal JM, Kopacz DJ (2005) Extended-duration analgesia: update on microspheres and liposomes. Reg Anesth Pain Med 30:275–285

    CAS  PubMed  Google Scholar 

  • Sammeta SM, Vaka SR, Murthy SN (2009) Transdermal drug delivery enhanced by low voltage electropulsation (LVE). Pharm Dev Technol 14:159–164

    CAS  PubMed  Google Scholar 

  • Sammeta SM, Repka MA, Narasimha MS (2011) Magnetophoresis in combination with chemical enhancers for transdermal drug delivery. Drug Dev Ind Pharm 37:1076–1082

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scalia S, Young PM, Traini D (2015) Solid lipid microparticles as an approach to drug delivery. Expert Opin Drug Deliv 12:583–599

    CAS  PubMed  Google Scholar 

  • Sharata HH, Katz KH (1996) Liposomes. Int J Dermatol 35:761–769

    CAS  PubMed  Google Scholar 

  • Sharma G, Kamboj S, Thakur K, Negi P, Raza K, Katare OP (2017) Delivery of thermoresponsive-tailored mixed micellar nanogel of lidocaine and prilocaine with improved dermatokinetic profile and therapeutic efficacy in topical anaesthesia. AAPS PharmSciTech 18:790–802

    CAS  PubMed  Google Scholar 

  • Sunderland S, Yarnold CH, Head SJ, Osborn JA, Purssell A, Peel JK, Schwarz SK (2016) Regional versus general anesthesia and the incidence of unplanned health care resource utilization for postoperative pain after wrist fracture surgery: results from a retrospective quality improvement project. Reg Anesth Pain Med 41:22–27

    CAS  PubMed  Google Scholar 

  • Takenami T, Yagishita S, Nara Y, Tsai YH, Hiruma H, Kawakami T, Hoka S (2009) Spinal procaine is less neurotoxic than mepivacaine, prilocaine and bupivacaine in rats. Reg Anesth Pain Med 34:189–195

    CAS  PubMed  Google Scholar 

  • Takenami T, Wang G, Nara Y, Fukushima S, Yagishita S, Hiruma H, Kawakami T, Okamoto H (2012) Intrathecally administered ropivacaine is less neurotoxic than procaine, bupivacaine, and levobupivacaine in a rat spinal model. Can J Anaesth 59:456–465

    PubMed  Google Scholar 

  • Tofoli GR, Cereda CM, de Araujo DR, de Paula E, Brito RB Jr, Pedrazzoli J Jr, Meurer E, Barros FA, Groppo FC, Volpato MC, Ranali J (2010) Pharmacokinetic and local toxicity studies of liposome-encapsulated and plain mepivacaine solutions in rats. Drug Deliv 17:68–76

    CAS  PubMed  Google Scholar 

  • Tofoli GR, Cereda CM, Groppo FC, Volpato MC, Franz-Montan M, Ranali J, de Araujo DR, de Paula E (2011) Efficacy of liposome-encapsulated mepivacaine for infiltrative anesthesia in volunteers. J Liposome Res 21:88–94

    CAS  PubMed  Google Scholar 

  • Tofoli GR, Cereda CM, Araujo DR, Franz-Montan M, Groppo FC, Quaglio D, Pedrazzoli Junior J, Calafatti SA, Barros FA, de Paula E (2012) Pharmacokinetic study of liposome-encapsulated and plain mepivacaine formulations injected intra-orally in volunteers. J Pharm Pharmacol 64:397–403

    CAS  PubMed  Google Scholar 

  • Vahabi S, Eatemadi A (2017) Nanoliposome encapsulated anesthetics for local anesthesia application. Biomed Pharmacother 86:1–7

    CAS  PubMed  Google Scholar 

  • Veneziano G, Tripi J, Tumin D, Hakim M, Martin D, Beltran R, Klingele K, Bhalla T, Tobias JD (2016) Femoral nerve blockade using various concentrations of local anesthetic for knee arthroscopy in the pediatric population. J Pain Res 9:1073–1079

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner A, Vorauer-Uhl K (2011) Liposome technology for industrial purposes. J Drug Deliv 2011:591325

    PubMed  Google Scholar 

  • Wakita R, Oono Y, Oogami S, Hayashi S, Umino M (2009) The relation between epinephrine concentration and the anesthetic effect of lidocaine iontophoresis. Pain Pract 9:115–121

    PubMed  Google Scholar 

  • Wang Y, Wang X, Wang X, Song Y, Wang X, Hao J (2019) Design and development of lidocaine microemulsions for transdermal delivery. AAPS PharmSciTech 20:63

    CAS  PubMed  Google Scholar 

  • Weiniger CF, Golovanevski M, Sokolsky-Papkov M, Domb AJ (2010) Review of prolonged local anesthetic action. Expert Opin Drug Deliv 7:737–752

    CAS  PubMed  Google Scholar 

  • Wen H, Jung H, Li X (2015) Drug delivery approaches in addressing clinical pharmacology-related issues: opportunities and challenges. AAPS J 17:1327–1340

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wiziack Zago PM, Baroni DB, Groppo FC, de Paula E, Ranali J, Volpato MC (2011) Anesthetic efficacy of liposomal prilocaine in maxillary infiltration anesthesia. J Liposome Res 21:81–87

    CAS  PubMed  Google Scholar 

  • Yang S, Liu C, Liu W, Yu H, Zheng H, Zhou W, Hu Y (2013) Preparation and characterization of nanoliposomes entrapping medium-chain fatty acids and vitamin C by lyophilization. Int J Mol Sci 14:19763–19773

    PubMed  PubMed Central  Google Scholar 

  • You P, Yuan R, Chen C (2017) Design and evaluation of lidocaine- and prilocaine-coloaded nanoparticulate drug delivery systems for topical anesthetic analgesic therapy: a comparison between solid lipid nanoparticles and nanostructured lipid carriers. Drug Des Devel Ther 11:2743–2752

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu HY, Li SD, Sun P (2002) Kinetic and dynamic studies of liposomal bupivacaine and bupivacaine solution after subcutaneous injection in rats. J Pharm Pharmacol 54:1221–1227

    CAS  PubMed  Google Scholar 

  • Yuan JS, Ansari M, Samaan M, Acosta EJ (2008) Linker-based lecithin microemulsions for transdermal delivery of lidocaine. Int J Pharm 349:130–143

    CAS  PubMed  Google Scholar 

  • Zhang X, Liang N, Gong X, Kawashima Y, Cui F, Sun S (2019) Tumor-targeting micelles based on folic acid and alpha-tocopherol succinate conjugated hyaluronic acid for paclitaxel delivery. Colloids Surf B Biointerfaces 177:11–18

    CAS  PubMed  Google Scholar 

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Acknowledgements

Authors thank Jilin University for the generous support.

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  1. Department of Anesthesiology, The Second Hospital of Jilin University, No 218 Ziqiang Street, Changchun, 130041, Jilin, People’s Republic of China

    Mingxin Ji, Guoliang Liu, Yunfeng Cui & Peng Zhao

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  1. Mingxin Ji
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  2. Guoliang Liu
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Correspondence to Peng Zhao.

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Ji, M., Liu, G., Cui, Y. et al. Safety and efficacy concerns of modern strategies of local anesthetics delivery. 3 Biotech 10, 333 (2020). https://doi.org/10.1007/s13205-020-02309-y

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