Delivery of Local Anesthesia: Current Strategies, Safety, and Future Prospects

Author(s): Guo-Liang Liu, Wen-Chao Bian, Peng Zhao, Li-Hua Sun*.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 6 , 2019

Graphical 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.

Keywords: Anesthesia, liposome, drug delivery, nanotechnology, levobupivacaine, nanomedicine.

Hewson, D.W.; Worcester, F.; Sprinks, J.; Smith, M.D.; Buchanan, H.; Breedon, P.; Hardman, J.G.; Bedforth, N.M. Anaesthetist-controlled versus patient-maintained effect-site targeted propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia: Study protocol for a parallel-group randomised comparison trial. Trials, 2019, 20(1), 129-131.
Hashim, P.W.; Nia, J.K.; Taliercio, M.; Goldenberg, G. Local anesthetics in cosmetic dermatology. Cutis, 2017, 99(6), 393-397.
Bordianu, A.; Bobirca, F. Facial skin cancer surgery under local anesthesia. J. Med. Life, 2018, 11(3), 231-237.
Visconti, G.; Salgarello, M. Free-style capillary perforator-based island flaps for reconstruction of skin cancer defects of the face, body, and extremities. Ann. Plast. Surg., 2018, 81(2), 192-197.
Reorganized text. JAMA Otolaryngol. Head Neck Surg., 2015, 141(5), 428.
Tasbihgou, S.R.; Vogels, M.F.; Absalom, A.R. Accidental awareness during general anaesthesia - a narrative review. Anaesthesia, 2018, 73(1), 112-122.
Lee, B.H.; Kumar, K.K.; Wu, E.C.; Wu, C.L. Role of regional anesthesia and analgesia in the opioid epidemic. Reg. Anesth. Pain Med., 2019, 13, 100-102.
Vahabi, S.; Eatemadi, A. Nanoliposome encapsulated anesthetics for local anesthesia application. Biomed. Pharmacother., 2017, 86, 1-7.
Sunderland, S.; Yarnold, C.H.; Head, S.J.; Osborn, J.A.; Purssell, A.; Peel, J.K.; Schwarz, S.K. 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., 2016, 41(1), 22-27.
Raymond, S.A.; Steffensen, S.C.; Gugino, L.D.; Strichartz, G.R. The role of length of nerve exposed to local anesthetics in impulse blocking action. Anesth. Analg., 1989, 68(5), 563-670.
Saeki, S.; Kobayashi, M.; Miyake, E.; Suzuki, T. Crisis management during regional anesthesia including peripheral nerve block, epidural anesthesia and spinal anesthesia. Masui, 2009, 58(5), 595-603.
McCarthy, D.; McNamara, J.; Galbraith, J.; Loughnane, F.; Shorten, G.; Iohom, G. A comparison of the analgesic efficacy of local infiltration analgesia vs. intrathecal morphine after total knee replacement: A randomised controlled trial. Eur. J. Anaesthesiol., 2019, 36(4), 264-271.
Essving, P.; Axelsson, K.; Aberg, E.; Spannar, H.; Gupta, A.; Lundin, A. Local infiltration analgesia versus intrathecal morphine for postoperative pain management after total knee arthroplasty: A randomized controlled trial. Anesth. Analg., 2011, 113(4), 926-933.
Kampitak, W.; Tanavalee, A.; Ngarmukos, S.; Amarase, C.; Songthamwat, B.; Boonshua, A. Comparison of adductor canal block versus local infiltration analgesia on postoperative pain and functional outcome after total knee arthroplasty: A randomized controlled trial. Malays. Orthop. J., 2018, 12(1), 7-14.
Ruetsch, Y.A.; Boni, T.; Borgeat, A. From cocaine to ropivacaine: The history of local anesthetic drugs. Curr. Top. Med. Chem., 2001, 1(3), 175-182.
Swennen, C.; Bredin, S.; Eap, C.; Mensa, C.; Ohl, X.; Girard, V. Local infiltration analgesia with ropivacaine in acute fracture of thoracolumbar junction surgery. Orthop. Traumatol. Surg. Res., 2017, 103(2), 291-294.
Tam, K.W.; Chen, S.Y.; Huang, T.W.; Lin, C.C.; Su, C.M.; Li, C.L.; Ho, Y.S.; Wang, W.Y.; Wu, C.H. Effect of wound infiltration with ropivacaine or bupivacaine analgesia in breast cancer surgery: A meta-analysis of randomized controlled trials. Int. J. Surg., 2015, 22, 79-85.
Dominguez, D.A.; Ely, S.; Bach, C.; Lee, T.; Velotta, J.B. Impact of intercostal nerve blocks using liposomal versus standard bupivacaine on length of stay in minimally invasive thoracic surgery patients. J. Thorac. Dis., 2018, 10(12), 6873-6879.
Parascandola, S.A.; Ibanez, J.; Keir, G.; Anderson, J.; Plankey, M.; Flynn, D.; Cody, C.; De Marchi, L.; Margolis, M.; Blair Marshall, M. Liposomal bupivacaine versus bupivacaine/epinephrine after video-assisted thoracoscopic wedge resectiondagger. Interact. Cardiovasc. Thorac. Surg., 2017, 24(6), 925-930.
Ng, A.; Swami, A.; Smith, G.; Davidson, A.C.; Emembolu, J. The analgesic effects of intraperitoneal and incisional bupivacaine with epinephrine after total abdominal hysterectomy. Anesth. Analg., 2002, 95(1), 158-162.
Wolfe, J.W.; Butterworth, J.F. Local anesthetic systemic toxicity: update on mechanisms and treatment. Curr. Opin. Anaesthesiol., 2011, 24(5), 561-566.
Mutlu, I.N.; Kocak, B.; Baykara Ulusan, M.; Ulusan, K.; Cakir, M.S.; Kilickesmez, O. Regional anesthesia with epinephrine-containing lidocaine reduces pericatheter bleeding after tunneled hemodialysis catheter placement. Hemodial. Int., 2018, 23(1), 26-32.
Zink, W.; Graf, B.M. Local anesthetic myotoxicity. Reg. Anesth. Pain Med., 2004, 29(4), 333-340.
Singh, S.; Kumar, A.; Karakoti, A.; Seal, S.; Self, W.T. Unveiling the mechanism of uptake and sub-cellular distribution of cerium oxide nanoparticles. Mol. Biosyst., 2010, 6(10), 1813-1820.
Vassie, J.A.; Whitelock, J.M.; Lord, M.S. Endocytosis of cerium oxide nanoparticles and modulation of reactive oxygen species in human ovarian and colon cancer cells. Acta Biomater., 2017, 50, 127-141.
Chang, H.I.; Yeh, M.K. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int. J. Nanomedicine, 2012, 7, 49-60.
Patel, H.M.; Moghimi, S.M. Serum-mediated recognition of liposomes by phagocytic cells of the reticuloendothelial system - The concept of tissue specificity. Adv. Drug Deliv. Rev., 1998, 32(1-2), 45-60.
Benvegnu, T.; Lemiegre, L.; Cammas-Marion, S. New generation of liposomes called archaeosomes based on natural or synthetic archaeal lipids as innovative formulations for drug delivery. Recent Pat. Drug Deliv. Formul., 2009, 3(3), 206-220.
Savaliya, R.; Singh, P.; Singh, S. Pharmacological drug delivery strategies for improved therapeutic effects: Recent advances. Curr. Pharm. Des., 2016, 22(11), 1506-1520.
Savaliya, R.; Shah, D.; Singh, R.; Kumar, A.; Shanker, R.; Dhawan, A.; Singh, S. Nanotechnology in disease diagnostic techniques. Curr. Drug Metab., 2015, 16(8), 645-661.
Li, H.; Marotta, D.E.; Kim, S.; Busch, T.M.; Wileyto, E.P.; Zheng, G. High payload delivery of optical imaging and photodynamic therapy agents to tumors using phthalocyanine-reconstituted low-density lipoprotein nanoparticles. J. Biomed. Opt., 2005, 10(4), 41203.
Kim, J.K.; Yuan, H.; Nie, J.; Yang, Y.T.; Leggas, M.; Potter, P.M.; Rinehart, J.; Jay, M.; Lu, X. High payload dual therapeutic-imaging nanocarriers for triggered tumor delivery. Small, 2012, 8(18), 2895-2903.
Ambati, J.; Lopez, A.M.; Cochran, D.; Wattamwar, P.; Bean, K.; Dziubla, T.D.; Rankin, S.E. Engineered silica nanocarriers as a high-payload delivery vehicle for antioxidant enzymes. Acta Biomater., 2012, 8(6), 2096-2103.
Sudimack, J.; Lee, R.J. Targeted drug delivery via the folate receptor. Adv. Drug Deliv. Rev., 2000, 41(2), 147-162.
Arap, W.; Pasqualini, R.; Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science, 1998, 279(5349), 377-380.
Karakoti, A.S.; Shukla, R.; Shanker, R.; Singh, S. Surface functionalization of quantum dots for biological applications. Adv. Colloid Interface Sci., 2015, 215, 28-45.
Fatima, M.T.; Islam, Z.; Ahmad, E.; Barreto, G.E.; Md Ashraf, G. Ionic gradient liposomes: Recent advances in the stable entrapment and prolonged released of local anesthetics and anticancer drugs. Biomed. Pharmacother., 2018, 107, 34-43.
Haran, G.; Cohen, R.; Bar, L.K.; Barenholz, Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim. Biophys. Acta, 1993, 1151(2), 201-215.
Oliveira, J.D.; Ribeiro, L.N.M.; Da Silva, R.G.H.; Casadei, B.R.; Couto, V.M.; Martinez, E.F.; De Paula, E. Sustained release from ionic-gradient liposomes significantly decreases etidocaine cytotoxicity. Pharm. Res., 2018, 35(12), 229.
De Paula, E.; Schreier, S.; Jarrell, H.C.; Fraceto, L.F. Preferential location of lidocaine and etidocaine in lecithin bilayers as determined by EPR, fluorescence and 2H NMR. Biophys. Chem., 2008, 132(1), 47-54.
Springer, B.D.; Mason, J.B.; Odum, S.M. Systemic safety of liposomal bupivacaine in simultaneous bilateral total knee arthroplasty. J. Arthroplasty, 2018, 33(1), 97-101.
Bagsby, D.T.; Ireland, P.H.; Meneghini, R.M. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J. Arthroplasty, 2014, 29(8), 1687-1690.
Meneghini, R.M.; Bagsby, D.; Ireland, P.H.; Ziemba-Davis, M.; Lovro, L.R. Liposomal bupivacaine injection technique in total knee arthroplasty. J. Knee Surg., 2017, 30(1), 88-96.
Wu, Z.Q.; Min, J.K.; Wang, D.; Yuan, Y.J.; Li, H. Liposome bupivacaine for pain control after total knee arthroplasty: A meta-analysis. J. Orthop. Surg. Res., 2016, 11(1), 84.
Uskova, A.; O’Connor, J.E. Liposomal bupivacaine for regional anesthesia. Curr. Opin. Anaesthesiol., 2015, 28(5), 593-597.
Franz-Montan, M.; Cereda, C.M.; Gaspari, A.; Da Silva, C.M.; de Araujo, D.R.; Padula, C.; Santi, P.; Narvaes, E.; Novaes, P.D.; Groppo, F.C.; De Paula, E. Liposomal-benzocaine gel formulation: correlation between in vitro assays and in vivo topical anesthesia in volunteers. J. Liposome Res., 2013, 23(1), 54-60.
Mura, P.; Maestrelli, F.; Gonzalez-Rodriguez, M.L.; Michelacci, I.; Ghelardini, C.; Rabasco, A.M. Development, characterization and in vivo evaluation of benzocaine-loaded liposomes. Eur. J. Pharm. Biopharm., 2007, 67(1), 86-95.
Tofoli, G.R.; Cereda, C.M.; Araujo, D.R.; Franz-Montan, M.; Groppo, F.C.; Quaglio, D.; Pedrazzoli, Junior J.; Calafatti, S.A.; Barros, F.A.; De Paula, E. Pharmacokinetic study of liposome-encapsulated and plain mepivacaine formulations injected intra-orally in volunteers. J. Pharm. Pharmacol., 2012, 64(3), 397-403.
Tofoli, G.R.; Cereda, C.M.; Groppo, F.C.; Volpato, M.C.; Franz-Montan, M.; Ranali, J.; De Araujo, D.R.; De Paula, E. Efficacy of liposome-encapsulated mepivacaine for infiltrative anesthesia in volunteers. J. Liposome Res., 2011, 21(1), 88-94.
Franz-Montan, M.; Silva, A.L.; Cogo, K.; Bergamaschi Cde, C.; Volpato, M.C.; Ranali, J.; De Paula, E.; Groppo, F.C. Liposome-encapsulated ropivacaine for topical anesthesia of human oral mucosa. Anesth. Analg., 2007, 104(6), 1528-1531.
Zhan, C.; Wang, W.; McAlvin, J.B.; Guo, S.; Timko, B.P.; Santamaria, C.; Kohane, D.S. Phototriggered local anesthesia. Nano Lett., 2016, 16(1), 177-181.
Zhan, C.; Wang, W.; Santamaria, C.; Wang, B.; Rwei, A.; Timko, B.P.; Kohane, D.S. Ultrasensitive phototriggered local anesthesia. Nano Lett., 2017, 17(2), 660-665.
Arakawa, Y.; Kawakami, S.; Yamashita, F.; Hashida, M. Effect of low-molecular-weight beta-cyclodextrin polymer on release of drugs from mucoadhesive buccal film dosage forms. Biol. Pharm. Bull., 2005, 28(9), 1679-1683.
Kamada, M.; Hirayama, F.; Udo, K.; Yano, H.; Arima, H.; Uekama, K. Cyclodextrin conjugate-based controlled release system: Repeated- and prolonged-releases of ketoprofen after oral administration in rats. J. Control. Release, 2002, 82(2-3), 407-416.
Nakanishi, K.; Masukawa, T.; Nadai, T.; Yoshii, K.; Okada, S.; Miyajima, K. Sustained release of flufenamic acid from a drug-triacetyl-beta-cyclodextrin complex. Biol. Pharm. Bull., 1997, 20(1), 66-70.
Cook, O.; Nusstein, J.; Drum, M.; Fowler, S.; Reader, A.; Draper, J. Anesthetic efficacy of a combination of 4% prilocaine/2% lidocaine with epinephrine for the inferior alveolar nerve block: A prospective, randomized, double-blind study. J. Endod., 2018, 44(5), 683-688.

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Article Details

Year: 2019
Page: [533 - 539]
Pages: 7
DOI: 10.2174/1389200220666190610155049
Price: $58

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