Safety and efficacy concerns of modern strategies of local anesthetics delivery

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.

Introduction

Administration of local anesthesia agents is used to obtain analgesia during trans-and postoperative procedures to control the pain conditions in patients (McLure and Rubin 2005; Rose et al. 2005). Considering their value as one of the essential components of operative procedures, they are of tremendous clinical value (Weiniger et al. 2010; Kuzma et al. 1997). Mechanistically, these agents induce a potent but reversible inhibition of nerve impulses mediated by binding with sodium channels, thus impede the exchange of sodium ions across the nerve fibers. 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. For example, limb operations, cosmetic reconstruction of face, skin, and other body parts are very commonly being executed under the awake condition of the patients (Hewson et al. 2019; Hashim et al. 2017; Bordianu and Bobirca 2018). Therefore, the role of local anesthesia has recently been realized beyond the life-threatening diseases to cosmetic dermatology. Along with novel formulations, improved delivery strategies of local anesthetic agents have also facilitated better management of pain in patients. This review article has been prepared to comprehensively cover the various formulations of local anesthesia and discuss their advantages and associated risks.

Need of local anesthesia and effective delivery system

General and regional anesthesia are frequently involved with side effects and other serious concerns; therefore, research on local anesthesia (LA) is on the rise. Contrary to general and regional anesthesia, local anesthesia affects only a small and targeted area of the body required for the operative procedures. In addition, under local anesthesia, the patient may be awake, since the anesthetic effect persists for only a short period, the post-operation discomfort to the patient is minimum (Vahabi and Eatemadi 2017; Sunderland et al. 2016; McCartney et al. 2004). LAs are generally of low molecular weight, which helps them to be absorbed faster and, therefore, produce quicker response but for a shorter duration (Veneziano et al. 2016). Operative procedures are needing more extended duration analgesia to administer a combination of adjuvants and LA. These strategies are successful; however, they present high systemic toxicity (Takenami et al. 2012, 2009). Specific operative procedures requiring neural blockades seldom prefer LA injection, because either they need multiple doses of LA or achieved by catheter technique or disposable pumps (Grant et al. 2001; Klein et al. 2000). The novel formulations of analgesics could offer a variety of benefits, including slow-release leading to lower (safe range) concentrations in plasma, the prolonged effect of analgesia to match the operative procedures, an equivalent effect to naked LA but at lower concentration and longer duration. Several research groups around the world have been involved in developing novel LA delivery systems such as micelles, liposomes, polymers. These delivery systems could be selected based on the required physicochemical properties of each LA. The appropriate carrier could improve the LA encapsulation, bioavailability, and analgesic effect. Local anesthetics are well-known for modulating the electrophysiology of nerve conduction to offer the anesthetic effect, which could be achieved by either altering the resting potential of nerve, threshold potential, decrease the rate of depolarization, or extending the rate of repolarization. Furthermore, there are two well-known mechanisms are reported to explain the anesthesia effect, acetylcholine-based mechanism, and calcium displacement theory, where former offers nerve conduction as well as neurotransmitter role at nerve synapse, however, facilitates local nerve block by displacement of calcium that controls the permeability of sodium across the nerve membrane.

Types of drug delivery systems

There have been several drug delivery systems developed for achieving the high loading and sustained release at the desired site of disease. These delivery systems could be liposomes (bilayer of lipid molecules arranged in the spherical pattern), multifunctional liposomes (consists of elastic lipids or other functional lipid molecules), micelles, reverse micelles, adhesives, niosomes, and hydrogels (Ali et al. 2019; Bnyan et al. 2018; Cerqueira-Coutinho et al. 2016; Gorantla et al. 2020).

Nanotechnology-based delivery systems

A typical liposome has an aqueous central compartment encapsulated by one or several lipid bilayers (Scalia et al. 2015; Badri et al. 2016). Based on the phospholipid membrane layers, liposomes are designated as unilamellar vesicles (SUVs) or multilamellar vesicles of lipids (MLVs) (Giannantoni et al. 2006). SUVs (20–200 nm) are smaller than MLVs (200–400 nm) and are composed of an aqueous interior part surrounded by one bilayer or multiple bilayers of lipids, respectively. The lipid bilayer part is generally hydrophobic, which can encapsulate hydrophobic therapeutic agents, whereas the interior aqueous portion can hold hydrophilic agents. Phospholipids and cholesterol are the major constituents of liposomes, where their concentrations and extrusion determine the size. Phospholipids of egg and soybean constitute ~ 90% of a liposome; however, the presence of polyunsaturated fatty acids impart instability (Daraee et al. 2016). In addition, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or Polyethyleneglycol (PEG) modified DSPC is the most commonly used phospholipids in liposome synthesis. The hydrophobic lipid tails of phospholipids are directed toward the center, and the hydrophilic/polar heads face the liposome surface toward the exterior aqueous phase.

Cholesterol is another major component of a liposome, which imparts stability and fluidity to the lipid bilayer (Magarkar et al. 2014). The amount of cholesterol in liposomes could vary from 30–50% of the total lipid concentration. The presence of cholesterol in liposomes offers bilayer membrane elasticity, fluidity, and permeability due to its hydrophobic nature and interior localization (Magarkar et al. 2014). Cholesterol also associates with filling the gaps developed due to the defective packing of phospholipid molecule bilayers during liposome formation. Along with stability and rigidity to liposomes, cholesterol also avoids the phase transition of phospholipid bilayers, and due to this property, the unwanted leakage of encapsulated drugs can be prevented (Manes and Martinez 2004; Khodabakhsh et al. 2020). However, a very high amount of cholesterol makes liposomes brittle and thus unstable, because the final phase transition temperature of the phospholipid bilayer could also be altered. There are two methods frequently used for loading drugs/pharmaceutical agents in liposomes, passive, and active approach of drug encapsulation. In the passive approach, loading of the drug occurs during the formation of liposomes; however, the active approach involves drug loading after the liposome formation. The loading efficiency of a drug is determined by the hydrophilicity or hydrophobicity of drug which leads to the retention in either aqueous core or hydrophobic lipid bilayers of liposomes (Sharata and Katz 1996).

Although liposomes are established as one of the attractive ways to deliver drugs at the desired site, they face several limitations, including easy hydrolysis and oxidation, cost-intensive, difficult to sterilize, and challenging large scale production (Wagner and Vorauer-Uhl 2011; Wen et al. 2015). Lipids from liposomes are prone to be oxidized when exposed to high temperatures, light, metal ions, and other chemicals. Hydrolysis of phospholipids is one of the common reasons for liposome degradation; therefore, the use of ethylenediaminetetraacetic acid (EDTA) and freeze-drying is recommended for protecting liposomes against hydrolysis (Grit and Crommelin 1993; Yang et al. 2013).

Liposome-based delivery of local anesthetic drugs

Delivery of local anesthetic drugs is realized after the success of various drug delivery systems for the treatment of human diseases. Several liposomal formulations of LA are developed (Fig. 1), and comprehensive analysis of the synthesis method and related applications is provided in the following section (Table 1).

Fig. 1.

Schematic representation of different types of liposomes, empty liposomes, and ligand functionalized liposomes, and drug loaded ligand functionalized liposomes

Table 1.

Liposomal formulations of local anesthetics described in literature for different applications

Liposome composition	Type of LA	Administration route	Test subject	Results	Ref
Egg phosphatidylcholine, cholesterol and α-tocopherol	Prilocaine	Infraorbital nerve blockade	Rat	Prilocaine in liposomes facilitated the controlled release of prilocaine (increasing the time of duration of the sensory nervous blockade)	Cereda et al. (2004)
Egg phosphatidylcholine, cholesterol and α-tocopherol	Bupivacaine (BVC) and Mepivacaine (MVC)	Sciatic nerve blockade	Mice	Liposomal BVC showed no advantage relatively to the plain BVC injection, while liposomal MVC improved both the intensity and duration of sensory blockade	Araujo et al. (2004)
Egg phosphatidylcholine, cholesterol and α-tocopherol	Prilocaine (PLC), Lidocaine (LDC), and (MVC)	Infraorbital nerve-blockade	Rat	Mepivacaine effect was improved to the greatest extent, while LDC benefited least from liposome encapsulation	Cereda et al. (2006)
Egg phosphatidylcholine, cholesterol and phosphatidic acid	Bupivacaine	Pinprick testing of the skin	Humans	Liposomal formulation showed favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner	Grant et al. (2004)
Egg phosphatidylcholine, cholesterol and phosphatidic acid	Bupivacaine	Tail-flick test	Rat	Bupivacaine liposomes elevated the intensity and prolonged the duration of the local anaesthetic effect and suppressed the systemic absorption rate of bupivacaine	Yu et al. (2002)
Egg phosphatidylcholine, cholesterol and phosphatidic acid	Mepivacaine	Intra-orally	Rat	Liposomal mepivacaine protected the tissues against local inflammation evoked by plain mepivacaine	Tofoli et al. (2010)
Egg phosphatidylcholine, cholesterol and phosphatidic acid	Mepivacaine	Electrical pulp tester and injection discomfort	Humans	Encapsulation of mepivacaine increased the duration of anesthesia and reduced the injection discomfort caused by vasoconstrictor-associated formulations in healthy volunteers	Tofoli et al. (2011)
Egg phosphatidylcholine, cholesterol and α-tocopherol	Prilocaine	Injection pain	Humans	Liposomal prilocaine showed similar anesthetic efficacy in relation to plain prilocaine and lower efficacy, in comparison to prilocaine with felypressin in maxillary infiltration	Wiziack Zago et al. (2011)
Egg phosphatidylcholine, cholesterol and α-tocopherol	Prilocaine	Paw edema test and histological analysis	Rat	Formulation was found stable for ~ 30 days and did not induce significant inflammatory effects both in the paw edema test and in histological analysis	Cereda et al. (2008)
Egg phosphatidylcholine and cholesterol	Bupivacaine	Chronical lumbar epidural and femoral arterial catheters	Rabbit	The liposomal formulation of bupivacaine led to prolong motor effects	Malinovsky et al. (1999)
Egg phosphatidylcholine and cholesterol	Mepivacaine	Intra-oral injection	Humans	Liposomal formulation of 2% mepivacaine exhibited similar systemic absorption to the local anesthetic with vasoconstrictor	Tofoli et al. (2012)

The encapsulation of LA in liposomes offers an extended duration of sustained release and action in several clinical applications. Bupivacaine is one of the major LAs and classified as an amide-based anesthetic with amide group acting as a linker for the amino group/piperidine ring with aromatic ring. In an attempt by Prabhakar et al., bupivacaine was encapsulated in liposomes and used to improve the perioperative pain control in patients (Prabhakar et al. (2019)). The developed liposome showed sustained release of bupivacaine for up to 72 h, which allowed to decrease the administration of postoperative opioids significantly. Continuous release of bupivacaine was observed when suspended in sucrose acetate isobutyrate solution. It is challenging to obtain consistent efficacy of LAs even after 24 h; therefore, liposomal and other formulations are studied, which can impart extended-release and effect. Dale et al. have compared the pain control after wrist operations using liposomal bupivacaine and free bupivacaine HCl (Dale et al. 2019). In 52 patients, it was found that patient’s pain score was found to be similar in the case of liposomal bupivacaine and free bupivacaine. The liposomal encapsulation of bupivacaine did not alter the efficacy of the LA. Contrary to this study, in a study following pain score after retropubic mid-urethral sling placement, the liposomal formulation of bupivacaine was found significantly lower than free LA and placebo (Mazloomdoost et al. 2017). The patients who administered liposomal bupivacaine did not use narcotics after the operation. Although beneficial, the extra cost associated with developing liposomal formulation could be a point of concern; however, in the future, cost-effective formulations could be developed. Furthermore, the development of methods that could provide large scale synthesis of the liposomal formulation may assist in bringing the cost down.

Grant et al. (Grant et al. 2004) have developed a biocompatible liposomal formulation of lignocaine, which showed a prolonged (> 48 h) effect of anesthesia and pain management, where the average duration of analgesic effect by 0.5% standard bupivacaine was 1 h. The hydrodynamic diameter of these multi-vesicular liposomes was ~ 2400 nm, with a drug-to-phospholipid ratio of 1.8. This formulation showed the slowest release kinetics when studied at 4 ℃. Similarly, another report showed that the liposomal formulation of bupivacaine could enhance the effect (2-fold) of analgesia in patients undergone abdominal surgery (Boogaerts et al. 1994). It was observed that the liposomes increased the duration of analgesia without blocking the motor neuron and almost negligible side effects. Liposomal formulation of LAs has also been used to provide intraoral topical anesthesia. For example, Franz-Montan et al. studied the impact of a liposomal formulation of ropivacaine (2%) in topical anesthesia and other subsequent responses (Franz-Montan et al. 2010). The results suggest that the liposomal formulation of 2% ropivacaine was as effective as 20% benzocaine gel when evaluated for the ability to reduce pain. In another study, the efficiency of the liposomal formulation of ropivacaine in different concentrations for providing topical anesthesia of the palatal mucosa. Results revealed that compared with the placebo, there was no significant decrease in pain during the insertion of a needle (Franz-Montan et al. 2012). In a study by Tofoli et al. it was reported that the liposomal formulation of 3% mepivacaine could offer the extended effect of anesthesia, with respect to a commercial formulation of 3% anesthetic (Tofoli et al. 2011). Along with the extended anesthesia, reduced injection discomfort was also observed due to the vasoconstrictor-associated formulations in healthy volunteers.

There have been some unique systems developed for encapsulation of hydrophobic anesthetics in the aqueous core of liposomes with the inclusion of some external complexes. Among these complexes, cyclodextrins are very frequently used, because they could avoid the use of organic solvents and facilitate the synthesis of drug-in cyclodextrin-in liposome systems (Maestrelli et al. 2010). Cyclodextrins are made up of 6–8 sugar units arranged in a ring structure, which may give rise to α-, β-, and γ-cyclodextrins. Cyclodextrins are well-known to have hydrophobic drug solubilizing ability as well as in the synthesis of classic and deformable liposomes (Agarwal et al. 2016). This double-loading method is used to prepare drug encapsulating liposomes, which gives rise to a quick and sustained drug effect, in comparison with the corresponding formulations of free drug and drug encapsulated in the aqueous or lipophilic phase of liposomes (Bragagni et al. 2010).

Use of micelles

Micelles are small and spherical structures made up of a few hundred to thousand molecules of surfactants that form such structures to reduce surface tension. It is well-known that when the concentration of surfactant molecules exceeds the critical concentration, the surfactant molecules arrange themselves in such a way that the hydrophobic ends are oriented towards the interior, whereas the hydrophilic ends towards the exterior of the spherical structure. This spherical structure is known as micelle. The micelles are also developed by blending the block co-polymers, which allow them to encapsulate the drug molecules. These block co-polymers also possess hydrophilic (polyethylene glycol, PEG) and hydrophobic (polyaspartic acid) ends; therefore, the developed micelles could encapsulate hydrophilic as well as hydrophobic drugs in their core. The diameter of micelles is also manipulated so that EPR effect could be observed allowing the stay of the therapeutic molecules at the site of action for longer duration. Micelles are other attractive drug delivery vehicles which are also reported to be used for the topical delivery of LAs to maximize the percutaneous absorption across various layers of the skin. For example, a thermoresponsive mixed micellar nanogel system was developed to prepare a formulation of lidocaine and prilocaine. This multifunctional system could alter its phase state, such as sol-to-gel or gel-to-sol) in response to the change in temperature. The system was thoroughly characterized by measuring hydrodynamic size spreadability (for topical application), bioadhesive index, skin permeation, retention, and other dermatokinetic studies. The system was then tested for anesthetic effect in in vivo experimental models of rabbit and mice. Results suggested that the developed system could be used an alternative to the conventional topical anesthesia (Sharma et al. 2017). Micellar formulations are also used to decrease the toxicity associated with the drugs. In an attempt by Cheng et al., an amphiphilic folic acid-cholesterol-chitosan (FACC) micelles were developed for paclitaxel delivery (Cheng et al. 2017). The developed formulation showed low critical concentration (64 µg/mL) and self-assemble to form nanosize micelles (~ 250 nm). This micellar system showed encapsulation efficiency and loading capacity of ~ 65% and ~ 9%, respectively. The cumulative release of the encapsulated drug was higher at pH 5 (~ 85%) than at pH 7.4 (~ 75%); therefore, this system could be used for releasing encapsulated LAs in an acidic environment of disease cells/tissues. Micelles could also be developed for targeted delivery of drugs. A conjugate of folic acid and α-tocopherol succinate conjugated hyaluronic acid (FA-HA-TOS) was developed to self-assemble into nanomicelles in aqueous suspension. This micellar system showed drug loading and entrapment efficiency of ~ 21 and ~ 90%, respectively. In vitro and in vivo experimental data revealed that the developed micellar formulation could be used for targeted antitumor activity (Zhang et al. 2019).

Polymeric nanostructures mediated delivery

Polymeric nanoparticles are the most commonly used strategies for drug encapsulation and delivery to the desired site. Polymers are biodegradable and generally associated with homo or copolymers, which offer to control the hydrophobicity as well as hydrophilicity (Corre et al. 1997). The polymeric nanoparticles offer stability to volatile agents of therapeutic value, and increase the efficiency and effectiveness compared to the traditional oral drug administration methods. The tiny structures of polymers could be either nanocapsule form, drug is confined in a cavity and protected by a surrounding polymer membrane, or nanospheres form, a matrix system, where the drug is uniformly and physically distributed. These properties make polymeric nano and microstructures as an attractive encapsulating material for both hydrophilic as well as hydrophobic drugs to a similar extent. In addition, polymeric drug delivery vehicles remain in blood circulation for longer durations leading to the sustained release of the encapsulated drug in the blood (Weiniger et al. 2010; Kuzma et al. 1997). In an attempt by Han et al., supercritical fluid polymer and poly(lactic-co-glycolic acid) were used to encapsulate ketamine and develop biodegradable nanoparticles. The produced particles showed drug loading and encapsulation efficiency of ~ 10–60%, and 60–100%, respectively. The ketamine release from polymeric particles showed sustained release up to 4 weeks. In addition, dexamethasone supplemented polymeric microcapsules encapsulating bupivacaine showed a much longer duration of sustained release of LA and thus anesthesia effect than with microcapsules without dexamethasone addition (Weiniger et al. 2010). Liu et al., have developed a polymeric formulation of tetracaine using poly(l-lactide) and solid lipid-based nanoparticles (Liu and Zhao 2019). The particle size of these nanoparticles was found to be ~ 100 nm. The cytotoxicity study revealed that these nanoparticles showed a moderate effect on the cell viability. Under in vivo experimental conditions, these nanoparticles showed excellent outcomes in improving skin permeation, prolong analgesic effect, and pain control. Subsequently, other anesthetic drugs, lidocaine, and prilocaine, were also encapsulated in polymeric nanostructures and used for topical applications to induce dermal anesthesia (You et al. 2017). The efficacy study revealed that the use of a combination of these two LAs imposed excellent analgesic efficiency than when used singly. Subsequently, the skin permeability ability of these polymeric nanoparticles was also evaluated for producing stronger anesthesia under in vivo experimental conditions suggesting that such formulations are a promising approach for the simultaneous delivery of multiple topical LAs. A polymeric nanoparticle was used to develop a formulation of a eutectic mixture of lidocaine and prilocaine for intraoral topical use. The so developed formulation showed the potential of long-lasting topical anesthesia effect in oral mucosa during medical and dental procedures (Muniz et al. 2018).

Utilization of micro and nanoemulsions

Micro and nanoemulsions exhibit high penetration capacity; therefore, LAs are considered to be encapsulated as emulsions. Another advantage of microemulsions is that they can efficiently solubilize poorly water-soluble drugs as well as provide better pharmacokinetics and pharmacodynamics upon administration. The physicochemical and biopharmaceutical characteristics are easy to understand and link with the administration route, which helps to design the formulations. There have been several such formulations developed and studied for their faster dermal penetration and anesthetic effect (Cummings et al. 2011; He et al. 2010). In a study by Wang et al., it was shown that lidocaine (10%) could be formulated in the form of microemulsion and provide anesthetic effect for a longer time duration. In liposomal formulation, a eutectic mixture of lidocaine with thymol was prepared by kneading. It was further mixed with oil phase (12% of ethyl oleate) to form microemulsion by the addition of a surfactant (polyoxyl 15 hydroxy stearate) and co-surfactant (ethanol) (Wang et al. 2019). The microemulsion formulation was characterized by transmission electron microscope (TEM) and Fourier-transform infrared (FTOR) spectroscopy, and the data revealed that lidocaine was homogeneously dispersed in the microemulsions. Subsequently, the in vitro (skin permeation) and in vivo (anesthesia) experiments suggested that the anesthetic effect can be extended with better biocompatibility and negligible irritation to the dermal layer.

In another attempt, an alcohol-free lecithin-based microemulsion with the linker was developed to realize the transdermal delivery of lidocaine. The linker was made up of sodium caprylate and caprylic acid (hydrophilic) and sorbitan monooleate (hydrophobic) linker. Subsequently, isopropyl myristate-based carrier oil was used to dissolve the local anesthetic drug (Yuan et al. 2008). The study of transdermal delivery of the formulated lidocaine showed that compared to the conventional alcohol-based microemulsion, linker-based formulation offered 2-fold better absorption and penetration through the skin. The linker-based microemulsion system quickly transfers the skin mass by reduction of interfacial rigidity by hydrophobic linkers, which ultimately results in better penetration in the skin. Compared to the alcohol-based system, the linker-based microemulsion system was found to be significantly less toxic to mammalian cells. There are several biologically important drugs such as retinoic acid, 5-fluorouracil, triptolide, ascorbic acid, diclofenac, and prilocaine hydrochloride formulated in the form of microemulsion and have studied for transdermal delivery (Kogan and Garti 2006). Thus, it can be concluded that microemulsions of local anesthetics could be used to effectively deliver the encapsulated agents, protect them from degradation, hydrolysis, and oxidation. Since microemulsions contain a large concentration of surfactants and co-surfactants, they may cause toxicity to mammalian cells, induce hemolysis to blood cells, and histopathological changes in organs (He et al. 2010). Therefore, some strategies must be evolved to improve the biocompatibility of the microemulsions and providing stability to LAs in the digestive tracts.

Other advanced approaches to anesthetic delivery

Apart from nanotechnology-based delivery, other novel methods have also been developed for site-specific delivery of local anesthesia. The following section will cover a few major delivery strategies, which are currently in use.

Transdermal delivery

Transdermal is one of the best methods for local anesthesia and other drug delivery in patients. It is well known that the use of topical anesthetic cream is a painless approach with respect to the application of anesthetics by permeation using minor skin procedures, therefore, show limited and inconsistent efficacy. In this context, the recent developments in transdermal delivery approaches have led to the acceleration of the anesthesia effect within 20 min or less with more consistent skin analgesia. Transdermal delivery approaches often create transient micro channels to promote the delivery of flux of drugs/anesthetics of all sizes, thus facilitate the effective delivery in the skin. The outermost layer of skin (k/a stratum corneum) avoids the infiltration of anesthetic drugs across various segments; therefore, hydrophilic and ionized drugs face difficulty in permeabilization (Sammeta et al. 2009). Thus, to better diffuse through the layers of skin, the drug must be hydrophobic or lipophilic with a molecular weight of < 500 Daltons (Sammeta et al. 2011; Murthy et al. 2010). The transdermal approach of permeabilization of local anesthetics through skin layers, energy-intensive processes are also used. In these methods, a eutectic mixture of LAs and controlled temperature or other methods such as electroporation, sonophoresis, and magnetophoresis can be applied (Sammeta et al. 2009). The following section will summarize these processes of administration of LAs.

Magnetophoresis

In this method, the magnetic field is applied to increase the permeation of LAs across the biological barriers. Murthy et al. have studied the delivery of lidocaine across the skin using magnetophoresis, where a magnetophoretic transdermal patch system was developed and the mechanism of transdermal delivery (Murthy et al. 2010). The magnetophoresis-based delivery of lidocaine was found to be increased with the strength of the applied magnetic field. Mechanistically, it was observed that the magnetic field-mediated permeation of the drug across the transdermal layer was due to the “magnetokinesis” and not due to the modulation of the permeability of stratum corneum layer. In addition, Sammeta et al. have studied the effect of chemical enhancers over a combination with megnetophoresis on transdermal delivery of LAs (Sammeta et al. 2011). Results revealed that the developed magnetophoretic patch was able to increase the delivery of lidocaine to ~ 3-fold than the corresponding control (without magnetophoretic patch). Interestingly, with the use of a chemical enhancer along with megnetophoresis, ~ 4–7-fold increased delivery flux of lidocaine was observed. A schematic representation has been shown in Fig. 2, which presents the release of encapsulated drugs under the influence of megnetophoresis.

Fig. 2.

Schematic representation showing the release of encapsulated local anesthetic from a liposome under the influence of magnetic field

Sonophoresis

There have been attempts to use sound waves to deliver the local anesthetic drugs across the various layers of skin, and this process is well known as sonophoresis. In this method, ultrasound waves of frequency (1–16 MHz) matching with the frequency of transducer tip (displaced per second) are used (Polat et al. 2011). However, for the past two decades, only low low-frequency sonophoresis (20–100 kHz) has been investigated. Using sonophoresis acoustic cavitation is created in the skin, which increases the permeability of the skin and thus the delivery of drugs is realized. In addition, surfactants are also included to improve the permeation of hydrophilic drugs even at the low-frequency sonophoresis. Utilizing this mechanism delivery of macromolecules, and drugs encapsulated in liposomes or coated on nanoparticle surface are realized (Polat et al. 2010). Recently, the transdermal administration of LAs has also been performed, where an ultrasound frequency of 0.5 MHz was used for creating cavitation, which led to the delivery of lignocaine (Kim et al. 2007). In an attempt by Cagnie et al., it was studied to examine the effect of ultrasound-based delivery of ketoprofen in humans and compared the delivered drug concentration after continuous and pulsed application (Cagnie et al. 2003). The results revealed that sonophoresis mediated delivery of ketoprofen led to attaining higher concentrations and thus this attempt could be developed as one of the attractive methods for transdermal delivery of LAs.

Electroporation

Electroporation is another approach, which is considered as a minimum invasive method to deliver therapeutic agents, including LAs. In electroporation, several short high voltage electrical pulses are applied to the skin, which increases its permeability and thus allows the diffusion of therapeutic molecules across skin layers (Sammeta et al. 2009). Since the electrical pulses are only applied for a fraction of second; therefore, the skin is depolarized during the intervals of the pulses, which allows the drug to permeate the skin. Subsequently, even though the polarization of skin is established, there occurs no interference to the flow of current or drug internalization. Sammeta et al. have shown ~ 8-fold more permeation of lignocaine hydrochloride across the porcine epidermis in the influence of low voltage electroporation (Sammeta et al. 2009). Certain studies have tested the influence of surfactants over the electroporation mediated delivery of biomolecules. Murthy et al. used 0.2% sodium dodecyl sulfate (SDS) during the transdermal delivery of molecules by electroporation in the porcine epidermis (Murthy et al. 2004). It was found that the resistance of epidermis was reduced by ~ 40% (in 24 h), which lead to the efficient transport of glucose and dextran molecules (of 4 and 8 kDa) by electroporation. In the presence of SDS, the electroporation threshold was reduced to 60 from 80 V, thus facilitate the delivery of molecules was achieved even with the less exposure of electric pulses. The likely mechanism could be the easy disruption of transport barrier in the presence of SDS as well as prolonging the lifetime of micropores created in the skin by pulse.

Eutectic patches

In eutectic patches, a mixture is made containing the patch material and drug/s. This mixture is developed in such a way that the melting point of the mixture remains lower than the melting points of the drugs. In such a case, the patch material holding the drug is decomposed first, leading to the release of drugs in the targeted organ. Following this strategy, several LAs are designed to be administered topically. For example, a eutectic patch was developed consisting of an equal weight of two LAs, lignocaine and tetracaine, and an integrated heating system to warm the skin and facilitate quick delivery of the encapsulated local anesthetics into the applied area (Masud et al. 2010). Results revealed that heated patches offered significant relief from pain in patients (n = 43) compared with unheated patches (n = 37), and all the subjects could well tolerate the patches, with minimum discomfort. Another study designed by Matry et al. established a comparison of analgesic and side effects of transdermal ketoprofen (30 mg) and a eutectic patch containing 30 mg of ketoprofen (EMLA) cream (Metry et al. 2018). Results revealed that the eutectic patch of ketoprofen, EMLA cream and lidocaine injection showed almost similar pain control (n = 105) caused by venous cannulation. Overall, the ketoprofen patch was found to be much superior as it generated less local inflammation than EMLA cream, and without double puncture as with lidocaine injection. In another approach, a comparison was established to assess the efficacy and side effects of transdermal diclofenac patch with EMLA cream in attenuating venous cannulation pain (Agarwal et al. 2007). Reports from patients concluded that while the venous cannulation pain was felt by 100% of the control group patients; however, only 37% and 48% of patients experienced pain when offered EMLA and diclofenac, respectively. Although the transdermal patch of diclofenac and EMLA showed almost similar efficacy in reducing venous cannulation pain, however, some signs of erythema, induration, and edema were of limited occurrence with the transdermal diclofenac patch. These observations were recorded from the three groups of patients with 150 individuals in each group.

Iontophoresis

The iontophoresis method has been recognized as an alternative to the strategy, where high-voltage may not be permissible to the patient requiring the delivery of the drug. Thus, iontophoresis uses low-voltage direct current to actively transport the drugs into the skin, along with the influence of opposite charges migrating between the electrodes (Wakita et al. 2009). Here the charge on the anesthetic molecules also plays avital role as in the case of positively charged lignocaine molecules, and the electrical current improves the dermal penetration under the influence of a positive electrode. This method is appropriate for the delivery of LAs, which cannot be delivered by other conventional methods. Furthermore, since this method does not include any formulation development, the probability of loss of anesthesia ability remains minimum. Therefore, iontophoresis could be used for drug molecules, which are considered as “difficult to deliver” by the use of other methods (Gratieri et al. 2011). Dubey et al. have shown the delivery of a functional protein, ribonuclease A, using the iontophoresis approach across the porcine skin (Dubey and Kalia 2010). The penetration of RNAse was quantified by several methods to demonstrate that a significant amount of functional protein was retained within the skin after iontophoresis. With the laser scanning confocal microscopy, the distribution of rhodamine B-labelled RNAse in epidermis and dermis was confirmed. In the case of passive administration, the fluorescence was found localized up to the skin surface. With the iontophoresis method, the fluorescence pattern confirmed that RNAse was present throughout the membrane. It has been shown that the fentanyl-HCl iontophoretic transdermal system is a well-known analgesic system approved in the United States and Europe to manage the post-operative pain in patients (Power 2007). With the advantages of iontophoresis, this system also allows patients to use it in transdermal LAs delivery as well as self-administer the doses of fentanyl with minimum invasion. It was also reported that the fentanyl-HCl iontophoretic transdermal system provides pain control equivalent to standard treatment of morphine. Thus, the iontophoresis offers safe delivery of drugs without much of the risks and complications from needle-related injuries and infections. Subsequently, the inclusion of pre-programmed electronics could also avoid the chances of manual errors such as over/underdosing. In addition, the amount of delivery of LAs could also be controlled by merely tuning the strength and duration of the current. With constant current iontophoresis, it may also be possible to control the transport rates of LAs or other biomolecules of therapeutic value and thus mimic some endogenous secretion profiles. The above-mentioned advantages of iontophoresis suggest that, in the near future, it may also be used for personalized therapy.

Conclusion and future prospects

The use of LAs has surged significantly in the last few years due to their importance in post-operative as well as intra-operative management of pain. Surgeries requiring facial reconstruction, cosmetic alterations, and other medical procedures are heavily dependent on LAs. Therefore, there has been tremendous demand for better delivery methods offering improved efficacy. Furthermore, novel formulations of LAs also offer enhanced pharmacokinetic properties and pharmacodynamic effects. These effects are required for prolonged action of LAs realized by novel delivery strategies. Liposome-based formulation of LAs is extensively studied due to their ease of synthesis and the opportunity to modify the surface of liposomes for the targeted delivery of LAs at the desired region. Furthermore, liposomes can also encapsulate multiple drugs in a required ratio, which could be used for targeting specific pathways of signaling cascade of a particular process to induce anesthesia. The use of micelles, polymeric nanostructures, and emulsions are other attractive strategies for safely deliver the LAs through different layers of skin. Nanoparticle-based delivery agents offer stability to the encapsulated LAs and keep them in circulation for a longer duration, which maintains their optimum levels. The precursor materials for synthesizing these nanostructures are biocompatible; therefore, the drugs encapsulated within them are not recognized by the reticuloendothelial system of the body. Such encapsulation of LAs into nanoparticles avoid systemic toxicity, and the nonconventional local anesthetics (tetrodotoxin, saxitoxin) also show promising efficacy. Apart from nanoparticle-based delivery, there have been other methods too in practice to deliver LAs locally. Among them, transdermal, magnetophoresis, electrophoresis, and iontophoresis are some of the frequently used strategies. These methods are minimally invasive and, therefore, preferred for inducing local anesthesia. In addition, these methods require low voltage electric pulses or weak magnetic fields to facilitate the delivery of LAs across different tissue layers. In the future, the synthesis of novel delivery systems for LAs must focus on how to achieve higher loading of the anesthetics into the carrier and how to control a sustained release in a suitable environment. Although there has been significant stress devoted towards the development of novel formulations of LAs, their comprehensive characterization is required to be performed before their clinical studies. In many instances, it has been observed that the toxicity of the formulation was due to some of the components of the formulation itself, while the drug was non-toxic. Thus, details characterization would rectify such issues. Some of the liposomal formulations encapsulating anticancer drugs are approved by FDA, and few are being studied in clinical trials. Therefore, to successfully clear the clinical trials, detailed characterization of any new LA formulation must be established. In addition, to comprehensively look at the development of such novel and effective formulations of LAs, a collaborative effort is required from the anesthesiologist, nanotechnologist, and formulation scientist.

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