Nanotechnology application to local anaesthesia (LA)

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.

Keywords:

• Anaesthesia
• nanotechnology
• liposome

Introduction

Pain management stands for part of the major therapeutical goals in [1]. While opioids has been identified has the standard in pain control [2]. Szmuk et al., however stated that their systemic administration is correlated with undesirable and harmful side effects [3] like respiratory depression, drowsiness and sedation, nausea, allergies and neutrophil dysfunction [4]. As such, many sustained release systems have been studied using local anaesthetic agents, especially liposomal bupivacaine been the most investigated [5]. This review gives a summary of available application of nanotechnology especially the formulation of liposomes to deliver various types of anaesthetic drugs.

Nano-formulated liposomal drug delivery systems

Liposomes are spherical, nanovesicles consisting in a phospholipid bilayer [6]. Phospholipids have a polar group and two hydrophobic groups, commonly an unsaturated fatty acid. In addition, they also possess a hydrophilic part; a number of water-soluble active substances can be encapsulated without the drug structure being distorted [7,8]. Drug delivery via liposomes is a nanotechnology-designed formulation with high clinical acceptance, as several drugs can be encapsulated into liposomes [7]. Previous study reviews have been reported in relation to drug delivery systems based on nanotechnologies including liposomes, biopolymers, cyclodextrins (CDs), lipid nanoparticles, hydrogels formulated to extend the anaesthetic effect and to reduce the toxicity of local anaesthetics in medicine [9]. The earliest report regarding the application of LAs compressed in liposomes was two decades ago, where they demonstrated that the topical application of a liposomal 5% tetracaine formulation delivered improved pain relief than a formulation containing 20% benzocaine gel in an infiltrative injection of 4% prilocaine in 30 subjects. In this review, we will give a concise summary of the various application of nanotechnology especially in relation to liposomal anaesthetic drug deliveries.

Nano-technology application to local anaesthesia (LA)

Bupivacaine is a synthesis derivate, with chemical structure analogous to cocaine (first local anaesthesia (LA) agent) [10]. Bupivacaine has been classified as a LA because of its unique characteristics like increased potency, sufficient duration of action, low systemic toxicity, low local toxicity, high solubility in water, easily sterilizing [11]. Figure 1 depicts the chemical structure of bupivacaine.

Figure 1. Showing bupivacaine – chemical structure. This figure was culled from [12].

The administration of bupivacaine clinically has been reported to be related with systemic toxicity [13], as such several researchers have applied nanotechnology formulated biomaterials like lipospheres, microspheres [14], cyclodextrin matrices, lipid–protein–sugar nanoparticles, microcrystals to decrease the toxicity associated with bupivacaine and liposomal bupivacaine [15–17] has been the most reported of them (Table 1).

Table 1. Showing summary of clinical trials investigating the efficacy of different nano-formulations in local anaesthesia. This table was culled from [19].

Formulations tested	Test method	Site and duration of application	Clinical study characteristics	Most effective formulation	Reference
Liposome encapsulated 5% tetracaine versus 20% benzocaine gel	Pain during needle insertion and LA injection	Not available	30 volunteers; double-blind, split-mouth design	Liposomal tetracaine	[20]
Transoral lidocaine delivery system versus placebo; 20% benzocaine gel	Pain during needle stick with a 25 G needle	Buccal gingiva apical to the molar-bicuspid pair in the maxilla or mandible	20 patients, randomized, placebo- controlled study.	DentiPatch	[21]
Transoral lidocaine delivery system versus placebo; 20% benzocaine gel versus placebo.	Pain during needle stick with a 25 G or 27 G needle.	Buccal gingiva apical to the molar-bicuspid pair in the maxillary arch	20 patients, randomized, placebo-controlled, double-blinded study.	DentiPatch	[22]
Lidocaine mucoadhesive patch.	Gingival anaesthesia for rubber dam clamp placement	Buccal or lingual gingiva ∼1 mm from the first two premolars	28 children, randomized, split-mouth design study.	All formulations tested were equally effective.	[23]
1% liposomal ropivacaine gel versus 1% plain ropivacaine gel; 20% benzocaine gel.	Pain during needle insertion	Maxillary right canine buccal fold.	30 volunteer subjects, randomized, blinded, cross-over study	Liposomal ropivacaine	[24]
2% liposomal ropivacaine gel versus 1% liposomal ropivacaine gel.	Pain during needle insertion.	Palatal mucosa at the right canine region.	40 volunteers subjects, randomized, single-blinded, placebo-controlled study.	No difference among anaesthetic formulations and placebo	[25]
Liposome-encapsulated 2% lignocaine with epinephrine	Repeated pinprick tests with a periodontal probe.	At the junction between the vertical and horizontal parts of the mucosa near the roots of the upper first molars.	32 volunteers subjects	Liposomal lignocaine with epinephrine	[26]
Liposome-encapsulated 5% lidocaine versus 5% lidocaine gel	Pain during needle insertion.	Maxillary buccal fold at the canine region bilaterally	No volunteers, randomized, double- blinded, placebo-controlled study.	Liposomal lidocaine	[27]
Lidocaine transmucosal delivery system	Pain during scaling	Buccal gingiva apical to the treated area in maxilla.	40 volunteers single-blind, randomized, two treatment, placebo- controlled study.	Only dentipatched was evaluated and was effective	[28]
1% liposomal ropivacaine gel versus 1% plain ropivacaine gel.	Pain during needle insertion	Maxillary right canine buccal fold	30 subjects, randomized, blinded, cross-over study	Liposomal ropivacaine	[24]

Application of nano-formulated liposome to local anaesthesia

Liposomal bupivacaine is made of liposomal spheres with 31.2 metres in diameter [16]. de Oliveira and colleagues were among the first to report the application of liposomal bupivacaine in form of DepoFoam bupivacaine, Exparelä, on healthy volunteers in order to achieve long-lasting pain relief in a single dose [16]. In their in vitro study, they compared the Exparelä complex with bupivacaine hydrochloride 0.5 and 1.31%, respectively, and established that the Exparelä complex was more efficient. In another experimental study conducted by McAlvin and co-worker [15], they investigated the result of liposomal bupivacaine on the sciatic nerve and recorded a sensory block for 4 and 2 h for the Exparelä complex and bupivacaine hydrochloride 0.5%, respectively. Furthermore, in a clinical study by Lonner et al. [18], they studied the efficacy of liposomal bupivacaine to relief pain after total joint arthroplasty.

They reported that the pharmacokinetics and pharmacodynamics of the liposomal bupivacaine maintained a minimum concentration needed to deliver the therapeutical effect for 3 days without increasing the concentration of the active constituent in the body. Finally, they concluded that liposomal bupivacaine has reduced cardiac toxic effects, without significant differences between Exparelä and placebo. Richard et al. [29] in their experimental study demonstrated that no significant haematological, biochemical and biological side effects of Exparel complex were recorded in their study. They went further to carry out histological study that confirmed no significant tissue damage, 15 days after administrating Exparelä formulation. Cohen and colleagues also demonstrated that liposomal bupivacaine administered to postoperative patients effectively diminishes the need for opioids, the hospital admittance time and hospital bills [30].

Soberón et al. [31] also reported the administration of liposomal bupivacaine to a 45-year old woman with digital ischaemia at the right hand. Blocking of the axillary nerve was achieved by injecting 3 mL of Exparel. They concluded that liposomal bupivacaine was efficient in restoring the normal ulnar artery and disappearance of finger cyanosis, as a result of vasodilation effect created by liposomal bupivacaine. In another clinical study by Bramlett et al. [32], they demonstrated the analgesic effect of liposomal bupivacaine in total knee arthroplasty patients and its blocking effect on femoral nerve. They finally concluded that liposomal bupivacaine leads to increased patient comfort and they also recommended that for a proper and effective analgesia up to 4 days, administration of 532 mg of Bupivacaine DepoFoam should be given. Figures 2 and 3 below compares the efficiency of liposomal bupivacaine to bupivacaine HCl.

Figure 2. Showing the plasma bupivacaine concentration after administration of DepoFoam bupivacaine or bupivacaine HCl to patients undergoing total knee arthroplasty. This figure was culled from [32].

Figure 3. Showing atomic force microscope image of PCL nanospheres loaded with LDC. Culled from [44].

Bramlett and colleagues also gave an insight into how safe these formulations are, they reported that the safety measures presented a similar adverse event (AE) profiles for the different dose levels of DepoFoam bupivacaine and for bupivacaine HCl. The pharmacokinetic valuation of increasing doses of DepoFoam bupivacaine showed a dose-related upsurge in exposure, with a rather less than dose-proportional upsurge in Cmax and a slightly greater than dose-proportional increase in area under the plasma concentration–time curve (AUC). Furthermore, they stated that 81.2% of the 138 subjects who were administered with the study drug stated that at least one AE during the study; 79.8% in the joint DepoFoam bupivacaine groups and 85.3% in the bupivacaine HCl group. DepoFoam bupivacaine 532 mg demonstrated excellent efficacy and predictable pharmacokinetics, with no clear increase in frequency or severity of AEs related to high plasma concentration compared with lower dose levels, thereby suggesting that this dose seems to be an applicable therapeutic dose for further clinical study in the setting of total knee arthroplasty.

Another application of nanotechnology to anaesthesia is the formulation of liposome loaded with ropivacaine. There have been studies to demonstrate liposome-encapsulated ropivacaine and example was reported by Franz-Montan and co-workers in a carbopol gel formulation administered to oral mucosa before LA injection enhanced the pain relief of inserting needles in a sham LA procedure in fit subjects [33]. In another study, a liposome-encapsulated lidocaine (LDC) formulation successfully passes through a porcine palatal epithelium. When compared to eutectic mixture of local anaesthetics (EMLA), they reported that it has same efficiency with the topical anaesthetic agent and both decreased pain during needle injection as well as LA injection into the palatal mucosa of healthy volunteers [27]. Furthermore, Paphangkorakit and co-workers [26] compared the efficacy of liposomal–lidocaine formulation and a combined formulation of benzocaine and tetracaine) to reduce pain during anaesthetic injection in the palatal mucosa of healthy volunteers, they concluded that the liposomal formulation demonstrated good results than the commercial formulation.

Application of nano-formulated cyclodextrins to local anaesthesia

Cyclodextrins (CDs) are cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrins basic structural composition is six glucopyranose units. Cyclodextrins have been demonstrated to offer advantages for delivery of drugs such as improved solubilization and higher absorption rate. There have been few reported studies on the application of LA–CD complexes. Arakawa and colleagues [34] investigated the ability of a β-CD polymer for controlled release of LDC (0.5%) drugs in a mucoadhesive buccal film. They concluded that there was a 40% delay in release of LDC from the mucoadhesive β-CD polymer film, compared to the control base film thereby suggesting that low molecular weight β-CD polymer is efficient in obtaining a controlled release of LDC in vitro.

Application of nano-formulated nanoparticle to local anaesthesia

The lipid nanoparticles matrix consists of both solid lipids and nano-structured lipid carriers with well-structured internal anatomy leading to improved entrapment of LA drug. Lipid nanoparticles have been preferred for LA delivery as a result of their nanometric size, large contact surface area and biocompatibility [35]. Wang and colleagues [36] compared the efficiency of liposomes and lipid–polymer hybrid nanoparticles with encapsulated LDC for anaesthesia. The lipid–polymer hybrid nanoparticles demonstrated increased encapsulation efficiency than liposomes and a better-sustained release rate of LDC. There have also been reports of alginate nanoparticles encapsulated with bupivacaine to lessen the toxicity of the LA and prolong the anaesthetic effect in mice [37]. Furthermore, Yin and colleagues in their report evaluated a long-term anaesthesia in rats, by using gels containing LDC, either free or encapsulated into nanoparticles of poly (ɛ-Caprolactone) (PCL). They concluded in their report that the gel containing LDC was efficient for an increased period of reducing pain, as well as it demonstrated less toxicity compared with the free LDC gel [38].

Application of nano-formulated hydrogel to local anaesthesia

Finally, another application of nanotechnology to anaesthesia is the use of hydrogels to deliver LA drugs for pain relief. Hydrogels are tri-dimensional semisolid substances made of networks of either natural or synthetic/fabricated polymers. Features like biodegradability, easy handling, patient compliance, softness, mucoadhesion, and rapid onset of anaesthesia has made them preferable for topical anaesthetic formulations include [39]. There have been few studies investigating the efficacy of hydrogels in delivery of LA; Abdel-Hamid and colleague demonstrated the application of mebeverine as a local anaesthetic drug encapsulated in Poloxamer-407 hydrogels for the cure and management of painful oral conditions. They concluded by reporting that the hydrogel formulation showed greater anaesthetic effect compared to a commercially obtainable formulation [40]. Furthermore, hydrogels formulated based on genipin-crosslinked catechol–chitosan for the buccal mucosa delivery of LDC has been applied as a typical drug and was reported to have a sustained release profile in an in vivo drug release experimental study in rabbits [41]. In a similar way, Pignatello and colleagues demonstrated a mucoadhesive LDC-loaded hydrogel for buccal applications, based on chitosan glutamate. They concluded via clinical evaluation that the formulation reduced pain related to oral mucosa disorders [42].

Application of nanospheres or nanocapsules to local anaesthesia

There are several experimental reports on the application of nanospheres to anaesthesia. Examples are Gorner and co-worker’s [43] report on the development of a nanospheres (NSs) of poly(D,L-lactic acid) via emulsion evaporation method to deliver LDC. In their report, they reported that the size of the particle is directly related to the amount of encapsulated drug but inversely related to the rate of release of LDC. In another experimental study by Ramos et al., they formulated PCL nanospheres (Figure 2) (Table 2) and loaded them with local anaesthetic LDC via an in vitro study to characterize and investigate the efficiency of the system. They resolved that the results of cytotoxicity tests demonstrated that the nanosphere formulation was significantly less toxic than the free drug demonstrating the protective effect of encapsulation and, in addition, they reported that the pharmacological assays established that link between LDC and nanospheres that improved the anaesthetic effect and prolonged the duration and intensity of analgesia [44].

Table 2. Showing summary of nano-formulated materials used for local anaesthesia. Culled from [51].

Nano-materials	Formulations	References
Nanorod	Gold nanorod-liposomes-tetrodotoxin	[50]
Micro-particles	PLGA-micro-particle-LDC	[47–49]
Nanospheres or nanocapsules	nanosphere-poly(D,L-lactic acid)-LDC, poly(ɛ-Caprolactone)-nanospheres-LDC, poly(ethylene-glycol)-poly(ɛ-caprolactone)-nanosphere-LDC nanocapsules-poly(L- lactide) compared to benzocaine-loaded PNs	[43–46]
Hydrogel	Poloxamer-407 hydrogels-mebeverine, Genipin cross-linked catechol-chitosan hydrogel-LDC	[40,41]
Nanoparticles	Lipid–polymer hybrid nanoparticles-LDC, nanoparticles-PCL-LDC	[36,38]
Cyclodextrin	β-CD-LDC	[34]

Silva de Melo and colleagues reported that nanocapsules based on poly(L- lactide) demonstrated a prolonged anaesthetic action after blocking the sensory sciatic nerve in mice, compared to other benzocaine-loaded PNs [45]. De Melo and co-worker [46] also evaluated diverse polymeric nanocarriers for articaine delivery. The best nanocapsule system was composed of poly (ethylene glycol)-poly(ɛ-caprolactone). This system diminished the drug toxicity and demonstrated sustained in vitro release, because of strong interaction that exists between articaine and the nucleus of the nanocapsule. They concluded that polymeric nano-particles could be used potentially for delivering anaesthesia drug.

Application of nano-formulated micro particles to local anaesthesia

Horie and colleagues evaluated poly (lactic-co-glycolic acid) (PLGA) microparticles encapsulated with LDC for long-duration anaesthesia of the cochlea. They concluded by reporting that the release profile results recorded in vitro show the efficacy of the encapsulated LDC to maintain anaesthesia, and it was confirmed in vivo that there was a continuous release of LDC in the cochlear fluid [47]. Klose et al. in their experimental study evaluated the effect of the microparticle/bulk fluid ratio on the release of different drugs from PLGA microparticles by comparing the efficacy of porous and non-porous particles enclosing LDC, propranolol, with varying concentrations of the microparticles. They concluded that at a concentration of 5 mg/mL, no morphological changes were recorded in the particles. However, at a concentration of 20 mg/mL, they recorded an aggregation of the particles and more rapid drug release because of greater polymer degradation [48].

In another study designed to investigate the release efficacy of a micro-particle loaded with LDC, Holgado and co-workers carried out an investigative study to compare two different techniques for the formulation of PLGA microparticles containing LDC, namely solvent evaporation and flow focusing. They concluded in their report that the flow-focusing method produced particles that presented a narrower size distribution, higher drug loading and a slower release profile [49].

Application of nanorod to local anaesthesia

The use of nanorod has been reported in efficiently delivering LA and achieving continuous release of LA. In a recent study carried out by Changyou et al. [50], they reported a phototriggerable formulation capable of repeated and on-demand anaesthesia with reduced toxicity in vivo. Briefly gold nanorods (GNRs) that are capable of converting near-infrared (NIR) light into heat were coupled to liposomes (Lip-GNRs) (Figure 3) (Table 2) enabling light-triggered phase transition of their lipid bilayers with a resultant release of payload. They concluded that irradiation with an 808 nm continuous wave NIR laser produced on-demand and constant infiltration anaesthesia in the rat footpad in proportion to the irradiance, with reduced toxicity (Figure 4).

Figure 4. Showing characterization of blank liposomes conjugated with gold nanorods (Lip-GNR) and cryo-electron microscope image displaying gold nanorods (yellow arrows). Culled from [50].

Conclusion

Different biomaterials (nanoparticles, liposomes, nanospheres, nanocapsules, nanorod, cyclodextrins and hydrogels) have successfully been developed through the knowledge of nanotechnology with the need to increase the effectiveness of LA drugs in pain relief. Though these different formulations have demonstrated interesting characteristics in vitro, there have been no or a few in vivo clinical trials, as such more clinical studies to further confirm pharmacological improvements, especially in the case of liposomal formulations.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.