Advances in the use of local anesthetic extended-release systems in pain management

Abstract

Pain management remains among the most common and largely unmet clinical problems today. Local anesthetics play an indispensable role in pain management. The main limitation of traditional local anesthetics is the limited duration of a single injection. To address this problem, catheters are often placed or combined with other drugs in clinical practice to increase the time that local anesthetics act. However, this method does not meet the needs of clinical analgesics. Therefore, many researchers have worked to develop local anesthetic extended-release types that can be administered in a single dose. In recent years, drug extended-release systems have emerged dramatically due to their long duration and efficacy, providing more possibilities for the application of local anesthetics. This paper summarizes the types of local anesthetic drug delivery systems and their clinical applications, discusses them in the context of relevant studies on local anesthetics, and provides a summary and outlook on the development of local anesthetic extended-release agents.

Graphical abstract

Keywords:

• Pain management
• local anesthetics
• extended-release system
• drug delivery system

1. Introduction

With an aging population and emergence of fast-paced lifestyles in recent years in recent years, pain can be caused by a variety of factors such as physical stress, emotional highs and lows, and social and cultural pressures; thus, the need for pain management is increasing (Mills et al., 2019). Rational medication use is essential for pain management. According to the three-step approach to pain management, opioid analgesics are the most effective drugs, but due to their potentially addictive nature, opioid analgesics are commonly abused and involve, many serious complications, causing serious public health and social problems (Stayner & Copenhaver, 2012; Dowell et al., 2016; Andreu & Arruebo, 2018). To improve the reliability and safety of pain treatment, a variety of nonopioid drugs as well as new analgesic techniques are gradually being used in clinical practice. Local anesthetics exhibit several advantages, as they have diverse forms of application, widespread clinical applications, relatively few complications, and low impacts on the physiological function of the patient; thus, local anesthetics occupy an important position in pain treatment and are undoubtedly among the first choices for development and utilization (Barletta & Reed, 2019).

However, the current clinical management of pain based on local anesthetics, whether it is nerve blocks or catheter placement, is greatly limited by the short duration of action generated by a single injection. Moreover, it can be accompanied by many complications, such as catheter displacement, obstruction, local hematoma, nerve injury, infection, and local anesthetic toxicity (Jeng et al., 2010). Therefore, a sustained-release dosage form that can release local anesthetics for a long period is urgently needed to solve these problems in the clinical setting.

With the continuous development of material science and technology, several types of drug delivery carriers have been developed, including liposomes, microemulsions, polymer-based carriers, metallic particles, and others (Joudeh & Linke, 2022), all of which have been investigated in the context of local anesthetic agents. In this paper, we will initially summarize various local anesthetic drug delivery carriers and analyze their advantages and disadvantages, as well as discuss them in the context of relevant studies on local anesthetics. Furthermore, a summary and outlook on the clinical applications and developments related to local anesthetic retardants will be provided.

2. Lipid-based local anesthetic drug delivery system

2.1. Liposomes

Liposomes are spherical vesicles with a hydrophilic nucleus surrounded by a phospholipid bilayer, which can be loaded with both hydrophilic and hydrophobic substances (Euliss et al., 2006). As first described by Bangham in 1965, liposome were the first nano drug delivery system to transition from conceptual to clinical application and are highly accepted in the clinic (Allen & Cullis, 2013; Beiranvand et al., 2016). Liposomes are biodegradable, soluble, nonimmunogenic, and inexpensive; exhibit low toxicity; and have proven to be an effective carrier for a variety of drugs, such as antineoplastic drugs, insulin, amphotericin B, methotrexate, and local anesthetics, etc. (Chang & Yeh, 2012; Beiranvand et al., 2016; de Araújo et al., 2019).

Bupivacaine liposome suspension for injection (trade name Exparel™) is a long-acting local anesthetic formed by the DepoFoam technology, which consists of multivesicular liposomes (DepoFoam particles). A single division of the outer membrane of the DepoFoam particles releases only a portion of the bupivacaine within them, so this multivesicular nature also provides for the sustained release of bupivacaine (Figure 1) (Ye et al., 2000; Lu B et al., 2021). Bupivacaine liposome suspension for injection was approved for marketing by the FDA in 2011, making it the first local anesthetic extended-release formulation approved for clinical use. The FDA approved Exparel™ primarily for postoperative local infiltration anesthesia, cystectomy, and hemorrhoidectomy and later approved the intermuscular sulcus approach for brachial plexus block (Kaye, Armstead-Williams, et al., 2020; Kaye, Novitch, et al., 2020). In addition, it has applications related to knee and hip replacements, hysterectomies, third molar extractions and cesarean sections, mastectomies, open-heart surgeries, and other types of surgery (Hutchins et al., 2015; Jacob et al., 2017; Lieblich & Danesi, 2017; Chiu et al., 2018; Prabhu et al., 2018; Lee CY et al., 2019).

Figure 1. Flow chart of DepoFoam technology and structural characteristics of bupivacaine multivesicular liposomes. Reprinted with permission from Lu B et al. (2021), copyright© 2021 Elsevier B.V.

However, the results obtained by a series of recent clinical studies with bupivacaine liposomes raised concerns regarding their efficacy and value. The results obtained by many different clinical studies have shown no significant differences with standard bupivacaine preparations (Ottoboni et al., 2020). In addition, bupivacaine liposomes do not reduce postoperative opioid use in some procedures, and their role in improving postoperative pain and accelerating functional recovery is unclear (Cloyd et al., 2018). Due to the strong mobility, poor stability, and low drug loading capacity of liposomes, several problems remained to be solved; for example, the drug encapsulation rates should be increased and drug leakage should be reduced (Rideau et al., 2018).

2.2. Solid lipid nanoparticles

Solid lipid nanoparticles (SLNs) are a solid drug delivery systems consisting of solid lipids and surfactants with an average diameter of 50–1000 nm, which are solid at room temperature and can bind lipophilic or hydrophilic drugs. To overcome the problems caused by poor stability of physicochemical properties and low encapsulation efficiency of hydrophobic drugs, SLNs were created as a substitute for traditional carriers (liposomes, emulsions, particles, etc.) (Wang J et al., 2012; Andreu & Arruebo, 2018). Therefore, SLNs are particularly suitable for encapsulating hydrophobic drugs. SLNs have the advantages of good stability, resistance to chemical degradation, controlled release, targeting capabilities, biocompatibility and biodegradability, low toxicity, and sterilization; furthermore, SLNs can be easily mass produced (Wang J et al., 2012; Rajpoot, 2019).

Pathak, P. et al. used ultrasonic dispersion to prepare lidocaine SLNs and lidocaine nanostructured lipid carriers (NLCs) hydrogels for application on the skin surface of guinea pigs. The duration of anesthesia was increased 5-fold and 6-fold, respectively, compared with that of lidocaine gel alone (Pathak & Nagarsenker, 2009). Leng, F. et al. used different lipids, such as monostearin (MS), glyceryl palmitostearate (GP), and stearic acid (SA), to prepare lidocaine-loaded SLN for epidural anesthesia. The duration of epidural block was prolonged for different times with each lipid class (Leng et al., 2012). However, SLNs also exhibits some limitations, as the drug migration rate in the solid state being reduced compared to the oil state; in addition, the drug loading capacity and drug efflux are insufficient during production and storage (Wang J et al., 2012).

2.3. Nanostructured lipid carriers

Nanostructured lipid carriers (NLCs) are the second generation of lipid nanoparticles. Compared with SLNs, NLCs add liquid lipids and contain a mixture of liquid and solid lipids; as a result, when the temperature drops, the drug is unlikely to precipitate out of the solid lipids. thus, the limitations of SLNs are overcome, drug loading is increased, drug efflux is reduced, and the drug release are properties; in addition, the risk of drug loss during the curing step in the synthesis process and storage is reduced (Figure 2) (Wang J et al., 2012; Rajpoot, 2019; de Souza Guedes et al., 2021).

Figure 2. SLN and NLC structure model diagram. Reprinted with permission from de Souza Guedes et al. (2021), copyright© 2021 MDPI.

Some investigators prepared SLNs and NLCs coloaded with lidocaine and proparacaine, and the results showed that the NLCs system induced more significant anesthesia in comparison, but the permeation efficiency of SLNs was superior to that of NLCs (You et al., 2017). Liu and Zhao used SLNs and NLCs loaded with tetracaine and similarly found that NLCs excelled in terms of analgesic duration and analgesic effect, while SLNs exhibited the best in vitro penetration efficiency (Liu & Zhao, 2019). Overall, both SLNs and NLCs have their advantages, and both carriers are promising dual delivery systems for surface anesthesia and analgesia. In addition, lidocaine-loaded NLCs developed by Suo, Meng et al. were noticeably more effective during skin surface anesthesia (10 h) compared to commercially available ointments (4 h), and the effect of sciatic nerve block was also significantly prolonged (Suo et al., 2020).

2.4. Lipid nanocapsules

Lipid nanocapsules (LNCs) are a type of nanocarrier prepared by the phase-inversion temperature (PIT) method. It consists of an oily lipid nucleus surrounded by a nonionic surfactant layer. The larger the number of surfactants, the smaller the size of the LNCs and the larger the contact area compared to SLNs and NLCs (Cordeiro Lima Fernandes et al., 2021). This results in very small particles (<100 nm) (de Araújo et al., 2019). The LNCs is highly stable and has an efficient drug-loading capacity with a much higher encapsulation rate than that of liposomes (Huynh et al., 2009). Organic solvents are not needed during the preparation of LNCs and the potential for toxicity after skin application is eliminated. In addition, LNCs has superiority in contact with the stratum corneum, which makes it more suitable for dermal administration (Zhai et al., 2014).

Zhai Y et al. prepared ropivacaine-loaded LNCs for in vitro transdermal administration to the dorsum of mice. The results showed that the cumulative penetration of ropivacaine-loaded LNCs in isolated mouse skin was more than twice that of propylene glycol ropivacaine (control), and the ropivacaine content in the dermis was increased compared with that in the control group. The interaction of LNCs with the skin altered the morphology of the stratum corneum, thereby enhancing skin penetration and increasing the surface anesthetic effects of local anesthetics (Zhai et al., 2014). In other studies, lipid nanocapsules loaded with lidocaine and prilocaine were mixed with carbopol gel, which have a 4-fold increase in anesthesia time compared to that of gels preparations prepared without LNCs and does not cause skin damage and can be used as a preanesthetic for mouth (Cordeiro Lima Fernandes et al., 2021).

2.5. Microemulsions

Microemulsions (MEs) consist of an oil phase, water phase, surfactant, and cosurfactant, and can be divided into water-in-oil (w/o) type, water-in-oil (o/w) type, and two-phase continuous type according to the structure (Karasulu, 2008; Gradzielski et al., 2021). MEs systems exhibit several advantages, including a strong solubilizing power, which can dissolve various drugs with different polarities and improve the solubility and bioavailability of drugs; thermodynamic stability, which enhances the stability of drugs; optical clarity, which is easy to prepare; strong permeability, high levels of diffusion, and a high absorption rate, and the ability to easily penetration into the keratin layer (Vadlamudi et al., 2014; Daryab et al., 2022). Therefore, MEs are a good vehicle for drug delivery.

The ratio of MEs components and the physicochemical properties of the local anesthetic are considered crucial to obtain a prolonged duration of action of the local anesthetic. MEs drug delivery systems are feasible for multiple modes of administration (injection, oral, transdermal, etc.) and are commonly used for transdermal administration, including lidocaine, benzocaine, bupivacaine, procaine, and many other types of local anesthetics have been studied. In addition, ropivacaine is not usually used for transdermal administration (Sapra et al., 2014; Lu I-J et al., 2019). Zhao L et al. prepared MEs of ropivacaine and ME gels of ropivacaine for transdermal administration, both of which showed significant analgesic activity (Figure 3) (Zhao L et al., 2014).

Figure 3. Ropivacaine microemulsions and microemulsion gels: a scheme for preparation, optimization, and evaluation steps. Reprinted with permission from Zhao L et al. (2014), copyright© 2014 Elsevier B.V.

However, MEs involve many shortcomings as drug carriers. For example, some of the surfactants necessary for MEs are toxic, so the choice of ingredients is somewhat limited. In addition, MEs are sensitive to changes in temperature and salinity, which may lead to structural damage to MEs (Callender et al., 2017). Therefore, much potential remains for the development of MEs as drug delivery carriers.

3. Polymer-based local anesthetic drug delivery system

3.1. Natural polymer local anesthetic drug delivery systems

3.1.1. Cellulose

Cellulose is one of the most widely distributed and abundant biopolymers in nature and exhibits a variety of properties, such as renewability, biocompatibility, biodegradability, and nontoxicity (Karimian et al., 2019). Cellulose is widely found in plants, animals, and bacteria as a natural material. Cellulose nanoparticles (CNs) are ideal materials for building new biopolymers with properties such as hydrophilicity, high tensile strength, high stiffness, large specific surface area, large aspect, and low coefficient of thermal expansion (Moon et al., 2011).

Some researchers have prepared fish-scale nanocellulose composite microneedles (MNs) loaded with lidocaine that can successfully penetrate the stratum corneum, and absorb moisture to separate the drug polymer matrix, thereby releasing the drug from the polymer material. This method not only replaces traditional transdermal drug delivery but also increases the permeability of the skin, thus improving the bioavailability of local anesthetics (Figure 4) (Medhi et al., 2017; Lee B-M et al., 2020). Hoare et al. used a rheological polymer blend of hyaluronic acid (HA) and hydroxypropylmethyl cellulose (HPMC) as a carrier for bupivacaine to perform sciatic nerve blocks in rats. The duration of the sensory nerve block could be prolonged approximately threefold. This mixture was not cytotoxic and caused only a mild short-term inflammatory response at the injection site (Hoare et al., 2010). Georgios K. et al. prepared hydroxypropyl methylcellulose-based film and developed an oral mucosal drug delivery system that enables codelivery of local anesthetics and nonsteroidal anti-inflammatory drugs (NSAIDs) to the oral mucosa for the treatment of oral diseases (Eleftheriadis et al., 2020).

Figure 4. Lidocaine cellulose composite microneedle preparation flow chart. (A) Microneedle manufacturing schematic. (B) Transmission electron microscopy (TEM) showing cellulose microfibrils. (C) Lidocaine fish scale biopolymer nanocellulose MNs arrays. Reprinted with permission from Medhi et al. (2017), copyright© 2017 American Association of pharmaceutical scientists.

3.1.2. Chitosan

Chitosan (CH) is the second most abundant natural cationic polysaccharide after cellulose. CH is deacetylated from chitin and is widely used for drug delivery due to its nontoxicity, biodegradability, biocompatibility, and antibacterial, hemostatic, antibacterial and anticancer properties (Ali & Ahmed, 2018). Thus far, chitosan has been studied as a carrier for local anesthetics in various routes of administration, including oral, transdermal, injectable, and transmucosal drug delivery (Kp & R, 2021; Deng et al., 2022; Hou et al., 2022).

Zhang Y et al. prepared chitosan (CH)-coated poly(ε-caprolactone) (PCL) nanoparticles to co-deliver ropivacaine and dexamethasone complexes. The results obtained by in vivo and in vitro experiments after transdermal administration in mice showed that CH-PCL nanoparticles can act as effective drug carriers to prolong and enhance the anesthetic effect of ropivacaine (Zhang et al., 2017). In other experiments, Ma RR et al. prepared a dressing containing lidocaine using chitosan, porous gelatin, and calcium alginate. This dressing provides a rapid release of 90.5% lidocaine in 18 min, after which the remaining lidocaine is released slowly, resulting in better pain control (Ma R-R et al., 2022). Harrison et al. prepared chitosan membranes loaded with cis-2-decenoic acid (C2DA) and bupivacaine as biofilms that provided pain relief while preventing infection (Harrison et al., 2021). Hanif, S. et al. prepared a chitosan adhesive that performs oral mucosal adhesion to deliver iodinated tebuconazole and lidocaine hydrochloride; this adhesive is used to treat oral diseases, such as sore throat, using the characteristics of chitosan like its mucosal adhesion and its anti-microbial activity (Hanif et al., 2021).

3.1.3. Cyclodextrins

Cyclodextrins (CDs) are nontoxic cyclic oligosaccharides formed from α-1,4-bonded D-glucopyranose units. They are obtained by the degradation of straight-chain starch by cyclodextrin glucosyltransferase. Common natural CDs are classified as α-CD, β-CD, and γ-CD depending on the number of glucose subunits, and consist of 6,7, and 8 glucose subunits, respectively (Hammoud et al., 2019). CDs have a hydrophilic outer shell and hydrophobic inner lumen, which can improve drug solubility, increase drug stability, enhance drug absorption, improve drug bioavailability, mask drug odor, control drug release, reduce gastrointestinal irritation, reduce drug toxicity, etc. (Zhang & Ma, 2013).

One investigator used a cyclodextrin-based drug delivery system to prepare levobupivacaine complexes containing maltosyl-β-cyclodextrin (G2-β-CD). The results showed that the complexes of levobupivacaine with G2-β-CD showed significantly prolonged anesthetic effects in intrathecal and sciatic nerve blocks in rats (Karashima et al., 2007). Additionally, some studies have reported an almost twofold increase in the duration of epidural anesthesia with bupivacaine in combination with hydroxypropyl-β-cyclodextrin in rabbits compared with bupivacaine (Fréville et al., 1996). Similar results have been reported with sciatic nerve blocks. In sheep, it was also confirmed that bupivacaine cyclodextrin epidural anesthesia was more effective than bupivacaine (Estebe et al., 2002). Lidocaine (LDC)-loaded sulfobutyl ether β-cyclodextrin (SCD)/hyaluronic acid (HA) hydrogels were prepared by Zhou et al. compared to free lidocaine, SCD/HA-LDC showed significantly prolonged analgesic effects and lower cytotoxicity (Zhou et al., 2022).

3.1.4. Hyaluronic acid

Hyaluronic acid (HA) is a naturally occurring negatively charged mucopolysaccharide with a variety of properties, including biocompatibility, biodegradability, water absorption, water retention, and high viscosity. HA is mainly found in the dermis of the skin, synovial fluid, heart valves, vitreous humor of eyeglasses, cartilage, and extracellular matrix. Gelatin is naturally degraded in the body by an enzymatic mechanism (Schanté et al., 2011).

Yang et al. (2020) prepared lidocaine dissolving microneedles (Li-DMN) using hyaluronic acid as a backbone. A minimally invasive method was used to deliver lidocaine to the skin. Based on in vivo experiments, the onset of Li-DMN action is rapid, and can be achieved within 10 min. In addition, the effects last for a long time, the effects does not cause various adverse skin reactions, and the drug exhibits high clinical safety (Figure 5). Qiao et al. (2022) combined hydroxypropyl chitin thermo-sensitive hydrogel (HPCH) and HA in combination to construct a ropivacaine sustained release system. It takes advantage of the negatively charged property of HA, which shows mutual attraction with positively charged ropivacaine, thus increasing the drug delivery rate. The duration and effect of sciatic nerve block in rats were significantly better than that of ropivacaine hydrochloride, and less cytotoxicity was observed.

Figure 5. Flow chart of HA-loaded lidocaine for the preparation of dissolving MNs. Reprinted with permission from Yang et al. (2020), copyright© 2020 MDPI.

3.2. Synthetic polymer local anesthetic delivery system

3.2.1. Polylactic acid

Polylactic acid (PLA) is formed by the polymerization of lactic acid (LA), which is hydrolytically degraded and then converted into LA monomer, which is eventually decomposed into CO2 and H2O without the presence of enzymes. PLA is now commonly used in biomedicine because of its environmental nontoxicity, biocompatibility, biodegradability, mechanical strength, and processability (Singhvi et al., 2019).

Some researchers have prepared nanocapsules loaded with benzocaine using three polymers, PLA, polylactic-co-glycolic acid (PLGA), and polycaprolactone (PLC), and compared their anesthetic activity. The results showed that compared to free benzocaine, benzocaine formulations using polymeric nanocapsules had a slower release rate, and the PLA system exhibited the slowest release rate. PLA nanoparticle encapsulated benzocaine reduced the release rate, prolonged the duration of the analgesic effect, and increased the intensity of the analgesic effect. Therefore, PLA can be used as a carrier for local anesthetics to achieve slower in situ drug delivery (De Melo et al., 2012).

3.2.2. Poly lactic-co-glycolic acid

Poly lactic-co-glycolic acid (PLGA) is a polymerization of lactic acid (LA) and glycolic acid (GA). PLGA is hydrolyzed in vivo by ester bonding to produce the corresponding monomeric acid, lactic acid, and glycolic acid, and then converted to CO2 and H2O after the tricarboxylic acid cycle; thus, PLGA is nontoxic, biocompatible, and degradable (Harada et al., 2020).

Bragagni et al. prepared proparacaine-loaded PLGA particles using a double emulsion method and administered them to rats by subcutaneous injection. In vivo experiments revealed a 1.6-fold and 2-fold increase in anesthetic effect and anesthetic time, respectively, with this treatment compared to an equivalent amount of proparacaine hydrochloride in aqueous solution (Figure 6) (Bragagni et al., 2018). Wang C et al. prepared PLGA microspheres containing ropivacaine and betamethasone (RPC/BTM-PLGA-MS). In vitro release by this system can last up to 16 days. In addition, in vivo sciatic nerve block showed that PLGA microspheres (RPC/BTM-PLGA-MS) co-coated with local anesthetics and hormones exhibited a better anesthetic effect and duration compared to that of free ropivacaine and ropivacaine-only PLGA microspheres (RPC-PLGA-MS) (Wang C et al., 2022).

Figure 6. Flow chart for the preparation of PLGA particles loaded with proparacaine. Reprinted with permission from Bragagni et al. (2018), copyright © 2018 Elsevier B.V.

3.2.3. Polycaprolactone

Polycaprolactone (PCL) is a polymer formed from ε-caprolactone in the presence of a catalyst that is widely compatible and biodegradable; and can sustain prolonged drug release. It has been approved by the FDA as a suture material, drug delivery device, and adhesion barrier (Wang B et al., 2019). In the literature report, lidocaine (LDC) sustained release systems were prepared using PCL nanospheres (NS). The results showed that utilizing the NS-LDC formulation reduced the toxicity of lidocaine compared with free lidocaine and significantly increased the intensity of analgesia and the duration from 240 to 420 min (Ramos Campos et al., 2013). In another study, Zhao W et al. embedded bupivacaine in PCL nancapsules, which exhibited high physicochemical stability and remained stable for up to 120 days. Compared to free bupivacaine, its anesthetic duration was up to two times more effective, and no significant cytotoxicity was observed (Zhao W et al., 2022).

4. Inorganic local anesthetic drug delivery system

4.1. Sliver nanomaterials

Silver nanomaterials have many advantages as a drug carriers, including high density surface ligand attachment, adjustable size, and shape, protection of the attached therapeutic agent from degradation, the potential for improved timed/controlled intracellular drug delivery, and transmembrane delivery without irritant transfection agents (Qureshi, 2013; Ivanova et al., 2019). In addition, they have antibacterial, anti-inflammatory, and antitumor effects. Therefore, silver nanoparticles (AgNPs) are increasingly studied in the medical field (Noronha et al., 2017).

Some investigators have prepared lidocaine-ibuprofen ionic liquid stabilized silver nanoparticles (IL-AgNPs), and injecting it into the hind paw and tail of hairless rats for thermal and tactile experiments. The results showed that the onset of action of AgNPs was significantly faster than that of the control group. In addition, AgNPs generated a stronger and faster local anesthetic effect (Jiang et al., 2018). Researchers have also explored the interaction of AgNPs and gold nanoparticles (AuNPs) with procaine, dibucaine or tetracaine. Their interactions generate the synergistic effects exhibited by the components and lead to an increase in biological and medical effects induced by local anesthetics. However, none of the studies included had relevant efficacy data (Mocanu et al., 2012, 2013).

4.2. Gold nanomaterials

Gold nanoparticles have great potential as drug carriers due to their unique optical properties, biocompatibility, stability, hydrophilicity, non-immunogenicity, and low toxicity. Currently, gold nanoparticles are more extensively studied in cancer treatment and related to local anesthetics (Abu-Dief et al., 2021; Yafout et al., 2021).

Prieto, M et al. developed a triggerable drug delivery system of poly(oligo(ethylene glycol) methyl ether methacrylate (POEGMA) NG) and hollow gold nanoparticles (HGNPs) coloaded with bupivacaine. In vivo sciatic nerve block experiments have shown that it can block nevers for more than 6 h and can be reactivated multiple times by irradiation. The effect is significantly better than the 2-h block produced by free bupivacaine (Prieto et al., 2022). In addition, many researchers have prepared hollow gold nanoparticles (HGNPs), and gold nanorods (GNRs) and wrapped them in organic shells to form hybrid systems. The control of local anesthetic release was achieved by using their properties that can make the organic shell disintegrate under near-infrared light heating conditions. (Figure 7) (Zhan et al., 2016; Alejo et al., 2018)

Figure 7. Flow chart for preparation of hollow gold nanoparticles for the local anesthetic delivery system. Reprinted with permission from Alejo et al. (2018), copyright © 2018 Elsevier Inc.

4.3. Magnetic iron oxide nanomaterials

Magnetic iron oxide nanoparticles can be targeted for drug delivery by acting in the presence of an external magnetic field due to their inherent magnetic properties (Vangijzegem et al., 2019). In addition to these remarkable magnetic properties, their biocompatibility, stability, nontoxicity and low-cost production have led to their extensive research (Turrina et al., 2021).

Mantha et al. (2014) used magnetite (Fe₃O₄) compounded with ropivacaine to form ropivacaine-associated magnetic nanoparticles (MNP/Ropiv) and investigated the feasibility of MNP/Ropiv to produce block by intravenous injection at the ankle joint of rats and by utilizing magnet attraction. The results showed that MNP/Ropiv significantly increased the thermal pain threshold in rats. The absolute concentration of ropivacaine in the ankle tissue and the ratio of ankle tissue to plasma ropivacaine concentration were higher in the 30-min ankle joint using the magnet compared to the MNP/Ropiv group without the magnet. In addition, the combination of magnetic nanoparticles with ropivacaine was found to increase the clinically safe dose of ropivacaine intravenously by more than 14-fold (Figure 8). Su et al. (2021) prepared a novel ropivacaine nanocomposite hydrogel drug based on magnetic iron oxide, N-isopropylacrylamide-methacrylic acid/ropivacaine magnetic nanoparticles (NIP-MAA/Rop MNPs). This composite hydrogel can improve the stability and half-life and controllability of magnetic nanoparticles while retaining the magnetic properties of iron oxide to avoid neuro- and cardiotoxicity caused by excessive drug diffusion. These studies provide new opportunities for the application of clinical ropivacaine nerve block.

Figure 8. Preparation of a magnetic nanoparticle sustained release system for ropivacaine. Reprinted with permission from Mantha et al. (2014), copyright © 2014 International anesthesia research society.

4.4. Carbon nanomaterials

Carbon nanomaterials (including graphene, carbon nanotubes, nanodiamond, etc.) exhibit several beneficial properties, as they can easily cross cell membranes and exhibit a large specific surface area, high electrical and thermal conductivity, unique optical properties and mechanical properties. Therefore, these materials have received increasing attention in recent years (Kakran & Li, 2012; Diez-Pascual, 2021).

Reem Al Homsi et al. combined graphene oxide (GO) with chitosan (CS)/β-glycerophosphate (GP) thermosensitive hydrogels to encapsulate bupivacaine, enhancing the mechanical properties while improving the controllability of bupivacaine release. The results of in vivo studies showed that the composite hydrogel loaded with bupivacaine had a significantly longer local anesthesia time compared to the bupivacaine hydrochloride solution, along with a 6.5-fold increase in local anesthetic effect (Figure 9) (Al Homsi et al., 2022).

Figure 9. Graphene oxide/chitosan-based nanocomposite hydrogels loaded with bupivacaine. Reprinted with permission from Al Homsi et al. (2022), copyright © 2022 Elsevier B.V.

4.5. Silicon nanomaterials

Among silica nanoparticles, mesoporous silica nanoparticles (MSNs) are often chosen by researchers as drug delivery carriers because of their unique advantages such as a large specific surface area and pore volume (Wang Y et al., 2015). Wang H et al. prepared MSNs and mesoporous silica-coated gold nanorods (GNR@MSNs) loaded with ropivacaine by the vacuum aspiration method. Both exhibited an extended release mode in vitro, while the latter gold nanorods (GNRs) with the property of converting near-infrared (NIR) light into heat also exhibited a controlled release mode under NIR irradiation. The results showed that ropivacaine-loaded MSNs and GNR@MSNs initially induced sensory blockade that lasted 6 h in mice, which was almost 2–3 times higher than that of free ropivacaine solution. Both particles exhibited good biocompatibility, achieved high loading, and greatly reduced carrier-related toxicity and immunoreactivity (Figure 10) (Wang H et al., 2021). In addition, other researchers prepared complexes of MSNs encapsulated with lidocaine and showed that the skin release rate was faster than that of lidocaine alone (Nafisi et al., 2018).

Figure 10. Mesoporous silica drug delivery system for local anesthetics. Reprinted with permission from Wang H et al. (2021), copyright © 2021 acta Materialia Inc. Published by Elsevier Ltd.

5. Local anesthetic compound delivery system

5.1. Inorganic and polymer composite drug delivery systems

Inorganic and polymer composite drug delivery systems are increasingly emerging. Qi et al. used glycosylated chitosan (GCS)-encapsulated mesoporous silica nanoparticles (GCS-MONPs) loaded with ropivacaine, which could achieve controlled release of the drug under ultrasound stimulation to prolong the duration of analgesia and improve the analgesic effect (Qi et al., 2021). Li et al. prepared phototriggered lidocaine microneedles using iron oxide nanoparticles (Fe3O4NPs) coated with polydopamine (PDA), polyvinylpyrrolidone (PVP) and polycaprolactone (PCL) to achieve painless and effective transdermal drug delivery by programmed release of lidocaine (Li Y et al., 2022). In additional studies, dual-network microgels carrying ropivacaine were prepared using polymers, such as polyethylene glycol (PEG), with graphene oxide (GO). Anesthesia induced by an initial burst release triggered by body temperature and a subsequent controlled release induced by NIR radiation can be achieved (Pang et al., 2020).

5.2. Lipid-based and polymer drug delivery systems

As mentioned earlier, both lipids and polymers exhibit advantages and disadvantages as common drug delivery systems. To overcome the disadvantages of lipid and polymer nanoparticles, a variety of composite drug delivery carriers including lipid-polymer hybrid nanoparticles (LPNs) have been generated (Wakaskar, 2017).

LPN consists of two main components: a polymer core and a lipid shell. The polymer core is used to encapsulate the drug; the lipid shell imparts biocompatibility while acting as a barrier to reduce drug leakage (Hadinoto et al., 2013; Ma P et al., 2017). Pengju Ma et al. prepared LPN with PLGA, lecithin, and 1,2-distearoyl-snglycero-3-phosphoenthaolamine-N-[methoxy(polyethylene glycol)-2000(DSPE-PEG2000) to deliver bupivacaine. Its analgesic effect and duration were better than those of free bupivacaine and bupivacaine-loaded PLGA nanoparticles. It has enhanced stability and lower cytotoxicity in vitro (Ma P et al., 2017). Li M et al. prepared transactivated transcriptional activator-modified, levobupivacaine and dexmedetomidine codelivered LPN, which showed significant improvements in skin penetration, analgesic duration, and analgesic efficacy (Li M et al., 2020). In another experiment, ropivacaine lipid-polymer hybrid nanoparticles (RPV-LPNs), which were formed by wrapping ropivacaine (RPV) with poly-ε-caprolactone (PCL) as the polymer core and poly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE) as the lipid shell were significantly more effective than free ropivacaine anesthesia, with a rapid response within minutes, a long duration, and high penetration (Li A et al., 2019).

6. Clinical applications

Pain can be classified as nociceptive pain, inflammatory pain, neuropathic pain, cancer pain, etc., according to its mechanisms/etiology (Woessner, 2005; Abd-Elsayed & Deer, 2019). The clinical application of local anesthetics is very wide, and this paper will introduce the application of local anesthetic retardants in various types of pain and related research respectively.

6.1. Nociceptive pain

Nociceptive pain is pain caused by the activation of nociceptive receptors by stimuli such as mechanical, thermal, or chemical changes (Prescott & Ratté, 2017). Nociceptive pain has a variety of clinical manifestations and is usually acute. Injury is the most common cause, but it can also be caused by certain diseases. This may include broken bones, abrasions, burns, crush injuries, sprains, surgery, etc. (Baliki & Apkarian, 2015). Managing postoperative pain remains very challenging. Although several new analgesic drugs, techniques and methods have been applied clinically, the occurrence of postoperative pain is still very common. In today’s concept of ‘enhanced recovery after surgery’ (ERAS), there is an urgent need for more effective nonopioid medications to reduce postoperative pain, which is essential to reduce complications, shorten hospital stays, reduce medical costs, improve patient prognosis, and improve quality of life (Simpson et al., 2019).

HTX-011 (bupivacaine/meloxicam extended-release solution) was approved for marketing by the US FDA in May 2021, becoming the first FDA-approved extended-release dual-action local anesthetic to provide sustained analgesic capacity during the critical 72 h postoperatively providing an important option for reducing the need for opioids. Ottoboni, T. et al. (2020) used a porcine lumbar incision to establish a postoperative pain model, and subcutaneous injection of HTX-011 around the incision yielded good analgesia within 72 h post-operation. In addition, Wang Z et al. (2016) created a postoperative pain model through a rat hind paw incision and prepared ropivacaine nanoparticles for sciatic nerve block using polyethylene glycol copolylactic acid (PELA). The results of behavioral tests showed that ropivacaine nanoparticles inhibited the nociceptive pain induced by the incision for more than 3 days. All these studies have confirmed that local anesthesia sustained-release agents have a good analgesic effect in acute nociceptive pain caused by surgery, providing a new choice for clinical postoperative analgesia.

6.2. Neuropathic pain

The International Association for the Study of Pain (IASP) recently defined neuropathic pain as ‘pain caused by lesions or diseases of the somatosensory nervous system’ (Murnion, 2018) Common neuropathic diseases include painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), complex regional pain syndrome(CRPS), trigeminal neuralgia, human immunodeficiency virus (HIV) infection, leprosy, and phantom limb syndrome, among others (Colloca et al., 2017). With the aging of our population, neuropathic pain is gradually becoming among the major causes of pain in the elderly. The treatment of neuropathic pain is currently dominated by oral medication, and ultrasound-guided nerve block therapy based on local anesthetics occupies an important auxiliary position in clinical practice (Gilron et al., 2006; Shankarappa et al., 2012).

The sciatic nerve chronic compression injury (CCI) model is a classic neuropathic pain model. A researcher used electrostatic spinning technology to prepare a PLGA electrostatic spinning film containing bupivacaine hydrochloride and a PLGA-PEG-PLGA temperature-sensitive gel wrapped around the spinning film to prepare an extended -release system containing bupivacaine hydrochloride. A rat CCI model was used to observe the analgesic effects caused by these two drug delivery systems in vivo. The results showed that both drug delivery systems released drug in vivo for up to 14 days (Sun et al., 2022). This offers the possibility of applying local anesthetic extended-release formulations to treat neuropathic pain. If successfully applied to the clinical consultation and treatment process, it will bring great convenience to patients with neuropathic pain.

6.3. Inflammatory pain

Inflammatory pain is the most common type of pain in clinical practice (Tomic et al., 2018). Inflammatory pain is usually caused by the release of inflammatory factors (bradykinin, histamine, interleukin 1, interleukin 6, tumor necrosis factor α, 5-hydroxytryptamine, etc.) that stimulate nociceptive receptors (Nazemian et al., 2016). The common clinical conditions of frozen shoulder, appendicitis, synovitis, tenosynovitis, and compulsory spondylitis are all inflammatory pain.

Rodrigues da Silva et al. (2021) prepared an inflammatory pain model by injecting carrageenan into the soles of the rat feet. They prepared local anesthetic sustained-release agents by wrapping butamben (BTB) in a NLC. Mechanical pain threshold assay results showed that, compared with BTB suspension, NLC coated BTB pain sensitivity was reduced by another 7%, while the duration of local anesthetics was extended and the cytotoxicity of anesthetics was reduced. This study demonstrated that local anesthetics with sustained release also showed a more effective anesthetic effect in the inflammatory hyperalgesia test.

6.4. Cancer pain

Pain is a common symptom in cancer patients, and studies have shown that patients with cancer experience pain throughout the disease, with 30–50% of cancer patients having moderate to severe pain (Simone et al., 2012; Neufeld et al., 2017; Wiffen et al., 2017). Pain management has traditionally followed the World Health Organization’s (WHO) ‘three-step’ approach to analgesia (Scarborough & Smith, 2018). However, according to studies, in 10–30% of cancer patients, traditional analgesic treatment cannot effectively relieve pain or the patients cannot tolerate systemic treatment due to the side effects of drugs (Fumic Dunkic et al., 2022). As a result, interventional techniques are becoming an important adjunctive treatment for pain, including autonomic nervous system blockade, peripheral nerve blockade, and intralesional analgesia, among others (Lema, 2001). Local anesthetics play an important role in interventional techniques.

N. D. Lafont et al. used liposome-associated bupivacaine administered via a T6-T7 epidural catheter to treat pain in lung cancer patients with T4-T10 segments. Pain was completely relieved after 5 min and lasted up to 11 h, which was much longer than the 4-h analgesia of 0.25% bupivacaine, while liposome-associated bupivacaine did not produce motor blockade (Lafont et al., 1996). This effect is well suited to meet the clinical analgesic needs.

7. Summary and outlook

This article briefly outlines the characteristics and shortcomings of various local anesthetic delivery systems in the context of relevant recent studies and describes their clinical applications. The various local anesthetic delivery systems and their applications are summarized in Table 1. In recent years, although domestic and foreign research in drug sustained-release formulations has made certain advancements, especially in the fields of antitumor drugs and antibiotics, and the FDA has also approved four types of local anesthetic-related retardant dosage forms, Exparel™, Xaracoll™, Posimir™, and Zynrelef™, for clinical applications, but their clinical translation still faces difficulties (Cusack et al., 2012; Hadj et al., 2012; Alijanipour et al., 2017; Amundson et al., 2017; Coppens et al., 2019; Velanovich et al., 2019; Nair et al., 2020; Blair, 2021; Chaurasiya et al., 2021; Leiman et al., 2021; Pedoto et al., 2021; Ekelund et al., 2022; Otremba et al., 2022; Gailey & Ostrum, 2023; Yu et al., 2023) (Table 2). In recent years, local anesthetic control agents have also proliferated, such as mesoporous silica-coated gold nanorods controlled by infrared light and thermosensitive graphene oxide/chitosan-based nanocomposite hydrogels in local anesthetics; however, no FDA-approved local anesthetic control agents are available for clinical applications (Wang H et al., 2021; Al Homsi et al., 2022). To better meet clinical needs, stimulus-responsive drug delivery systems may be the future direction, which can achieve controllability of drug release and thus achieve ‘on-demand’ release to meet patients’ requirements.

Table 1. Summary of local anesthetic drug delivery systems.

Drug delivery systems	Classification	Local anesthetics	Studies	Ref.
Lipid-based drug delivery system	Liposomes	Bupivacaine	A bupivacaine liposome suspension, which provides up to 72 h of postoperative local analgesia, is commercially available.	(Kaye, Armstead-Williams, et al., 2020; Kaye, Novitch, et al., 2020)
	SLNs	Lidocaine	The ultrasonic dispersion technique for the preparation of lidocaine SLN hydrogel resulted in a 5-fold increase in anesthesia time compared to lidocaine gel alone.	(Pathak & Nagarsenker, 2009)
	NLCs	Lidocaine	Lidocaine-loaded nanostructured lipid carriers for sustained release for up to 10 h.	(Suo et al., 2020)
	LNCs	Ropivacaine	Ropivacaine-loaded LNCs for in vitro transdermal administration to the dorsum of mice. The cumulative penetration in the skin was more than twice that of the control and the ropivacaine content in the dermis was significantly increased.	(Zhai et al., 2014)
	MEs	Ropivacaine	Both microemulsions and microemulsion gel formulations loaded with ropivacaine for transdermal administration showed significant analgesic activity and did not cause any irritation	(Zhao L et al., 2014)
Polymer-based drug delivery system	Cellulose	Lidocaine	The penetration of lidocaine into porcine skin by lidocaine-loaded nanocellulose composite microneedles was evaluated, showing an increase in drug penetration from 2.5% to 7.5% w/w after 36 h.	(Medhi et al., 2017)
	CH	Ropivacaine	Chitosan (CH)-coated poly(ε-caprolactone) (PCL) nanoparticles codelivered ropivacaine and dexamethasone, and all nanoparticles loaded with RPV produced longer and more significant anesthetic effects compared to free ropivacaine.	(Zhang et al., 2017)
	CDs	Levobupivacaine	Sciatic nerve block with levobupivacaine compounded with maltosyl-β-cyclodextrin was twice as effective with 0.5% levobupivacaine compound and 4.1 times more effective with 1% levobupivacaine compound than with levobupivacaine.	(Karashima et al., 2007)
	HA	Lidocaine	Hyaluronic acid lidocaine dissolving microneedle, which works rapidly within 10 min. It overcomes the limitation of poor effect and slow onset of lidocaine cream.	(Yang et al., 2020)
	PLA	Benzocaine	Comparing benzocaine loaded nanocapsules prepared from three polymers, PLA, PLGA, and PLC, only PLA nanocapsules showed increased duration and intensity of analgesic effect.	(De Melo et al., 2012)
	PLGA	Proparacaine	PLGA particles loaded with proparacaine showed a 1.6-fold and 2-fold increase in anesthetic effect and time, respectively, compared to aqueous proparacaine hydrochloride.	(Bragagni et al., 2018)
	PCL	Lidocaine	PCL nanospheres loaded with lidocaine increase the duration of analgesia from 240 to 420 min compared to free lidocaine	(Ramos Campos et al., 2013)
Inorganic drug delivery system	Sliver nanomaterials	Lidocaine	Lidocaine-bupropion ionic liquid stabilized silver nanoparticles (IL-AgNPs) had a faster onset of action (approximately 10 min) and a stronger effect compared to the control lidocaine and prilocaine cream (EMLA^TM).	(Jiang et al., 2018)
	Gold nanomaterials	Bupivacaine	Hollow gold nanoparticle-loaded bupivacaine has great potential for controlled release of bupivacaine on demand.	(Alejo et al., 2018)
	Magnetic iron oxide nanomaterials	Ropivacaine	Magnetite (Fe3O4) complexed with ropivacaine found that the combination of magnetic nanoparticles with ropivacaine can increase the clinically safe dose of ropivacaine by more than 14 times	(Mantha et al., 2014)
	Carbon nanomaterials	Bupivacaine	Graphene oxide (GO) combined with chitosan (CS)/β-glycerophosphate (GP) thermosensitive hydrogel loaded with bupivacaine, significantly prolonging the duration of local anesthesia and increasing the effect by up to 6.5 times compared to bupivacaine hydrochloride solution	(Al Homsi et al., 2022)
	Silicon nanomaterials	Lidocaine	Mesoporous silica nanoparticles (MSNs) loaded with lidocaine release faster than pure lidocaine and have a higher skin penetration rate.	(Wang H et al., 2021)
Compound delivery system	Inorganic and polymer	Ropivacaine	Glycosylated chitosan (GCS)-encapsulated mesoporous silica nanoparticles (GCS-MONPs) loaded with ropivacaine release the drug under ultrasound irradiation with enhanced controlled release capability, providing a prospective technique for clinical pain.	(Qi et al., 2021)
		Lidocaine	Fe3O4NPs and polymers such as PCL were used to prepare lidocaine microneedles, which were programmed to release under light-out trigger for painless transdermal drug delivery.	(Li Y et al., 2022)
	LNPs	Bupivacaine.	LPNs prepared using LGA, lecithin and DSPE-PEG2000 to deliver bupivacaine have the advantages of overcoming poor liposome stability and rapid drug leakage, prolonging the anesthetic effect and low cytotoxicity	(Ma P et al., 2017)
		Levobupivacaine	LNPs prepared with PCL as the polymer core and PEG-DSPE as the lipid shell, encapsulated with ropivacaine, are highly permeable, respond rapidly within minutes of application, and have a long analgesic duration.	(Li A et al., 2019)

Table 2. Local anesthetic extended-release agents that have been approved for marketing by the FDA.

Brand name	Generic name	Listing year	FDA approved scope of use	Technology	Lasting time	Ref.
Exparel	Bupivacaine liposome injection suspension	2011	It is approved primarily for postoperative local infiltration anesthesia, cystectomy, hemorrhoidectomy, and later for brachial plexus nerve blocks in the intermuscular groove approach.	DepoFoam® technology	48–72 h	(Lafont et al., 1996; Alijanipour et al., 2017; Amundson et al., 2017; Chaurasiya et al., 2021; Pedoto et al., 2021; Otremba et al., 2022; Gailey & Ostrum, 2023; Yu et al., 2023)
Xaracoll	Bupivacaine hydrochloride implant	2020	It is primarily approved for implantation after open inguinal hernia repair.	Collarx® technology	24h	(Cusack et al., 2012; Velanovich et al., 2019; Leiman et al., 2021)
Posimir	Bupivacaine solution	2021	It is primarily approved for analgesia after arthroscopic decompression of the acromion.	SABER® technology	72h	(Hadj et al., 2012; Coppens et al., 2019; Ekelund et al., 2022)
Zynrelef	Bupivacaine/meloxicam extended release solution	2021	It is mainly approved for postoperative pain in the torso caused by small and medium-sized surgical wounds such as bunions fenestrations, open inguinal hernia repairs, and after total knee replacements.	Biochronome® technology	72h	(Nair et al., 2020; Blair, 2021)

Authors contributions

Yulu Chen: Writing – Original Draft and drawing the Figures and Tables; Jingmei Xu: Reviewing and Editing; Ping Li, Liyang Shi, Sha Zhang and Qulian Guo: Conceptualization and Editing; Yong Yang: Reviewing and Editing, Supervision. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

This study is supported by the Natural Science Funding Project of Hunan Province [grant number 2022JJ30975].