NANO REVIEW Open Access

New Updates Pertaining to Drug Deliveryof Local Anesthetics in ParticularBupivacaine Using Lipid NanoparticlesSiavash Beiranvand1, Ali Eatemadi2 and Arash Karimi1*

Abstract

Lipid nanoparticles (liposomes) were first described in 1965, and several work have led to development ofimportant technical advances like triggered release liposomes and drug-loaded liposomes. These advances have ledto numerous clinical trials in such diverse areas such as the delivery of anti-cancer, antifungal, and antibiotic drugs;the delivery of gene medicines; and most importantly the delivery of anesthesia drugs. Quite a number ofliposomes are on the market, and many more are still in developmental stage. Lipid nanoparticles are the firstnano-medicine delivery system to be advanced from laboratory concept to clinical application with highconsiderable clinical acceptance. Drug delivery systems for local anesthetics (LAs) have caught the interest of manyresearchers because there are many biomedical advantages connected to their application. There have been severalformulation techniques to systemically deliver LA that include encapsulation in liposomes and complexation incyclodextrins, nanoparticles, and to a little extent gold nanoparticles. The proposed formulations help to decreasethe LA concentration utilized, increase its permeability, and most importantly increase the localization of the LA fora long period of time thereby leading to increase in the duration of the LA effect and finally to reduce any localand systemic toxicity. In this review, we will highlight on new updates pertaining to drug delivery of localanesthetics in particular bupivacaine using lipid nanoparticles.

Keywords: Local anesthetics, Drug delivery, Lipid nanoparticles, Bupivacaine, Toxicity

ReviewIntroductionA drug delivery system should have reduced tissue reac-tion, an efficient drug release capability, and a steadydegradation rate for biodegradable carrier until all non-harmful products are passed out [1, 2]. For local anes-thetics (LAs), the formulations of new potent deliverysystems is aimed at modulating and controlling the re-lease rate of these drugs, improve their anesthetic effect,and enhance their localization thereby reducing side ef-fects associated with systemic toxicity [3]. LAs are im-portant clinically for anesthesia and analgesia formanagement of acute and chronic pain after surgery andalso reducing systemic toxicity and blocking sensory fi-bers though they may only last for few hours [4, 5].

For an excellent drug delivery system for LA to be de-signed/formulated, previous research studies have outlinedtwo important factors that must be considered: (1) thedrug has to be adequately transported in order to sustaina therapeutic concentration for a maximum period of timeand (2) carrier/drug excretion must be minimally reducedfor a decreased systemic concentration of the drug and itsconcentration on the site of injection [6]. It should also benoted that drug delivery systems for LA should act as astore house at the injection site in which the carried LAare slowly and gently released from these store housethereby reducing risk of increased plasma levels, increasedperiod of nerve block, and decreased risk of systemic tox-icity which is of great importance to patients with surgicalor chronic pain [7, 8].Recently, the application of local anesthetic drugs to

provide postsurgical analgesia has been welcomed bygreat scientific and clinical interest [9]. However, localanesthetic drugs have short action period, so neural

* Correspondence: a-eatemadi@razi.tums.ac.ir1Department of Anesthesiology, Lorestan University of Medical Sciences,Khoramabad, IranFull list of author information is available at the end of the article

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.

Beiranvand et al. Nanoscale Research Letters (2016) 11:307 DOI 10.1186/s11671-016-1520-8

blockade enhancers like dexamethasone are often ad-ministered in combination with these anesthetic drugs.There are varieties of local anesthetics available includ-ing lidocaine, bupivacaine, and ropivacaine being someof the most commonly used [10]. Bupivacaine and ropi-vacaine have demonstrated to produce longer peripheralneural blockade (4.5–12 h) than lidocaine (1–2 h) assuch bupivacaine is commonly used for long-actinganesthetic effects; however, it is also linked with compel-ling cardiotoxicity and neurotoxicity [11]. The toxicity ofbupivacaine has been overcome by ropivacaine, the pro-pyl analog of bupivacaine while still maintaining thesame duration of action [12]. Additionally, ropivacaineshows a lower lipid solubility and vasodilation whencompared with bupivacaine resulting in their increasedcirculation time within the delivered local environment[13]. While promising, local anesthetics need a continu-ous admixture to maintain and sustain an efficient post-surgical pain management, or else it can result tocomplex side effects like adverse local tissue reactionsand systemic toxicity [14]. The application of biomate-rials to develop a controlled release technique for localanesthetics has been efficient to deliver a non-lethal, lo-calized, and postsurgical pain management system [15].Over the years, researchers have formulated quite anumber of biomaterial-based carriers, including lipo-somes microparticles and nanoparticles. These materialshave been proven to be efficient in the release of encap-sulated drugs and in addition can diffuse freely from theinjection site [16].

Types of Local AnestheticsLocal anesthetics (LAs) are used mostly for anesthesiaand analgesia after surgery or for pain management,which normally last for a few hours. To prolong the dur-ation of local anesthesia, the use of catheter techniques,disposable pumps, or multiple injections can be adopted[D]. Prolonged LA action has only resulted in doubledor tripled plain drug effect time, together with the use ofadjuncts with LA agents of readily available agents.Local anesthetics can be categorized into two groups

based on the nature of the chemical link, namely amides[−NH–CO–] and esters [−O–CO–] (Figs. 1 and 2). The

amide group is more clinically important; it includes lig-nocaine, prilocaine, levobupivacaine, bupivacaine, mepi-vacaine, and ropivacaine.The ester group of LA includes cocaine, procaine,

chloroprocaine, and amethocaine, and they have beenreported to be weak bases and solubilized for injectionas strong conjugate acidic hydrochloride salts at a of pH3–6 by (Fig. 3) [17, 18].For topical and mucous formulations, benzocaine and

butamben are the most commonly used ester type oflocal anesthetics. Dewachter reported the clinical advan-tage of amide group over ester group in that anaphylaxisto local anesthetics is very rare and has reduced the fre-quency of acute allergic reaction because of the decreas-ing use of the ester group of local anesthetics [19]. Inaddition, the metabolic product of the ester localanesthetic like para-aminobenzoic acid is mostly respon-sible for allergic reactions [19]. Cross-reactivity amongesters is common.However, there are allergic reactions associated with

amide local anesthetics but remain anecdotal. It shouldbe noted that ingredients like antioxidants or preserva-tives included in local anesthetic may also produce aller-gic or adverse reactions [19].

Mechanisms of Action of Local AnestheticsLocal anesthetics directly block transmission of painsensation from nociceptive afferent nerves. Localanesthetic agents are injected directly, and their po-tency results from action on the nerve where the in-ward sodium ion (Na+) current is blocked at thesodium ionophore during depolarization process [20].LAs are also responsible for blocking calcium ions(Ca2+) and potassium ions (K+) channels and potentialvanilloid-1 receptors [21]. Local anesthetics also alterthe linking bond between some certain G proteinsand their associated chemical receptors; so throughthis ability, LAs are able to carry out their anti-inflammatory effects, especially on neutrophil primingreactions [22].

Lipid Nanoparticle/LA Drug InteractionWhen a lipid nanoparticle loaded with an anesthesiadrug interacts with a cell, the delivery of the localanesthesia drug and its distribution in the target cell canbe achieved in several ways: lipid nanoparticle loadedwith an anesthesia drug interacts with the cell, bindingto the surface via the receptors (1). Absorption onto theplasma membrane can also occur by electrostatic inter-actions (2). The delivery of the cargo into the cell cyto-plasm can take place through different ways. Lipidnanoparticles fuse with the plasma membrane of the celland empty the anesthesia drugs into the cell (3). Afterthe interaction with the cell, the structure of the lipid

Fig. 1 Basic structure of local anesthetics

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nanoparticle bilayer can be affected and the anesthesiadrug is released (4). Exchange of carrier-lipid compo-nents with the cell membrane can also occur (5). Lipidnanoparticles engulfed by endocytosis (6) can either fol-low these paths: endosomes fuse with lysosomes (7): inthis case, the anesthesia drug is released as a result ofbreakdown of the liposome membrane by low PH. Endo-somes follow another route (8): lipid nanoparticle re-leases their loaded drug after the degradation of theendocytic vesicle (Fig. 4) [23].

Toxicity of Local AnestheticsSystemic toxicity is caused by increased concentrationsof local anesthetics. They happen when there is an acci-dental discharge of anesthesia drugs into the systemiccirculation. The central nervous system is the mostprone and sensitive to the toxic action of local anestheticagents and cardiovascular system and can result intosymptoms like isolated muscle contractures, incoherentspeech, generalized convulsions, unconsciousness, etc.

[24]. Recently, Cai and his colleagues demonstrated intheir study that bupivacaine, tetracaine, and etidocaineincreases tendency and possibilities to impair the properfunctioning of both the cardiovascular system and cen-tral nervous system compared with lidocaine, mepiva-caine, and prilocaine [25]. The central nervous system ismore sensitive and prone to the toxic effects of local an-esthetics than the cardiac system because it dependsupon sodium channels for proper functioning, and it isthe first to typically manifest signs of toxicity above thenormal pharmacological dose of the administered LAdrug (Table 1).

Toxic Effects on Central Nervous SystemThe initial CNS symptoms are tinnitus, blurred vision,dizziness, tongue parathesias, and circumoral numbness.Excitatory signs such as nervousness, agitation, restless-ness, and muscle twitching are the result of blockade ofinhibitory pathways. While the early signs advance to

Fig. 2 Amide local anesthetics

Fig. 3 Amide local anesthetic (lignocaine) and ester local anesthetic (procaine)

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CNS depression with slurred speech, drowsiness, uncon-sciousness, and then respiratory arrest.

Toxic Effects on Cardiovascular SystemLocal anesthetics have directed toxic effects on the heartand peripheral blood vessels. They block the fast sodiumchannels in the fast-conducting tissue of Purkinje fibersand ventricles leading to a reduced rate of depolarizationas well as the effective refractory period and action po-tential duration (https://www.openanesthesia.org/loca-l_anesthetics_systemic_toxicity/).

Liposomal Bupivacaine and Its Functional Platform forAnesthesia Drug DeliveryRecently, liposomal bupivacaine has been applied in clin-ical practice and has been investigated in many clinicaltrial studies on healthy patient volunteers in order toprocure a long-lasting pain relief in a single dose admin-istration (DepoFoam bupivacaine, Exparel™) (Table 2).Liposomal bupivacaine is made up of liposomal sphereswith a radius size of 15.6 μm± 17.8 [26].Recent in vitro studies comparing the Exparel™ com-

plex with bupivacaine hydrochloride 0.5 % (w/v) and1.31 %, respectively, regarding controlled release system,with the same amount of active substance have been car-ried out, and it was reported that the release kineticsprofile was different in the case of hydrochloride fromfree bupivacaine with a peak time release of 48 h, whileconcerning Exparel™ complex and the peak time releasewas about 800 h [27] (Table 3).In Bramlett et al.’s study, bupivacaine-loaded lipid

nanoparticle was demonstrated to provide benefit intotal knee arthroplasty (TKA); in that study of 138 TKA,Bramlett compared several doses of DepoFoam (lipidnanoparticle bupivacaine) against bupivacaine hydro-chloric acid (HCl) in wound infiltration [28]; it was re-ported that the highest dose of bupivacaine-loaded lipidnanoparticle of 532 mg was the only effective dose thatwas capable of producing improved pain scores in theTKA patients at rest over the bupivacaine, and wasfound to be dose-related [29] (Fig. 5) (Table 4).

Fig. 4 Lipid nanoparticle-cell interaction

Table 1 Showing the pharmacological data for the two LAgroups

LA groups Max dose (mg/kg) Duration (h)

Esters

Chloroprocaine 12 0.5–1

Procaine 12 0.5–1

Cocaine 3 0.5–1

Tetracaine 3 1.5–6

Amides

Lidocaine 4.5/(7 with epi) 0.75–1.5

Mepivacaine 4.5/(7 with epi) 1–2

Prilocaine 8 0.5–1

Bupivacaine 3 1.5–8

Ropivacaine 3 1.5–8

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Lipid nanoparticles have several characteristics suchas biodegradable, decreased toxic, and solubilizeddrug delivery system that have been widely utilized inbiomedical field, also lipid nanoparticle formulationshave demonstrated several abilities to improve on thepharmacokinetics and pharmacodynamics of theloaded encapsulated drugs; in addition, it have beenshowed to be a potent drug carrier for several drugslike insulin, sildenafil citrate, amphotericin B, andmethotrexate [30] (Fig. 6). Presently, there are few orno research studies that have investigated the encap-sulation of LA into lipids nanoparticles [31]. However,

there are few available clinical studies that have inves-tigated and compared the differences between EMLA(lidocaine 2.5 % and prilocaine 2.5 %) and liposomalsystems for several local anesthesia agents (Table 4).Recently, lipid nanoparticle bupivacaine has been in-vestigated to provide up to 72 h of analgesia effectafter hemorrhoidectomy surgery, thereby decreasingadministration of opioids.One of such research studies results reported by

Bucalo and his colleagues stated that liposomal lidocainepreparations is more efficient than non-lipid nanoparti-cle vehicles in terms of increased time duration of

Table 2 Summary of liposomal bupivacaine application

Author Study design Result

McAlvin et al. [51] To evaluate the effect of liposomal bupivacaine on thesciatic nerve in experimental models

Histological evaluation reported that both Exparel complexand bupivacaine hydrochloride produce tissue reactionwith the liposomal complex being less aggressive.

Lonner et al. [52] To study the role of liposomal bupivacaine in painmanagement after total joint arthroplasty and observedthat liposomal bupivacaine pharmacokinetics andpharmacodynamics

Liposomal bupivacaine has less cardiac toxic effects, lesscardiac toxic effects, without significant differencesbetween Exparel™ and placebo: palpations andextrasystoles (≤2 %), tachycardia (3.9 %), bradycardia(1.6 %), hypertension and hypotension (≤2 %).

Richard et al. [53] To study any hematological, biochemical, and biologicalside effects of Exparel complex in laboratory animals

(1) Histological analysis reported that there was evidenceof granulomatous inflammation, 15 days afteradministration of Exparel™ formulation.(2) There was maintenance of optimum plasmaconcentration for about 96 h.(3) Administration of liposomal bupivacaine topostoperative patients reduces the intake of opioids, thehospital admission period, and costs of bills.

Soberón et al. [49] Study was carried out on a 45-year-old woman withdigital ischemia on the ring finger and little finger at theright hand.

(1) It was reported that the results were superior to thesubclavicular block due to a better and efficient paincontrol.(2) It was reported that after surgery, photo-plethysmography, showed a normal ulnar artery and lossof finger cyanosis, as a result of vasodilation effect pro-duced by liposomal bupivacaine.

Table 3 Examples of marketed liposomal for anesthesia drug and other drugs

Trade name Nanoparticle platform Drug Size Indication

Anti-cancer

Doxil/Caelyx (Janssen) PEG-liposomes Doxorubicin 100 nm Kaposi’s sarcoma, ovarian cancer, breast cancer,combination with bortezomib in multiple myeloma

DaunoXome (Galen) Lipid nanoparticle Daunorubicin 45–80 nm Kaposi’s sarcoma

DepoCyt (Pacira) Lipid nanoparticle Cytarabine 20 μm Malignant lymphomatous meningitis

Marqibo (Talon) Lipid nanoparticle Vincristine 100 nm Acute lymphoblastic leukemia

Myocet (Cephalon) Lipid nanoparticle Doxorubicin 80–90 nm Combination therapy with cyclophosphamide inbreast cancer

Analgesics

Diprivan (Fresenius Kabi) Lipid emulsion Propofol 180 nm Anesthesia

DepoDur (Pacira) Lipid nanoparticle Morphine 17–23 μm Postsurgical pain

Exparel (Pacira) Lipid nanoparticle Bupivacaine 24–31 μm Anesthesia

Antifungal

Abelcet (Sigma-Tau) Lipid drug particles Amphotericin B 2–5 μm Aspergillosis

AmBisome (Astellas) Liposome Amphotericin B <100 nm Antifungal, leishmaniasis

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anesthesia [32]. Furthermore, other studies have also in-vestigated clinical comparisons between EMLA (lido-caine 2.5 % and prilocaine 2.5 %) and 5 % lipidnanoparticle tetracaine for skin anesthesia. Taddio andhis research teammates demonstrated the effect of localanesthesia of a new lipid nanoparticle formulation made

up of 4 % lidocaine in a randomized controlled trial, andit was reported that the lipid nanoparticles formulationexhibited a brief action duration of about 30 min, beingpotent for cutaneous analgesia in children [33]. Anotherresearch study on the use of lipid nanoparticle to encap-sulate anesthesia drugs reported that after the injection

Fig. 5 Plasma bupivacaine concentration after administration of DepoFoam bupivacaine or bupivacaine HCl to patients undergoing totalknee arthroplasty

Table 4 Summary of studies assessing the efficacy of bupivacaine-loaded lipid nanoparticle

Author Study design Surgery Intervention/Placebo Primary end point Results

Gorfine et al.[54]

Randomcontrolled trial

Hemorrhoidectomy DepoFoam Bupivacaine300 mg compared with0.9 % sodium chloride

Numerical rating score(NRS), AUC 0–72 h

Pain intensity scores weresignificantly decreased in theextended release bupivacainegroup versus placebo (141.8 vs.202.5, P < 0.001).

Smoot et al.[55]

Randomcontrolled trial

Mammoplasty DepoFoam bupivacaine600 mg compared withbupivacaine HCL 200 mg þepinephrine 1:200,0000

NRS-Activity, AUC 0–72 h No statistical difference betweenthe groups (AUC NRS-A, 441 vs.468, P 1⁄4 0.3999).

Golf et al.[29]

Randomcontrolled trial

Bunionectomy DepoFoam 120 mgcompared to 0.9 % sodiumchloride

NRS AUC 0–24 h Pain intensity score wassignificantly decreased in lipidnanoparticle bupivacaine versuscontrol, 123.9 in DepoFoamversus 146 in placebo,P < 0.0005.

Bramlett et al.[28]

Randomcontrolled trial

Total kneearthroplasty

DepoFoam bupivacaine(133, 266, 399, and 532 mg)compared to bupivacaineHCl 150 mg withepinephrine 1:200,000

NRS-A, AUC 0–96 h No statically significantdifference between allDepoFoam groups versusbupivacaine HCl (P > 0.05).

Cohen et al.[56]

Cohort study Colectomy DepoFoam 366 mgcompared withpostoperative PCA

Total milligrams of opioidsconsumed after surgeryand total cost ofhospitalization

Mean total amount ofpostsurgical opioids significantlyless in DepoFoam compared toPCA group (57 vs. 115 mg, P 1⁄40.025). Average cost ofhospitalization significantly less inDepoFoam versus PCA (US$ 8766vs. US$ 11,850 P 1⁄4 0.027).

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of lipid nanoparticle bupivacaine, increased plasma con-centrations were sustained for longer time period withthe liposomal bupivacaine when compared with plainbupivacaine [34].In another recent clinical study, a large multi-vesicular

bupivacaine formulation was investigated in six healthyvolunteers through intradermal injections in various in-jection sites like the lower back, with different percent-ages of 0.5, 1.0, and 2 % of lipid nanoparticlebupivacaine; 0.5 % plain bupivacaine; 0.9 % saline; andsham liposomes. The calculated median time duration ofanalgesia effect with 0.5 % bupivacaine was 1 h; with 0.5,1.0, and 2.0 % liposomal bupivacaine; this was increasedto 19, 38, and 48 h, respectively [35].The introduction of lipid nanoparticle bupivacaine has

paved a way for several randomized trials investigatingthe potency and safety of this new delivery system(Table 3). Gorfine et al. carried out a multicenter, ran-domized, double-blind, parallel-group placebo-controlled phase 3 research study to compare the po-tency and time duration of postsurgical analgesia effectfrom a single dose of lipid nanoparticle bupivacaine withplacebo administered intra-operatively in patients under-going hemorrhoidectomy. In this study, all the patientswere randomly assigned to receive DepoFoam bupiva-caine placebo made up of 30 ml of 0.9 % sodium chlor-ide and 10 mg of morphine was administeredintramuscularly as postsurgical pain control for every 4to 6 h as necessary for the first 3 days of the postsurgicalperiod [36, 37]. The primary end point and secondaryoutcome of this study are summarized in Table 4. Con-clusively, it was reported that the administration of lipidnanoparticle bupivacaine resulted in a statistically sig-nificant pain reduction within 3 days, reduced opioid in-take compared with placebo after hemorrhoidectomy[38].In another randomized, multicenter, double-blinded

study conducted by Smoot et al., to investigate the

extent and time duration of analgesia effect achievedwith lipid nanoparticle loaded bupivacaine in patientsundergoing cosmetic and sub-muscular augmentationmammoplasty under general anesthesia, 136 patientswere randomized to either a single dose of lipid nano-particles bupivacaine 600 mg or bupivacaine HCl (0.5 %bupivacaine with epinephrine 1:200,000). Then, 1000 mgof acetaminophen was administered to all patients threetimes a day and rescue oxycodone as mandatory 3 daysafter surgery [39]. The primary end point and secondaryoutcome of this study are summarized in Table 4. Fi-nally, this study reported that the cumulative amountsof opioid taken were significantly lower in the lipidnanoparticle bupivacaine group through 24 h andthrough 48 h as such the authors concluded that lipidnanoparticle bupivacaine is promising as regards effi-ciency compared with bupivacaine HCl and required lessopioid intake [40].Furthermore, another randomized, double-blind phase

3 clinical study on bunionectomy patients, and a total of193 patients were randomized to receive either lipidnanoparticle bupivacaine 120 mg or placebo throughwound infiltration. All the patients were sedated by ad-ministering propofol with Mayo block with up to 25 mlof 2 % lidocaine with epinephrine. The patients receivedeither 180 mg (8 ml) of DepoFoam bupivacaine or theplacebo, and 8 ml of 0.9 % sodium chloride, 30 min afterthe Mayo block was administered. The primary endpoint and secondary outcome of this study are summa-rized in(Table 4. Conclusively, the study showed thatlipid nanoparticle bupivacaine provided improved painrelief and reduced intake of opioid after bunionectomy,compared with placebo [4].Cohen et al. carried out an open-label cohort study to

investigate the total opioid burden and health economicoutcomes in adult patients undergoing open segmentalcolectomy [41] with anastomosis with general anesthesiawho were administered with received lipid nanoparticle

Fig. 6 Lipid nanoparticle (a) and a loaded lipid nanoparticle with local anesthesia drug (b)

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bupivacaine for postsurgical pain compared with thosewho were administered with patient-controlled analgesia(PCA) with opioids. The primary end point and second-ary outcome of this study are summarized in Table 4.The results showed that the lipid nanoparticle bupiva-caine group had significantly reduced total postsurgicalopioid use than the PCA group [42].A new product, EXPAREL™ (Pacira Pharmaceuticals

Inc., NJ, USA), made up of DepoFoam (MLV) liposomalbupivacaine has been developed and according to a newclinical study, patients that were administered Depo-Foam bupivacaine had decreased rescue analgesia ur-gency compared with plain 0.5 % bupivacaine at 24 h[43]. However, the calculated mean cumulative painscores at rest or without rest were the same, as were res-cue medication necessities at all other time points up to3 days but it should be noted that muscular pain was re-ported in 6 out of 66 (9 %) patients administered withDepoFoam bupivacaine, but none was reported withplain bupivacaine [44].Recent research works have demonstrated the effi-

cacy of nanoparticle in a rat model where local anal-gesia was reported administered to nine of tenanimals treated with bupivacaine-loaded nanofibers,with the effect of the LA been observed at day 1 andmaximum effect observed at day 3; however, the ob-served effect was lost between 7 and 9 days. Inaddition, Chen and other researchers developed asandwich-structure electrospun fiber mat that is madeup of two outer layers and an inner layer consistingof PLGA/collagen fibers and PLGA fibers respectivelycontaining two antibiotics drugs and one anestheticdrug, namely gentamycin and vancomycin and lido-caine, respectively leading to promising repair of in-fected wounds in a rat model carried out in vivo.Weldon and his colleagues also developed an electro-spun nanofiber that provided a promising sustainedlocal analgesia using bupivacaine [45].Furthermore, and recently, there has been a develop-

ment of local anesthetics skin-delivery systems usinglipid nanoparticles, and this technique has been chan-neled into commercial formulations such as lidocaineand prilocaine cream, leading to modified release rate ofdrugs, increased bio-adhesive abilities, and reduced tox-icity, thereby improving therapeutic potency [46].Previous research works have developed a safe and

sustained analgesia effect for 48 h after administration oflocal anesthetic injection of 2 % lipid nanoparticle ligno-caine [47]. In addition, it was reported that after an epi-dural injection of lipid nanoparticle bupivacaine, therewas a twofold increase in the time duration of the anal-gesia effects [48]. Furthermore, research studies in thefield of intraoral topical anesthesia reported that lipidnanoparticle-encapsulated 2 % ropivacaine gel was as

potent as 20 % benzocaine gel in decreasing pain incurredduring needle injection and activating soft-tissueanesthesia [49]. Recently, in a randomized single-blinded,placebo-controlled research study, lipid nanoparticle-encapsulated ropivacaine formulations (1 %, 2 %) was noteffective in decreasing the pain of needle injection into thepalatal mucosa. In another blinded cross-over study, twoanesthesia drug effects were compared and evaluated inintraocular patients [17]. The injection discomfort wascompared between 2 and 3 % lipid nanoparticle-encapsulated mepivacaine with 2 % mepivacaine with1:100,000 adrenalines and 3 % mepivacaine. The encapsu-lation of mepivacaine was responsible for the increase inthe time duration of anesthesia drug effects and decreasedthe discomfort or side effects caused by thesevasoconstrictor-associated formulations [50].

ConclusionsThe development of local anesthetic drugs has becomean alternative to decrease pain and anxiety linked to in-vasive surgeries. Anesthesia drug like DepoFoam bupiva-caine is a promising and efficient new method to deliverbupivacaine and may serve as a potent instrument inpostoperative pain control. A good comparison betweenplain bupivacaine and lipid nanoparticle bupivacaine hasdemonstrated to showcase many advantages when usedin wound infiltration that includes opioid-sparing effect,prolonged analgesia, higher patient satisfaction, promptdischarge, and reduced hospital bills.Presently, different strategies and techniques have

been purposed for local anesthetic drug delivery that in-clude mostly lipid nanoparticles and formulations ofhydrogels leading to a fast and specific delivery and pro-longation of the duration of anesthesia; however, withthe promising future of lipid nanoparticles application inbio-medical fields, more multicenter clinical trials areneeded to be carried out.

Competing InterestsThe authors declare that they have no competing interests.

Authors’ ContributionsSB and AE conceived of the study and participated in its design andcoordination. AK supervised the whole study. All authors read and approvedthe final manuscript.

AcknowledgmentThe authors thank the Department of Medical Biotechnology, School ofadvance Science in Medicine, Tehran University of Medical Sciences and theDepartment of Anesthesiology, Lorestan University of Medical Sciences,Khoramabad, Iran.

Author details1Department of Anesthesiology, Lorestan University of Medical Sciences,Khoramabad, Iran. 2Department of Medical Biotechnology, School ofAdvanced Technologies in Medicine, Tehran University of Medical Sciences,Tehran, Iran.

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Received: 3 April 2016 Accepted: 7 June 2016

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