Local Anesthesia - Hindawi Publishing Corporationdownloads.hindawi.com/journals/focusissues/984893.pdfEditorialBoard Peter Andrews, UK Neal H. Badner, Canada Enrico M. Camporesi, USA

Local Anesthesia

Anesthesiology Research and Practice

Local Anesthesia

Anesthesiology Research and Practice

Local Anesthesia

Copyright © 2012 Hindawi Publishing Corporation. All rights reserved.

This is a focus issue published in volume 2012 of “Anesthesiology Research and Practice.” All articles are open access articles distributedunder the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, pro-vided the original work is properly cited.

Editorial Board

Peter Andrews, UKNeal H. Badner, CanadaEnrico M. Camporesi, USAJacques E. Chelly, USAHans De Boer, The NetherlandsD. John Doyle, USAJames B. Eisenkraft, USAMichael R. Frass, AustriaYoshitaka Fujii, JapanYukio Hayashi, JapanSteven K. Howard, USAGirish P. Joshi, USAMasahiko Kawaguchi, Japan

S. Kozek-Langenecker, AustriaPeter Kranke, GermanyArthur M. Lam, USAJean Jacques Lehot, FranceAlex Macario, USAColin McCartney, CanadaFrancis McGowan, USAOlivier Mimoz, FranceKouichiro Minami, JapanMohamed Naguib, USAS. Neustein, USATakashi Nishino, JapanKeiichi Omote, Japan

Nicholas A. Pace, UKRonald G. Pearl, USAFerenc Petak, HungaryUwe Rudolph, USAGerhard Schneider, GermanyGeorge Silvay, USAAudun Stubhaug, NorwayBenoit Vallet, FranceRuth E. Wachtel, USAChih Shung Wong, TaiwanMichael W. Zenz, GermanyHaibo Zhang, Canada

Contents

Subcutaneous Single Injection Digital Block with Epinephrine, Motoki Sonohata, Satomi Nagamine,Kazumasa Maeda, Kenji Ogawa, Hideki Ishii, Kenji Tsunoda, Akihiko Asami, and Masaaki MawatariVolume 2012, Article ID 487650, 4 pages

Lipid Emulsion for Local Anesthetic Systemic Toxicity, Sarah Ciechanowicz and Vinod PatilVolume 2012, Article ID 131784, 11 pages

Pre-Emptive Treatment of Lidocaine Attenuates Neuropathic Pain and Reduces Pain-RelatedBiochemical Markers in the Rat Cuneate Nucleus in Median Nerve Chronic Constriction Injury Model,Chi-Te Lin, Yi-Ju Tsai, Hsin-Ying Wang, Seu-Hwa Chen, Tzu-Yu Lin, and June-Horng LueVolume 2012, Article ID 921405, 9 pages

New Formulations of Local Anaesthetics—Part I, Edward A. ShiptonVolume 2012, Article ID 546409, 11 pages

New Delivery Systems for Local Anaesthetics—Part 2, Edward A. ShiptonVolume 2012, Article ID 289373, 6 pages

Hindawi Publishing CorporationAnesthesiology Research and PracticeVolume 2012, Article ID 487650, 4 pagesdoi:10.1155/2012/487650

Research Article

Subcutaneous Single Injection Digital Block with Epinephrine

Motoki Sonohata,1 Satomi Nagamine,1 Kazumasa Maeda,1 Kenji Ogawa,1 Hideki Ishii,2

Kenji Tsunoda,2 Akihiko Asami,2 and Masaaki Mawatari1

1 Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga-shi, Saga 849-8501, Japan2 Department of Orthopaedic Surgery, Saga Insurance Hospital, 3-8-1 Hyogo Minami, Saga-shi, Saga 849-8522, Japan

Correspondence should be addressed to Motoki Sonohata, [email protected]

Received 23 May 2011; Accepted 6 June 2011

Academic Editor: D. John Doyle

Copyright © 2012 Motoki Sonohata et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The aim of this study was to investigate the anesthetic effect and risk of epinephrine for subcutaneous single injection digital block.Either 3.0 mL 1.0% Lidocaine or a 3.0 mL 1.0% Lidocaine with (1 : 100,000) epinephrine was injected into the subcutaneous spaceat the middle point of the palmar digital crease of the 18 middle fingers of 9 healthy volunteers. The SpO2 of the fingers decreasedto a maximum of 97. No subjects showed any symptoms of ischemic injury. The time to anesthesia for the fingers was significantlyshorter (P < 0.05), and the duration of anesthesia was significantly longer (P < 0.01) for the fingers in the epinephrine group. Inconclusion, a subcutaneous single injection digital blocks with 3.0 mL of 1.0% Lidocaine and (1 : 100,000) epinephrine were safe,reducing the time to the onset of anesthesia, while also markedly prolonging the anesthesia.

1. Introduction

Many specialists feel that local anesthesia with epinephrineshould not be used for a digital block. Epinephrine is a strongalpha- and beta-receptor agonist and, therefore, results inthe activation of alpha-receptors in digital arteries leadingto vasoconstriction. The digital arteries are terminal or endarterioles, and this vasoconstriction can lead to ischemia andgangrene [1]. However, a careful review of the literature from1880 to 2000 revealed that there were only 48 case reportsof digital gangrene and necrosis following local anesthesia inthe digits, and most of those were published before 1950 [2].

In addition, those cases of digital gangrene were asso-ciated with procaine and cocaine injection with or withoutepinephrine. Necrosis has never been reported in patientstreated with a commercial lidocaine-epinephrine mixture.Early reports in the second half of the 20th century supportthe safety of lidocaine with epinephrine in digital anesthesia.Three studies reported no complications after performingdigital blocks using local anesthetics with epinephrine in 93and 98 patients, respectively [3, 4].

However, the digital block techniques in those reportswere classical digital blocks, using the so-called Oberst

procedure. This technique requires at least two injec-tions. Various protocols for single injection digital block havebeen reported since 1990 [5–8]. In particular, a subcuta-neous single injection digital block is simple procedure [8].

The purpose of this study was to investigate the anestheticeffect and risk of epinephrine for subcutaneous single injec-tion digital block.

2. Materials and Methods

This study was enrolled on 9 normal, healthy volunteers, whowere junior medical residents and whose hands had sufferedno nerve trauma or disease. The mean age of the 7 male and2 female volunteers was 26 (range 20–37) years. The protocolof this study and informed consent conformed to the ethicalguidelines of the 1975 Declaration of Helsinki. The study wasexplained to the volunteers, who signed a consent form andwere reimbursed for their time.

A 3.0 mL solution of 1.0% Xylocaine (Lidocaine, Astra-Zeneca, Japan) and a 3.0 mL solution of 1.0% Xylocaine with(1 : 100,000) epinephrine (Lidocaine, AstraZeneca, Japan)were prepared at room temperature. The solutions were

2 Anesthesiology Research and Practice

Figure 1: Subcutaneous single injection at the middle point of thepalmar digital crease.

injected into the subcutaneous space at the middle pointof the palmar digital crease of the 18 middle fingers ofthe 9 volunteers using a 5 mL syringe and a 27-gauge needle(Figure 1). A 3.0 mL 1.0% Lidocaine was injected in 9right middle fingers, and a 3.0 mL 1.0% Lidocaine with(1 : 100,000) epinephrine was injected into the left middlefingers.

The subjects themselves determined the loss of pinpricksensation and its reappearance at their fingertip (palmardistal) every ten seconds up to 60 minutes and each 10minutes after 60 minutes using the contralateral hand of theinjected side. The time to the loss and reappearance of thesensation was measured by the authors using a stopwatch.

The extent of anesthesia was also determined using thepinprick test by the subjects themselves, and they finished atthe time when normal sensation was recovered. The extent ofanesthesia was recorded by the authors. Each middle fingerwas divided into 6 zones; the palmar and dorsal areas ofthe distal segment, middle segment, and proximal segmentcorresponding to the two surfaces and the three phalangealsegments of the finger [8].

The circulation in the fingers was measured using PulseOximeter NPB-40 (COVIDIEN Japan Co., Ltd., Japan)before the digital blocks and at 0.5, 1, 3, 5, 10, 20, 30, 60minutes after digital blocks.

The data are presented as the mean± SD. Student’s t-testwas used to compare the mean variables using the Stat View5.0 for Windows software package (SAS Institute, USA). Thelevel of significance was set at P < 0.05.

3. Results

There was completely white area around the injection siteimmediately following the injection of 3.0 mL 1.0% Lido-caine with (1 : 100,000) epinephrine into the subcutaneousspace at the middle point of the palmar digital crease of themiddle fingers (Figure 2).

There was no significant difference in the value of SpO2

before each digital block (P = 0.27). The mean value ofSpO2 was 96.7 ± 0.98 in the Lidocaine group 20 minutesafter the digital block and 98.4 ± 0.95 in the Lidocaine

Figure 2: The area around the injection point is completely white.The filled black circle is the injection point.

70

75

80

85

90

95

100

Lidocaine

(minute)

SpO

2

0.5 10 3 5 10 20 30 60Beforeinjection

∗∗

Lidocaine with (1 : 100,000) epinephrine

Figure 3: Transitional change of SpO2 after a subcutaneous singleinjection at the middle point of the palmar digital crease. ∗∗P <0.01.

with (1 : 100,000) epinephrine group. There was a significantdifference between the two groups (P < 0.01). There was nosignificant difference in the value of SpO2 between the groupsat any other time points after the digital block (Figure 3).

The mean time to anesthesia for the fingers in the 3.0 mL1.0% Lidocaine injection group was 4.0 ± 0.85 minutes,and 2.8 ± 0.83 minutes in the 3.0 mL 1.0% Lidocainewith (1 : 100,000) epinephrine group. There was a significantdifference in the time to onset between the two groups (P <0.05). The mean duration of anesthesia in the 1.0% Lidocaineinjection group was 48.1 ± 23.5 minutes, and that in the3.0 mL 1.0% Lidocaine with (1 : 100,000) epinephrine groupwas 280.7 ± 23.5 minute. There was a significant differencein the duration of anesthesia (P < 0.01; Figure 4).

Anesthesiology Research and Practice 3

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Lidocaine

(min

ute

)

P < 0.05

Lidocaine with (1 : 100,000)epinephrine

(a)

Lidocaine

(min

ute

)

0

50

100

150

200

250

300P < 0.01

Lidocaine with (1 : 100,000)epinephrine

(b)

Figure 4: (a) Time to anesthesia. (b) Duration of anesthesia.

All palmar and dorsal distal and middle segments wereanesthetized in both groups. The anesthesia of the dorsalproximal segment was insufficient in all fingers. There wereno late complications.

4. Discussions

This is the first report to demonstrate that a subcutaneoussingle injection using Lidocaine with (1 : 100,000) epineph-rine was safe for healthy subjects.

The skin color around the injection point turned whiteafter a subcutaneous single injection digital block using Lido-caine with (1 : 100,000) epinephrine, due to Epinephrine’smarked vasoconstriction, as in previous reports [9]. Sylaidisand Logan [10] reported that the digital artery blood flowrapidly decreases in the first 5 to 10 minutes after a digitalblock using 2% Lidocaine with (1 : 80,000) epinephrine, andthe blood flow returns to normal within 1 hour.

However, the value of SpO2 after a subcutaneous singleinjection digital block using 1% Lidocaine with (1 : 100,000)epinephrine was stable for 60 minutes in the currentstudy. The value of SpO2 in the Lidocaine group was onlysignificantly different than the Lidocaine with (1 : 100,000)

epinephrine group 20 minutes after digital block; however,the reason for this difference is unclear.

The mean time to anesthesia for the fingers in the Lido-caine with (1 : 100,000) epinephrine group was faster thanthat in the Lidocaine group. This is an intriguing result. Manyreports have noted that epinephrine prolongs anesthesia, andthat is consistent with the current findings [10]. However, noreport has previously indicated the ability of epinephrine toaccelerate anesthesia onset. This accelerated activity could bedue to the vasoconstrictive effect of epinephrine, which mayhave decreased the clearance of the anesthetic and enhancedthe efficacy of Lidocaine [11].

The current study demonstrated that a subcutaneoussingle injection digital block using epinephrine was a safeprocedure. However, there may be a possible risk of necrosiswith a higher concentration of epinephrine or a greatervolume of solution. Digits are very resistant to ischemia [2].Fitzcharles-Bowe reported that there were no instances ofnecrosis or skin loss in 59 fingers injected with high-dose(1 : 1,000) epinephrine [9].

However, all subjects were young healthy volunteers inthe current study, and the possible risk of ischemic injuryby using epinephrine in patients with preexisting vascularinsufficiency cannot be denied.

In conclusion, the subcutaneous single injection digitalblocks of 3.0 mL 1.0% Lidocaine with (1 : 100,000) epineph-rine were safe and provided a shorter time to onset ofanesthesia and markedly prolonged anesthesia.

Disclosure

The authors did not receive and will not receive any benefitsor funding from any commercial party related directly or in-directly to the subject of this paper.

References

[1] A. L. Krunic, L. C. Wang, K. Soltani, S. Weitzul, and R. S.Taylor, “Digital anesthesia with epinephrine: an old mythrevisited,” Journal of the American Academy of Dermatology,vol. 51, no. 5, pp. 755–759, 2004.

[2] K. Denkler, “A comprehensive review of epinephrine in thefinger: to do or not to do,” Plastic and Reconstructive Surgery,vol. 108, no. 1, pp. 114–124, 2001.

[3] P. J. Burnham, “Regional block anesthesia for surgery of thefingers and thumb,” Industrial Medicine & Surgery, vol. 27, no.2, pp. 67–69, 1958.

[4] H. A. Johnson, “Infiltration with epinephrine and localanesthetic mixture in the hand,” Journal of the AmericanMedical Association, vol. 200, no. 11, pp. 990–991, 1967.

[5] D. T. Chiu, “Transthecal digital block: flexor tendon sheathused for anesthetic infusion,” Journal of Hand Surgery, vol. 15,no. 3, pp. 471–473, 1990.

[6] S. Harbison, “Transthecal digital block: flexor tendon sheathused for anaesthetic infusion,” Journal of Hand Surgery, vol.16, no. 5, p. 957, 1991.

[7] T. P. Whetzel, S. Mabourakh, and R. Barkhordar, “Modifiedtransthecal digital block,” Journal of Hand Surgery, vol. 22, no.2, pp. 361–363, 1997.


[8] S. Sonohata, A. Asami, K. Ogawa, S. Nagami, and T. Hotoke-buchi, “Single injection digital block: is a transthecal injectionnecessary?” Journal of Hand Surgery, vol. 34, no. 1, pp. 94–98,2009.

[9] C. Fitzcharles-Bowe, K. Denkler, and D. Lalonde, “Fingerinjection with high-dose (1:1,000) epinephrine: does it causefinger necrosis and should it be treated?” Hand, vol. 2, no. 1,pp. 5–11, 2007.

[10] P. Sylaidis and A. Logan, “Digital blocks with adrenaline. Anold dogma refuted,” Journal of Hand Surgery, vol. 23, no. 1,pp. 17–19, 1998.

[11] M. Concepcion, R. Maddi, D. Francis, A. G. Rocco, E. Murray,and B. G. Covino, “Vasoconstrictors in spinal anesthesia withtetracaine—a comparison of epinephrine and phenylephrine,”Anesthesia and Analgesia, vol. 63, no. 2, pp. 134–138, 1984.


Review Article

Lipid Emulsion for Local Anesthetic Systemic Toxicity

Sarah Ciechanowicz and Vinod Patil

Department of Anaesthesia, BHR University Hospitals NHS Trust, Romford, London RM7 0AG, UK

Correspondence should be addressed to Vinod Patil, [email protected]

Received 11 July 2011; Accepted 4 August 2011

Academic Editor: James B. Eisenkraft

Copyright © 2012 S. Ciechanowicz and V. Patil. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The accidental overdose of local anesthetics may prove fatal. The commonly used amide local anesthetics have varying adverseeffects on the myocardium, and beyond a certain dose all are capable of causing death. Local anesthetics are the most frequentlyused drugs amongst anesthetists and although uncommon, local anaesthetic systemic toxicity accounts for a high proportion ofmortality, with local anaesthetic-induced cardiac arrest particularly resistant to standard resuscitation methods. Over the lastdecade, there has been convincing evidence of intravenous lipid emulsions as a rescue in local anesthetic-cardiotoxicity, andanesthetic organisations, over the globe have developed guidelines on the use of this drug. Despite this, awareness amongstpractitioners appears to be lacking. All who use local anesthetics in their practice should have an appreciation of patients athigh risk of toxicity, early symptoms and signs of toxicity, preventative measures when using local anesthetics, and the initialmanagement of systemic toxicity with intravenous lipid emulsion. In this paper we intend to discuss the pharmacology andpathophysiology of local anesthetics and toxicity, and the rationale for lipid emulsion therapy.

1. Introduction

Local anesthetics (LAs) can be defined as drugs thatreversibly block transmission of a nerve impulse, without af-fecting consciousness. Medical use of local anesthetic agentsbegan some years after the isolation of cocaine from Peruviancoca in the 1860s. Chance discovery in 1884 by Freud whileusing cocaine to wean a morphine addict lead Koller touse cocaine successfully in ophthalmic surgery as a topicalanesthetic. Halsted and Hall took more invasive steps bydirectly injecting cocaine into oral cavity nerves in order toproduce anesthesia for removal of a wisdom tooth [1].

However, the euphoria, subsequent addiction, and casesof mortality from the clinical use of the natural ester cocainecreated a drive to the development of the less toxic neweramino esters. Einhorn’s synthesis of procaine in 1905 wasto dominate LA use for the next forty years, but withamino esters slow onset of action and allergen potential, thehypoallergenic amino amides gradually came into force withlignocaine appearing in 1948 and is still the most commonlyused LA in dentistry.

Amino amides mepivacaine, prilocaine, and bupivacainewere all developed by 1963 and all have roles in modern

dentistry. In 1969, articaine was synthesized by chemistMuschaweck, and with its potency and safety profile is nowthe most common LA for dental procedures in most ofEurope [2].

Despite these efforts, all of the amide LAs harbor varyinglevels of cardiovascular (CVS) and central nervous system(CNS) toxicity that is still a major complication seen today.Methods of administration have also progressed since AugustBier first practiced intravenous regional anesthesia in 1908,allowing a whole limb to be anesthetized with the aid of atourniquet and LA [3].

Simultaneously, plexus anesthesia came about in theearly 1900s with brachial plexus blocks for upper limbsurgeries, these peripheral techniques more refined in recentdecades to prolong blocks via continuous infusion regionalanesthesia using catheters and pumps [4].

The use of LA in neuraxial anesthesia is another sig-nificant development that began with James Corning’sexperiment in 1885 of spinal anesthesia on a dog [5], but itwas not used clinically until 1899 by August Bier [6]. Lumbarepidural anesthesia came about later in 1921 by Spanishmilitary surgeon Fidel Pages. It was popularized by the Italiansurgeon Dogliotti in the 1930s [7].


Figure 1: Mechanism of action of local anesthetics. Unionized LAenters nerve axon and becomes ionized to block sodium channels.LA also has direct effects by expanding the cell membrane toincrease fluidity.

The idea of continuous infusion of epidural anesthesia,however, was not started until use of caudal blocks for emer-gency caesareans in 1942 [8], and in more recent decades theintroduction of small flexible catheters has improved safety,delivery, and duration of epidural anesthesia.

2. Mechanism of Action

The physicochemical properties of LAs determine their prop-erties as anesthetic agents. They have three structural groups,an aromatic ring, connecting group (ester or amide), andan ionizable amino group. This lipid-soluble hydrophobicaromatic group and a charged, hydrophilic amide groupenables them to exert their effects by two mechanisms: intheir uncharged (unionized) state they lipid soluble and ableto traverse the lipid bilayer of the neuronal cell membrane, tothen gain a hydrogen ion and become ionized making themable to bind intracellularly to voltage-gated sodium channels,rendering the channel reversibly inactive, and so unable toallow for sodium entry to generate and propagate the actionpotential [9] (see Figure 1). Binding can also occur to theclosed sodium channel to retain its inactive state. Secondly,LAs have direct effects on the lipid bilayer, disruptingimpulses by incorporating into the cell membrane, causingexpansion [10, 11]. The sensitivity of nerve fibers dependsupon their axonal diameter and degree of myelination withsmall, myelinated fibers more susceptible. Generally thesmall pain and temperature fibers (C unmyelinated, A-δmyelinated) are blocked first with the larger touch andpressure (A-Υ, A-β) fibres next, and large muscle tone andpostural A-α fibres last. It is thought that the prolongedaction potential of smaller fibres provides more time for LAentry, and more frequently stimulated nerves show increasedsusceptibility from a high degree of open channels. The storydoes not end there, however, in addition to blocking sodiumchannels, newer amino amide ropivacaine has been foundto bind to human cardiac potassium channels (hKv 1.5)to block repolarization of the membrane [12]. A numberof anesthetics, including bupivacaine and ropivacaine, havealso been shown to block L-type Ca2+ channels in rat

Table 1: Pharmacology of common local anesthetics. Potency isrelative. Potency: toxicity ratio is a useful evaluation to consider,articaine has the best ratio making it clinically efficacious as wellas safe. %PB = protein binding.

Potency Pot : Tox LWPC Onset pKat1/2

(min)%PB

Bupivacaine 8 2 27.5 Slow 8.1 162 95.6

Articaine 3 3.3 17 Fast 7.8 20 94

Lignocaine 2 2 2.9 Fast 7.9 96 64.3

Mepivacaine 2 2.2 19.3 Fast 7.8 114 78

Prilocaine 2 2.7 0.9 Fast 7.7 93 55

Ropivacaine 4 2.25 2.9 Mod 8.1 96 94

cerebrocortical membranes. From a systemic viewpoint, LAsmay improve pain by inhibiting local inflammatory responseto injury by decreasing inflammatory cytokine release fromneutrophils.

3. Clinical Pharmacology

Potency is decided by the lipid solubility of the agent and canbe expressed as a lipid : water partition coefficient (LWPC),the ratio of the amount of agent in each phase. Highcoefficients increase lipophilic properties and allows for easeof passage into the cell membrane thus facilitating potency.Onset of action is determined by the ionization constant orpKa value, which determines the proportion of ionized tounionized form of the agent at a given pH. Agents with apKa value closer to the physiological pH permit more LAin the unionized, lipid soluble form to enter the cell. Sofactors that alter tissue pH also affect the proportion of LAin the unionized form and hence can slow onset of actionin an acidic, infected wound. Table 1 demonstrates theseproperties in some common anesthetic agents.

4. Pharmacokinetics and Metabolism

The primary aim of local anesthetic administration is tosaturate the targeted nerves while causing minimal sys-temic absorption. Infiltration of skin, subcutaneous tissues,intrathecal, and epidural spaces will result in varyingabsorption into the systemic circulation depending on thesurface area for absorption and vascularity of the area.Intercostal muscles and epidural administration being par-ticularly susceptible, and in dentistry the gingiva of themaxillary alveolar ridge is prone to inducing rapid systemicabsorption. Lignocaine has a vasodilatatory effect and sois often mixed with adrenaline or phenylephrine to reducevascular absorption and hence prolong action and reducethe risk of systemic toxicity. Conversely, cocaine is a potentvasoconstrictor.

High protein binding of the LA to plasma protein alpha1-glycoprotein will protect it from metabolism and henceprolong its duration of action. All amino esters exceptfor cocaine are rapidly degraded by circulating plasmaesterases, and excreted in the urine. The amide prilocaine is


also metabolized extrahepatically. All other amides such aslignocaine and bupivacaine are more slowly metabolized bythe liver and hence are of higher risk of accumulation.

5. Local Anesthetic Systemic Toxicity

5.1. Incidence. Before 1981, epidural use for labor analgesiahad reported LA systemic toxicity (LAST) in 100 per 10,000cases [13].

Improvements in regional techniques and precautionshave greatly improved the safety profile over the past 30 years,including the withdrawal of higher concentration 0.75%bupivacaine preparations for obstetrics. Although incidenceof bupivacaine cardiotoxicity has declined since 1980 it stillposes a potentially fatal risk for patients. Epidemiologicalreports have been clinically diverse and with differentoutcome measures used, but overall rate of systemic toxicityhas been reported in France to be 0–20 per 10,000 in 2002and is greatly dependent on the site of peripheral nerve block[14]. A study by Brown in 1995 showed seizures associatedwith interscalene and supraclavicular brachial plexus blocksto be as high as 79 in 10,000 [15].

For example, dentists administer thousands of local anes-thetic injections every day with few adverse events. However,LAST can occur even with the most experienced practitioner.Human error misjudging dose, anatomy, patient factors, orbad luck can contribute to the unintended developmentof serious systemic complications. Lignocaine is the mostcommon LA used in dentistry and has been reported tocause systemic toxicity [16, 17]. Articaine, even with itsexcellent safety profile, may cause systemic intoxication ifunintentional intravascular injection is performed duringa block: it has been reported that the rate of intravenousinjection for inferior alveolar nerve block is as high as 15.3%[18], which can occur due to the high vascularization of theoral mucosa.

5.2. Clinical Manifestations. The signs of LAST are an exten-sion of pharmacological action. The classic description is of aprogressive “biphasic” effect on the CNS and then CVS, twoareas highly sensitive to changes in tissue electrophysiology.CNS excitation (agitation, auditory change and metallictaste) progresses to seizures or CNS depression (drowsiness,coma, and respiratory arrest). This is followed by CVS excita-tion (tachycardia, ventricular arrhythmia, and hypertension)then depression (bradycardia, conduction block, asystole,and cardiac depression) [19].

Of particular importance is the nature of this collapse,with high incidence of LA-cardiac arrest being resistant tostandard resuscitative measures.

However, a recent review of 93 published case reportsof LAST found that over 40% of presentations did not fitthis classic description [20]. This includes the simultaneouspresentation of CNS and CVS signs, and cases with only CVSeffects manifest. CVS-only effects were seen in 4 out of 10cases under general anesthesia or form of sedation, and weremore likely to show delayed onset of signs.

Regarding CNS symptoms, the prodromal features, forexample, perioral numbness, dizziness, confusion, obtunda-tion, and dysarthria totaled only 18% of symptom frequency,with seizures seen in 68% of cases and loss of consciousnessand agitation also frequent. Half of CVS signs were arrhyth-mias, with bradycardia/asystole seen in 27%.

They reported that timing is variable, for single injectionsalthough most onset of LAST occurred “rapidly,” at 50seconds or less in half of cases, 25% were delayed by 5minutes or more. Interestingly, all instances of LAST duringcontinuous infusions were substantially delayed, often by anumber of days after initiation.

5.3. Toxic Plasma Levels. Systemic toxicity from local anes-thetic overdose occurs due to accidental intravascular injec-tion, absorption from tissue depot, or repeated doses withoutbalanced elimination. The concentration of bupivacainepresent in the aqueous portion of plasma is directly relatedto the myocardial tissue absorption, and hence cardiotoxicity[21]. The degree of toxicity is therefore dependent on plasmalevels of LA; with highly aerobic tissues vulnerable to hypoxiabeing most vulnerable, that is, myocardium, lungs andcentral nervous system. For regional blocks, the plasma levelsof lignocaine are typically 3–5 mcg/mL, with toxic plasmalevels seen at 6–10 mcg/mL.

5.4. Risk Factors. Intuitively, one would speculate that theplasma levels of a given dose of drug would have strong cor-relation to the weight or body mass index of the individual.In the case of LAs, this is largely true in children, but in adultswe see that the methods of administration, nature of the drugpreparation, and the physiological status of the patient havefar greater association. A poorly vascular injection site ofthe block, vasoconstrictor activity of the LA, and concurrentuse of adrenaline would slow systemic absorption, hencereducing plasma levels, but physiologically, impairment ofhepatic and renal function involved in metabolism andelimination can have a profound effect to maintain plasmalevels.

Accidental intravascular injection is the major cause ofsystemic toxicity, for example, regional anesthesia of theneck (interscalene block, cervical plexus block, and stellateganglion block) can cause direct intra-arterial injection andcause rapid toxicity from early entry to the cerebral circula-tion. Epidural anesthesia holds a risk of intravenous injectioninto the engorged epidural venous plexus of the parturient[22], and the oral mucosa is also highly vascular. Regardingsite of injection, rapid absorption occurs via infiltration ofhighly vascular tissues such as intercostal muscles, the oralmucosa, and the epidural space. High cardiac output statesalso promote systemic uptake by maintaining the gradientfor diffusion.

Choice of agent also has clear implications for toxicity.Longer-acting amide LAs such as bupivacaine improve an-algesia after surgery and have use in cutaneous infiltra-tion, regional nerve blocks, epidural anesthesia, and spinalanesthesia. However, bupivacaine is more cardiotoxic thanshorter-acting lignocaine, with smaller doses often result-ing in cardiotoxic symptoms without prior CNS effects


[23]. Addition of vasoconstrictors such as epinephrine candramatically slow the absorption of LAs from the siteof injection, improving their safety and prolonging theanesthesia, which is why higher doses of some agents arepossible with a vasoconstrictor additive.

Patient physiological factors also have influence on theLA toxicity threshold. Rosen studied the effect of both ligno-caine and bupivacaine in anesthetised sheep and found thatacidosis, hypoxia, and hypercarbia potentiated cardiotoxiceffect [24]. In this sense the elderly are a prime example ofrisk of imbalance between absorption and metabolism of LA.

Reduction of hepatic blood flow by drugs or hypotensionwill decrease the hepatic clearance of amide LAs, andhaving reduced cardiac output and poor renal or hepaticfunction leads to prolonged absorption and drug accumu-lation, respectively. This has implications with use of therecent continuous infusion anesthesia for postoperativeorthopedics and acute pain [4, 25]. In addition, use ofpostoperative pain pumps in plastic surgery can involvebupivacaine combined with epinephrine, which can extendthe halflife of bupivacaine from 3.5 hours to 5–7 hours [26].

On top of this, underlying cardiac pathology of ischemicheart disease, conduction blocks, and cardiac failure willadditionally render the elderly more vulnerable to toxic CVSeffects. The majority of the cases of LAST seen in dentistryoccur in children, as due to their small size, dose- to- weightratio is more difficult to calculate and so overdose is morelikely. It is also more likely to progress in adversity because ahigh number of blocks are done with the child anesthetized.The early signs of paraesthesia and mental state changeswould not be detected [26]. Conversely, some studies showthat newborns and children can actually tolerate higherplasma levels of bupivacaine compared to adults [27, 28].Kiuchi et al. [29] reports that 2-week old rats (equivalent to3-year old children) exhibit a lethal dose 4 times higher than16-week-old animals, and that this difference can be seenas less profound cardiac depression. They speculate this tobe due to a difference in calcium regulation at the intracel-lular sarcoplasmic reticulum. However, in clinical practice,Bosenberg et al. [30] have reported the use of 3 mg/kgof ropivacaine in children without observing symptoms ofsystemic toxicity or plasma levels of ropivacaine in the rangeof potential risk for systemic toxicity.

In pregnancy, the higher cardiac output will speed upabsorption and with reduced plasma proteins this willincrease the free fraction of LA in the plasma. Plasma proteinlevels can also vary in different pathological states and thereis a reduction seen postoperatively, in chronic diseases suchas cancer, also old age, smoking increases the unbound freefraction of agent available to bind to cardiac myocytes andcause toxicity. Lerman et al. [31] have shown that alpha-1glycoprotein plasma levels are low in newborns and toddlersbut the clinical significance of this reduction is not clear.

Drug interactions are an important patient factor toconsider when determining risk of cardiotoxicity. Amidelocal anesthetics are metabolized by the liver and specificallythe cytochrome p450 system that has potential for druginteractions by competitive metabolism and up, or down-regulation of the system by chronic exposure to certain

Table 2: Factors affecting LA toxicity.

Site of injection Drug Patient factors

Surface areaVascularity

PotencyDose (volume ×concentration)Vasoactivity± vasoconstrictor

AgeGeneticsCardiac pathologyPregnancyDrug interactionsAcidosisHypoxiaHypercarbia

drugs. Cimetidine inhibits the cytochrome p450 systemand can allow the accumulation of plasma levels of LAs.Drugs altering plasma esterase activity have the potential todecrease hydrolysis of the lesser-used ester LAs. Increasedvigilance is also necessary in patients taking digoxin, calciumantagonists, or beta-blockers [32].

There is debate as to whether general anesthesia providessome protection from toxicity, the effect of general anesthesiain sheep caused plasma LA concentrations to increase due tocardiovascular depression, leading to slower efflux from visc-eral to nonvisceral organs; however, less severe CNS effectsand cardiovascular arrhythmias occurred in these sheep [33,34]. The clinical significance of this is not yet established. Fora summary of LAST risk factors see Table 2.

5.5. Ion Channels and the Lipid Bilayer. As there are sucha myriad of ion channels and processes affected by LAsthere is a risk of the culpable mechanism of cardiotoxicitybeing missed [35]. The pathophysiology of LAs are thoughtto be an extension of their uses, blocking cardiac voltage-gated sodium channels, preventing myocyte depolarization,blocking repolarization via potassium channels, and block-ing the sarcoplasmic reticulum voltage-dependent calciumchannels to limit the rise of intracellular calcium available forexcitation-contraction coupling [35, 36]. Mio et al. describea loss of sensitivity of rat ventricular muscle myofilamentsto calcium a basis for the loss of calcium-activated tensionin trabeculae following access of LA. Furthermore, myocyteATP is reduced, thus limiting the energy available forcoupling of actin-myosin cross-bridge cycles [37]. Work onion channel involvement is extensive but is not necessarilyconsistent with cardiotoxicity seen from different agents.Studies on biometric membranes support the notion ofincreasing lipid membrane fluidity to confer potency of agentand cardiotoxicity [11].

Animal studies and case reports indicate a differencein cardiotoxicity between short-acting agent lignocaine andthe longer-acting bupivacaine. For both agents there isdose-dependent cardiac depression but the greater toxicitypotential of bupivacaine is disproportionate and does notcorrelate entirely with potency of inhibition of cardiacsodium channels. This difference could rely on an alternativemechanism of toxicity for bupivacaine, and we see thisclinically in case reports of bupivacaine showing a more sig-nificant CVS toxicity than CNS, with arrhythmia and cardiacarrest often occurring without seizures. There appears to be


a more potent mechanism occurring at the myocardium, inanimal studies lignocaine induces dramatic hemodynamicdepression while bupivacaine markedly impairs both electro-physiologic and haemodynamic variables [38]. To examinemore specifically, Reiz and Nath [39] directly injectedlignocaine or bupivacaine into the coronary circulationof dogs and found that the difference in depression ofcontractility was proportional to their relative potencies,1 : 4. However, the effect on cardiac conduction was 1 : 16with recovery of the EKG taking longer for bupivacaineat a ratio of 1 : 8, confirming that the major difference incardiotoxicity between long-acting and shorter-acting agentsis their influence on conduction through the cardiac axis.Clarkson and Hondeghem suggest that bupivacaine has thispronounced effect due to the strength of binding to inactivesodium channels [40].

5.6. Cardiac Mitochondria. In light of work on the mito-chondrial pathogenesis of local anesthetic cardiotoxicity andinformation from studies and a case report [41] of a childwith carnitine deficiency, mitochondrial abnormalities alsoseem to confer increased susceptibility [42]. Bupivacaine-induced myopathies have led to rat and human cell studiesto demonstrate structural alterations in muscle, the sar-comere, and calcium homeostasis by LAs. High bupivacaineconcentrations caused abnormal mitochondrial autophagywith reduction in mitochondrial content, inhibition of ATPproduction by action on mitochondrial ATP-synthase, andinhibition of oxidative phosphorylation [43]. In cardiactissue, in vivo and vitro studies on rat hearts demonstratebupivacaine and ropivacaine’s ability to uncouple oxidativephosphorylation at complex I in the mitochondria [44],and block the enzyme carnitine acylcarnitine transferaseused for transporting acylcarnitines across the mitochondrialmembrane in fatty acids during aerobic metabolism [45,46]. Importantly, inhibition of the respiratory chain com-plexes was prevented by antioxidant treatment and reversedfollowing removal of the anesthetic thereby suggestingan oxidant-mediated feedback mechanism reinforcing theprimary inhibitory action of the anesthetic. Recent develop-ments implicate the mitochondrial phospholipid cardiolipin,involved in respiration, to be the major determinant ofLA cardiotoxicity, established by means of theoretic andstructural biological methods [47].

5.7. Vasoactivity. Secondly to these direct effects on themyocardium, a signif-icant cause of hypotension is due toperipheral vasodilatation from direct action on the vascula-ture. Bupivacaine and levobupivacaine cause vasodilatationat clinical doses, but lower doses appear to cause vasocon-striction [45]. Direct cardiac depression of bupivacaine hasbeen studied in vivo to demonstrate a deleterious double-whammy on the cardiac output via negative inotropic effectsand increasing afterload, which appears to be mediated by α1adrenoceptors [48]. Ropivicaine and levobupivacaine are farless toxic in this sense.

Thirdly, a mechanism of toxicity appears to be inhibitionof autonomic reflexes. There is evidence for inhibition of the

baroreceptor reflex in rats [49], and Pickering et al. showbupivacaine to be selectively toxic to the brainstem area forcontrol of cardiac sympathetic outflow, the nucleus tractussolitarius, without effecting respiration, leading to hypoten-sion and dysrhythmias [50]. Lida et al. reveal a differinginfluence of bupivacaine and ropivacaine on dog spinal pialvessel diameter, with ropivacaine causing vasoconstrictionand bupivacaine vasodilatation [51]. Laser doppler imagingstudies on human skin has revealed nitric oxide (NO) to beresponsible for the vasodilatatory effect of local anaesthetics,however, NO does not appear to be involved when the bloodvessel is uninnervated such as the in vitro umbilical artery[52, 53].

6. Lipid Emulsion Therapy

20% lipid infusion is the first safe intravenous lipid emulsion(ILE) used in medicine and has been around since 1962 forits use in parenteral nutrition. The commercial preparationIntralipid 20% is manufactured by Fresenius Kabi, 1 literconsists of 200 g purified soybean oil, 12 g purified egg phos-pholipids, and 22 g anhydrous glycerol, and it is a source ofomega-3 and -6 essential fatty acids with total energy content8.4 MJ (2,000 kCal). ILEs use in LAST came about froman unexpected finding by Weinberg in 1998. Following acase report of a carnitine-deficient patient showing increasedsusceptibility to bupivacaine cardiotoxicity, he postulated theimpaired fatty acid oxidation was the etiology and in seminalwork, preloaded rats with ILE prior to bupivacaine in hopeto establish this. The result was quite the opposite, withan increase in the mean lethal dose (LD50) by 50% [54].He later went further to demonstrate the efficacy of ILE byrescuing dogs from bupivacaine-induced cardiac arrest [55].ILE therapy for treatment of LAST is now well established,following a crop of over 19 peer-reviewed case reportsappearing since Rosenblatt’s successful application of ILE toclinical practice in 2006 [56], and supports the use of ILE forbupivacaine, levobupivacaine, and ropivacaine cardiotoxicity[56–61]. This year we also saw a successful case report fromseemingly intractable lignocaine-induced cardiac arrest [62].

This evidence strongly supports the use of ILE in theresuscitation of LAST and because of this efficacy, ILE is hasbeen incorporated into safety guidelines for management ofLA-induced cardiotoxicity in the UK since 2007 and in theUS since 2008 [63, 64]. In 2010, the American Society ofRegional Anesthesia and Pain Medicine (ASRA) published itspractice advisory on LAST [65], highlighting the importanceof airway management and early cardiopulmonary resusci-tation with addition of ILE therapy. In 2010 the AmericanHeart Association incorporated lipid emulsion for LAST-cardiac arrest in the special situations section of the ACLSguidelines [66].

6.1. Mechanism. The current agreed hypothesis for ILE’sefficacy in treating cardiotoxicty, although not well definedbut supported by in vitro studies, is the formation of a “lipidsink”; that is, an expanded intravascular lipid phase that actsto absorb the offending circulating lipophilic toxin, hence


Immediately

and

and

Give a maximum of two repeat

been restored or

Leave 5 min between boluses

A maximum of three boluses can be

given (including the initial bolus)

been restored or

Continues infusion until stable and

adequate circulation restored or

maximum dose of lipid emulsion given

After 5 min

Give an initial intravenous bolus

injection of 20% lipid emulsion

1.5 mL·kg−1 over 1 min

Start an intravenous infusion of 20%

lipid emulsion at 15 mL·kg−1·h−1

Continue infusion at same rate, but

Do not exceed a maximum of cumulative dose of 12 mL·kg−1

boluses (same dose) if

• cardiovascular stability has not

• an adequate circulation deteriorates

double the rate to 30 mL·kg−1·h−1 at

any time after 5 min, if

• cardiovascular stability has not

• an adequate circulation deteriorates

Figure 2: AAGBI local anaesthetic toxicity guideline 2010 (with permission) [63].

reducing the unbound free toxin available to bind to themyocardium. The effect of ILE has been disputed to be nomore than a haemodilution effect from the volume admin-istered, especially pronounced in rat models [67]. However,convincing evidence from rat studies by Weinberg show ILEto reduce the aqueous plasma bupivacaine concentrationthree-times greater than that predicted by haemodilutionalone [68], and subsequently ILE therapy has shown clearsuperiority over adrenaline and/or vasopressin in rats thatis directly linked to reduced myocardial tissue content andimproved cardiac function [21]. Influences on metabolismalso seem to confer the success of ILE; there is evidenceof increased washout of bupivacaine in rat hearts in thepresence of ILE [69]. ILE could be acting as a direct energysource to the myocardium, countering the deleterious effectof LAs on fatty acid delivery by acting as a lipid provider,the fatty acid substrate necessary to enrich mitochondrialrespiration in the heart and hence ATP production, thusimproving the cardiac output [70]. A further mechanismadvocated is that of action of raised triglyceride on cardiaccalcium channels to increase myocardial calcium concen-tration, hence enhancing cardiac function [71]. In additionto its use in LAST, but beyond the scope of this review, isa discussion about the more recent but no less significantdiscovery of ILE in treatment of cardiotoxicity from a rangeof other lipophilic drugs including chlorpromazine, beta-blockers, calcium channel antagonists, and bupropion [61].

6.2. Regimen. The AAGBI recommended ILE or Intralipidregimen following cardiac arrest from LAST involves a large

initial intravenous bolus injection of 20% lipid emulsionat 1.5 mL/kg over 1 minute; followed by an infusion of15 mL/kg/h. Cardiopulmonary resuscitation should be con-tinued throughout. In the absence of return of spontaneouscirculation or deterioration after 5 minutes, two furtherboluses (1.5 mL/kg) may be given at 5-minute intervals.The intravenous infusion rate should also be doubled to30 mL/kg/hr. A maximum of three boluses can be given,and a cumulative dose of 12 mL/kg should not be exceeded(Figure 2). The ASRA guidelines differ in that only oneadditional bolus is recommended, and the infusion shouldcontinue for 10 minutes after haemodynamic stability isreached, with a maximum dose of 10 mL/kg over 30 minutes[72].

Initial case reports show ILE to often succeed afterstandard resuscitation has failed and led to the suggestion ofILE as a “last resort” in severe resuscitation resistant LAST.However, there is growing evidence to support its use earlyin the management with successful case reports supportingthe immediate use in cardiac arrest [73–76].

Development of optimal dosing regimens for differentpatient groups in on the horizon, this year ILE has beenrecommended for use in obstetrics [77]. Support for ILEin pediatric LAST can be seen from a recent case report ofropivacaine and lignocaine-induced toxicity in a 13-year-oldgirl after lumbar plexus block [57]. Ventricular tachycardiawas impressively converted to sinus rhythm after a bolus of3 mL/kg of lipid emulsion was given over 3 minutes. Thisis encouraging to read and also poses the question as towhether we need to develop optimal dosing regimens for


Table 3: Safe doses of common LAs.

Maximum safe dose (mg/kg)

Bupivacaine 2.0

Levobupivacaine 2.5–3.0

Articaine 7.0

Lignocaine 4.0

with epinephrine 7.0

Mepivacaine 7.0

Prilocaine 6.0

Ropivacaine 3.0-4.0

children. There exists debate about the use of vasopressorswith ILE for treatment of LAST, and what combination,if any, is beneficial [78]. Weinberg shows greater survivalwith ILE alone than with epinephrine and/or vasopressinin rodent models, and combination of ILE and epinephrineworsened outcomes by impairing cardiac function andmetabolic indices [79], possibly by worsening coronaryperfusion. This is mirrored in the study use of epinephrineand/or vasopressin in cardiac arrest in humans that resultedin early survival but later demise [80, 81]. So perhaps onlysmall doses of epinephrine, if any, are advisable in thetreatment of LAST and vasopressin-vasoconstriction is likelyto worsen the LA-induced cardiac failure. Further studiesare needed to clarify the use of vasopressors in LA-inducedcardiac arrest, but at present it is not advised to deviate fromstandard resuscitation guidelines, with the addition of ILEtherapy.

Of interest, the commercial preparation Intralipid maynot be the most effective emulsion formulation to useclinically, as described by electrophoresis studies compar-ing it with liposome vesicle dispersions. The dispersionpreparations had increased interaction with local anestheticscompared to standard Intralipid [82], so when financiallyviable it should be considered for clinical use. There is alsodiscussion of the specific importance of omega-3 fatty acids[83].

7. Prevention of Toxicity

Prevention is better than cure, and although no singlepreventative measure can eliminate the risk of developingLAST, they do provide improved safety. Regarding site ofinjection, care must be taken to avoid intravascular injectionand awareness of tissues prone to rapid uptake, such asthe head and neck, is useful. Since the introduction of themeasures to prevent inadvertent intravascular injection thatbegan with the epinephrine test dose for labor epidurals byMoore and Batra in 1981 [84], the incidence of LAST hasfallen 10–100 fold [85]. The following methods, althoughsingularly unproven, likely promote safety.

(i) Incremental injection of 3–5 mL aliquots with pauseof one circulation time between each, although itincreases risk of needle migration. Note circulationtime greater in the lower limb.

(ii) Aspirate needle prior to each injection (but 2% falsenegatives).

(iii) For large volumes, first use intravascular marker,for example, epinephrine 10–15 mcg/mL in adultsand 0.5 mcg/kg in children and observe any CVSresponse.

Although these methods are useful for avoiding intravas-cular injection, they do not predict the possibility of rapidtissue absorption from the site. To this end, it is importantnot to exceed the safe dose of local anesthetic involved[86]. The cardiotoxic potential of the amide local anestheticscan be expressed as a maximum safe dose for administra-tion (Table 3). However, for procedures such as tumescentliposuction, the relative avascularity of subcutaneous fatand epinephrine-induced vasoconstriction account for slowlignocaine absorption, and this allows for doses of lignocaineas high as 18 mg/kg to be administered safely.

7.1. MLAC and Protocols. The minimum local analgesicconcentration (MLAC) of local anesthetics is a clinical modelintroduced in 1995 to compare the relative potencies ofepidural bupivacaine and lignocaine in laboring women.Trials follow up and down sequential allocation of theeffective concentration of local anesthetic that produceseffective analgesia in 50% of subjects (EC50), to providean equivalent of the volatile anesthetic “MAC” value [87].Adoption of this model has allowed for lowest adequate doseregimens and determination of the LA sparing efficacy ofadjunct analgesics in obstetrics [88].

7.2. US-Guided Regional Anesthesia. Ultrasound (US) can beused to guide the accurate placement of the needle for LAinjection over soft tissues, avoiding intravascular injectionand damage to surrounding structures and allowing smallervolumes of LA to be used, as direct application to the nerveis more likely. However, systematic review of the Cochranedatabase finds no difference in the success rate or durationof analgesia between landmark/peripheral nerve stimulatortechniques and US-guided blocks, with larger and higher-quality studies lacking [89]. A reduction in incidence ofLAST from US has also not yet been proven [90], and thereis debate as to whether the reduced volume blocks actuallycompromise postoperative analgesia [91].

7.3. Newer Agents. Stereoisomerism contributes to the dif-fering potency of local anesthetics. Molecules with an asym-metric carbon atom exist in three-dimensional forms thatare mirror images (enantiomers and stereoisomers), distin-guished by how they rotate polarized light. The terms R and Sare used for the two different enantiomers, and an equimolaramount of both R and S constitutes a racemic mixture.Racemic bupivacaine has been in use for decades but is notwithout its safety concerns. The relatively high toxicity ofbupivacaine had led for it to be the main agent implicatedin toxicity research. Ropivacaine and levobupivacaine areS-enantiomer pipecoloxylidines that have improved safetyprofiles compared to racemic bupivacaine. A recent study


by Tsuchiya et al. investigating the interaction of racemicbupivacaine and R+ and S-enantiomers of bupivacaine andropivacaine with biomimetic membranes of chiral lipidsdemonstrated the greater interaction of the R+ enantiomers,with S-Ropivacaine presenting least influence of all. This isconsistent with reported clinical cardiotoxicity of the agentsand also supports the hypothesis of potency of increasingthe lipid bilayer membrane fluidity [11]. For regional blocksinvolving sites of high vascularity, the use of alternativelong-acting amide levoenantiomers may be vindicated tofurther reduce the risk to patients, and this has already beensuggested in dentistry for interior alveolar nerve blocks [92].However, a median effective dose study shows ropivacaineand levobupivacaine to, respectively, have 35% and 3%reduced analgesic potency to racemic bupivacaine, and sodecisions to use these safer agents must be balanced against aloss of clinical efficacy [93].

7.4. Surgeon’s Awareness. Where LA is provided by nonanes-thetists, misdiagnosis and underreporting of LA-associatedcomplications is likely [94]. This includes offices, outpa-tients, and small surgical centers, and so the true incidenceof LAST in these settings is unclear. There are, however, casereports of significant morbidity following LA use in suchareas [95–98]. The importance of surgeon’s knowledge ofsafe use of LAs and management of complications is signifiedby the reported incidence of five deaths from suspected lig-nocaine systemic toxicity or related complication followingtumescent liposuction in New York between 1993–1998 [99–102]. It is of interest to note that this procedure is stillvery popular today and commonly performed without thepresence of an anesthesiologist. Also concerning is a recentsurvey in the UK by Collins that suggests only half of hospitalsurgeons know how to calculate the correct dose of localanesthetic being used and fewer than 25% of nonanestheticdoctors knew the recommended safe doses. Only 7% of non-anesthetic doctors knew the correct treatment to be intralipidand only 3% knew the initial dose [103]. These findinghighlight the importance of education, which is of particularsignificance to practitioners who regularly use LAs withoutthe presence of an anesthesiologist.

8. Summary

Vigilance is required when performing procedures thathave a potential for systemic toxicity. There are numerousexamples of local anesthetic systemic complications in theliterature, many in the hands of nonanesthesiologists. We seethat strategies to reduce the risk of LAST can never eliminateits risk. Although uncommon, the consequences can be fatal.Advances in ILE therapy and understanding is providing alife-saving rescue in the most dreaded situations faced bypractitioners, and further progress will likely improve onour safe use of LAs in the future. Rapid identification oftoxicity and a good recall of the ILE therapy regimen can savelives, but we need to expand awareness to practitioners inremote locations such as outpatients, offices, and especiallythose who work without an anesthesiologist. We encouragethese facilities to put together a “rescue kit” in a specified

location with the current guidelines readily available. LAsare used more frequently by surgeons and dentists thananesthesiologists, and on that note we feel that the respectivecolleges should also develop guidelines for management ofLAST incorporating lipid emulsion therapy.

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Research Article

Pre-Emptive Treatment of Lidocaine AttenuatesNeuropathic Pain and Reduces Pain-Related BiochemicalMarkers in the Rat Cuneate Nucleus inMedian Nerve Chronic Constriction Injury Model

Chi-Te Lin,1 Yi-Ju Tsai,2 Hsin-Ying Wang,1 Seu-Hwa Chen,1, 3

Tzu-Yu Lin,1 and June-Horng Lue1

1 Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan2 School of Medicine, College of Medicine, Fu Jen Catholic University, Taipei 24205, Taiwan3 Department of Anatomy, Taipei Medical College, Taipei 100, Taiwan

Correspondence should be addressed to June-Horng Lue, [email protected]

Received 31 July 2011; Accepted 8 September 2011

Academic Editor: Jacques E. Chelly

Copyright © 2012 Chi-Te Lin et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This study investigates the effects of lidocaine pre-emptive treatment on neuropathic pain behavior, injury discharges of nerves,neuropeptide Y (NPY) and c-Fos expression in the cuneate nucleus (CN) after median nerve chronic constriction injury (CCI).Behavior tests demonstrated that the pre-emptive lidocaine treatment dose dependently delayed and attenuated the development ofmechanical allodynia within a 28-day period. Electrophysiological recording was used to examine the changes in injury dischargesof the nerves. An increase in frequency of injury discharges was observed and peaked at postelectrical stimulation stage in thepresaline group, which was suppressed by lidocaine pre-emptive treatment in a dose-dependent manner. Lidocaine pretreatmentalso reduced the number of injury-induced NPY-like immunoreactive (NPY-LI) fibers and c-Fos-LI neurons within the CN in adose-dependent manner. Furthermore, the mean number of c-Fos-LI neurons in the CN was significantly correlated to the NPYreduction level and the sign of mechanical allodynia following CCI.

1. Introduction

Pre-emptive analgesia is broadly used in clinical practice forrelieving postoperation pain and preventing the subsequentdevelopment of chronic neuropathic pain after surgery [1,2]. In chronic constriction injuries (CCIs) of rat sciaticnerves [3], neuropathic pain behavior was also relieved bypre-emptive treatment of MK-801 [4], nociceptin [5], orlidocaine [6], but little is known about the effect of pre-emptive analgesia on neuropathic pain behavior after mediannerve CCI. Attenuating ectopic discharges, originating fromthe damaged nerves [7, 8] and/or their dorsal root ganglia(DRG) [9], were considered to be one of the pre-emptiveanalgesia mechanisms to relieve neuropathic pain. Topical orsystemic application of local anesthetics has been reportedto attenuate ectopic discharges [9, 10]. Clinical studieshave also indicated that neuropathic pain is alleviated by

application of local anesthetics to the painful target areas[11, 12]. Lidocaine is a local anesthetic that produces atransient analgesic effect in humans affected by neuropathicand postoperative pain [13, 14]. Local pretreatment oflidocaine effectively suppresses injury discharges induced bymedian nerve transection (MNT) [15], but lack of evidenceregarding the median nerve CCI model.

Injury to median nerve, neuropeptide Y-like immunore-active (NPY-LI) fibers are dramatically induced in the lesionside cuneate nucleus (CN), but not detected in the intactside [16]. Furthermore, given an electrical stimulation tothe injured median nerve, c-Fos-like immunoreactive (c-Fos-LI) cells are detected only in the ipsilateral CN [17, 18].The expression of Fos, which is the protein product of theimmediate-early proto-oncogene c-fos, has been acceptedas a neural marker of pain [19, 20]. Pre-emptive analgesiatreatment with lidocaine [21] effectively suppresses c-Fos


expression in the spinal cord after peripheral nerve injury.Furthermore, the expression of c-Fos is modulated by NPYand is considered to be involved in neuropathic pain [22]. Wepreviously demonstrated that lidocaine pre-treatment dose-dependently suppressed injury discharges to reduce NPYexpression in the CN, which in turn significantly attenuatedc-Fos expression after MNT along with electrical stimulation[15]. However, there is still only very little of behavioralevidence to support the effect of pre-emptive treatment onneuropathic pain relief after median nerve CCI.

In this study, we wanted to examine whether a singletopical application of lidocaine prior to median nervesundergoing CCI would influence the development of neuro-pathic pain and ectopic discharges after CCI. Furthermore,morphological changes in NPY and c-Fos expression in theCN were examined to evaluate whether their expressionlevels correlated with the degree of mechanical allodynia.

2. Materials and Methods

The experiments were inspected and approved by the Natio-nal Science Council Committee and the Animal Center Com-mittee, College of Medicine, National Taiwan University, Tai-wan (IACUCA Approval no. 20030114 and no. 20080267).Ethical guidelines from the International Association for theStudy of Pain [23] were followed in the use of animals.Animals were housed under approved circumstances witha 12/12 h light/dark cycle with food and water available adlibitum.

2.1. Chronic Constriction Injury (CCI) Operation. Thirty-three male Sprague-Dawley rats (175–200 g) purchased fromBioLASCO (Taiwan) were randomly divided into a controlgroup (sham operation, median nerve exposure withoutinjury, n 3), and pretreated with saline (presaline, n 10),1% lidocaine (pre-1% lido, n 10) and 5% lidocaine (pre-5% lido, n 10) groups along with CCI. Under chloralhydrate anesthesia (31.5 mg/100 g body weight, i.p.), theabove-mentioned pretreated groups alternatively underwentunilateral (n 5) or bilateral (n 5) median nerve CCIoperations, the nerves were carefully separated from thesurrounding tissue at the level of the elbow immediatelyproximal to entering between the two heads of the pronatorteres muscle. Saline and various concentrations of lidocaine(Sigma, St. Louis, Mo, USA) were applied topically tothe exposed median nerves (100 μL) at 15 min prior toCCI. Fifteen minutes after the application of the saline orlidocaine, four ligatures of 4.0 chromic gut were tied looselyaround the nerves [3, 17, 22]. After the operation, the woundwas subsequently sutured.

2.2. Behavior Assessment. We examined the behavioral signswith mechanical stimulation between 09:00 and 17:00 atone day before ( 1) and at 3, 7, 14, 21, and 28 days afterCCI to the median nerves of the pre-treatment groups,controls, or uninjured contralateral forepaw. All behavioralmeasurements were obtained by an investigator blind to thetreatment groups.

Mechanical allodynia was estimated by means of VonFrey filaments [24]. Von Frey filaments (Somedic Sales AB,

Horby, Sweden) of different bending forces including 0.145,0.32, 0.39, 1.1, 1.7, 3.3, 5.1, 8.3, 17, and 24 g were used totest the mechanical threshold of the rat forepaws [17, 22].Briefly, tests were started with the smallest bending force andcontinued in increasing order. Each filament was applied fivetimes in the medial surface of a forepaw; the first filament inthe series that elicited withdraw three times was regarded asthe paw withdrawal threshold. The thresholds of individualrats in each group were averaged and presented as mean andthe standard error of the mean (mean SEM).

2.3. Electrical Stimulation and Electrophysiological Recording.On the 29th day post-CCI operation, the right nerves of thecontrol and CCI rats were reexposed under anesthesia and atleast a 12 mm segment proximal to the CCI ligature or on thesame level in the control group were isolated. Then, two pairsof platinum hook electrodes were placed on the nerve; thedistal pair of the hook electrodes were connected to a GrassS88 stimulator (Grass, Quincy, Mass, USA) for electricalstimulation, and the proximal pair of hook electrodes wereconnected to an Xction View Data Acquisition System(Model XD-04; Singa, Tao Yuan, Taiwan) for recording.Warm paraffin oil was applied around the exposed nervesto prevent them from drying out. The discharges in themedian nerve at pre-electrical stimulation (pre-ES, a 5-min interval just prior to electrical stimulation) and post-ES (a 5-min interval immediately after stimulation) stageswere also collected, transformed into frequency histogram(Figure 3), and analyzed by Xction view software (Figure 4)[15]. For electrical stimulation, a 10-min electric square wavepulse current with 0.1 ms duration, 10 Hz frequency, 0.1 mAintensity [15, 17, 22, 25] was applied through a constantcurrent unit.

2.4. Tissue Preparation and Immunohistochemistry. Two hoursafter electrical stimulation (or, in the control group, 2 h afternerve exposure), the rats were reanesthetized and perfusedwith 500 mL 4% paraformaldehyde in 0.1 M phosphatebuffer (PB) at pH 7.4. The brain stems containing the CNwere removed, postfixed with the same fixative for 2 hr andstored in PB containing 30% sucrose. The tissue blockswere cut transversely into 30-μm-thick serial sections andorderly divided them into four sets. Two of the four serialsections were treated with 1% H2O2 and blocked with 5%normal goat serum in 0.1 M PB containing 0.2% TritonX-100 for 2 hr. They were incubated alternatively in rabbitpolyclonal anti-NPY (1 : 2000; DiaSorin, Stillwater, Mont,USA) [16, 22, 26] or anti-c-Fos (1 : 2000, Calbiochem,San Diego, Calif, USA) antibodies at 4 C for 48 hr. Afterseveral washing with phosphate buffered saline (PBS), thesections were processed with biotinylated anti-rabbit IgGsecondary antiserum (Vector, Burlingame, Calif, USA) atroom temperature for 2 hr, treated with avidin-biotin-HRPcomplex (ABC kit, Vector) for 1 hr, and visualized witha Vector SG Substrate Kit. Finally, they were mountedonto gelatinized slides and their images were captured witha digital camera (Nikon, D1X, Tokyo, Japan) through alight microscope (Zeiss, Axiophot, Goettingen, Germany) tomeasure the NPY-LI fibers or c-Fos-LI cells in the CN.


Table 1: Statistical comparison of mean values of the nervedischarges.

Group Pre-ES Post-ES

Control 8.21 0.48 Hz 7.65 0.95 Hz

Presaline 91.86 4.39 Hz 137.39 23.90 Hz

Pre-1% lido 50.31 2.90 Hz 56.86 2.97 Hz

Pre-5% lido 23.76 0.57 Hz 32.86 2.10 Hz

Control: sham operation with electrophysiological recording at the corre-sponding stages. ES: electrical stimulation. Data are presented as meanstandard error of the mean (SEM) and P 0.05 compared with the pre-ESstage.

−1 3 7 14 21 280

5

10

15

20

25

Control

∗∗ ∗ ∗ ∗ ∗

∗∗∗

∗∗∗

∗∗

∗

Post operation day

Paw

wit

hdr

awth

resh

old

(g)

Pre-1% lidocainePre-5% lidocainePresaline

Figure 1: Effects of pre-emptive treatment of saline or variousconcentrations of lidocaine on paw withdrawal threshold in CCIrats. Pre-treatment of lidocaine increased paw withdrawal thresholdand attenuated the TH in CCI rats. P 0.05 compared to thepresaline group.

2.5. Data Presentation and Statistical Analysis. All measure-ments of the behavior tests, rates of injury discharges, NPY-LI fibers, and c-Fos-LI cells in the CN were performedblind to drug treatments. The behavior test of the Von Freyfilaments was compared between groups at each time pointand statistical analysis was performed with the Student’s t-test. P 0.05 was considered as significant.

The rate of nerve discharges was presented as thenumber of discharges divided by the time period of therespective stages and presented as mean SEM. In orderto investigate the inter-pre-treatment group (Figure 3) andinterstage (Table 1) differences, the rates of discharges werecompared with two-way ANOVA with a Newman-Keulsposthoc test. P 0.05 was considered statistically significant.

For quantitative analysis, the sections of middle CN,which was defined as an area 0.3–0.7 mm caudal to theobex [16–18, 27], were collected from the entire rostrocaudalextent of the CN. Four sections were collected from themiddle region of each animal. To assess the changes inNPY and c-Fos immunoreactivity in the CN, sections wereinvestigated with a Zeiss light microscope and images were

0

61

122.1

0

61

122.1

0

61

122.1

0

61

122.1

Pre-ES Post-ES

20 s

200 ms

(a) Control

(b)

(c) Pre-1% lidocaine

(d) Pre-5% lidocaine

(spi

kes/

s)(s

pike

s/s)

(spi

kes/

s)(s

pike

s/s)

Presaline

Figure 2: Electrophysiological recording of chronic constrictedmedian nerves at pre- and postelectrical stimulation, (pre-ESand post-ES) stages. Data were collected and transformed intofrequency histogram for control (a), presaline (b), pre-1% lido (c),and pre-5% lido (d) groups. Original recordings presented abovethe histogram, respectively. Note that the rates of discharges weresignificantly reduced with increasing concentrations of lidocainepre-treatment.

captured with a Nikon digital camera at a magnificationof 200X. Pictures were processed and evaluated with acomputer-based image analysis system (MGDS) and ImagePro-Plus software (Media Cybernetics, Md, USA). The areaoccupied by NPY-LI fibers and the area of outlined CN weremeasured [15, 16, 22]. The former divided by the latterwas defined as the percentage of area occupied by NPY-LIfibers in the ipsilateral CN and were compared statistically,using two-way ANOVA, with the Newman-Keuls post-testbetween pretreatment groups (electrically stimulated andnonelectrically stimulated) (Figure 5). The mean numberof c-Fos-LI cells in the CN was defined as the numberof the surveyed c-Fos-LI cells divided by the number oftissue sections and were calculated and statistically comparedwith one-way ANOVA and posthoc with the Newman-Keuls test in the respective groups (Figure 7). In order toclarify the relationship between c-Fos-LI cells and the NPYreduction level caused by electrical stimulation (definedas the ratio of the NPY-LI fibers occupied area in thenonstimulated rat minus that in the stimulated rats indifferent treatment groups), the mean number of c-Fos-LIcells and NPY reduction level of the individual rats werecollected and analyzed by linear regression (Figure 8). Inorder to examine the relationship between c-Fos-LI cells andmechanical allodynia, the mean number of c-Fos-LI cellsin the CN and mechanical withdrawal scale (defined as the


Pre-ES Post-ES0

50

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∗

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eof

disc

har

ges

(spi

kes/

s)

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Figure 3: Average rate of discharges (spikes/sec) in different treat-ment groups at pre-electrical stimulation (pre-ES), and postelectri-cal stimulation (post-ES) stages. The rates of discharges decreasedwith increasing doses of lidocaine pre-treatment compared with thepresaline group ( P 0.05 compared with the presaline group).

logarithm of paw withdraw threshold to the base 10 andpresented as log10-gram) of the individual rats were analyzedby linear regression (Figure 9).

3. Results

3.1. Effect of Lidocaine Pretreatment on Mechanical Allodyniaof the CCI Rats. Von Frey filament assessment demonstratedthat there were no significant differences between bilateral-CCI and unilateral-CCI in mechanical allodynia throughoutthe experiment period. Von Frey filament tests also showedthat in CCI rats, paw withdrawal thresholds decreased froma control of 14.83 1.14 g to 0.75 0.20 g at three daysafter CCI in the presaline group. Rats established mechanicalallodynia three day after CCI, and throughout the 28-day experiment period (control: 15.53 1.26 g, presaline:0.75 0.20 g, Figure 1). However, pretreatment of lidocaineto CCI increased paw withdrawal threshold and attenuatedthe tactile hypersensitivity (TH) (Figure 1).

3.2. Effect of Lidocaine Pretreatment on Injury Discharges of theChronic Constriction Injured Median Nerves. At 29 days afterCCI, electrophysiological recording was used to examinethe changes in discharges of the median nerves before andafter electrical stimulation (pre-ES and post-ES stages) in allgroups (Figure 2). The nerves in the control group displayeda few spikes at pre-ES and post-ES stages (Figure 2(a)).Following median nerve CCI, the rates of discharges at bothpre-ES and post-ES stages in all CCI groups increased on theinjured nerves (Figures 2(b)–2(d)). Two-way ANOVA of therate of discharges displayed significant differences betweendifferent stages (F 15.09, P 0.05) and between thepretreatment groups (F 47.98, P 0.0001). The ratesof discharges at the post-ES stage were significantly higher

than that at the pre-ES stage in all CCI groups, respectively(Table 1). Of note, the rates of discharges at both pre-ESand post-ES stages in presaline and pre-1% lido CCI gro-ups were dramatically higher than those in the controlgroup (Figure 3). Furthermore, the rates of discharges inall the lidocaine pretreatment groups at pre-ES (pre-1%lido: 50.31 2.90 Hz, pre-5% lido: 23.76 0.57 Hz) andpost-ES (pre-1% lido: 56.86 2.97 Hz, pre-5% lido: 32.862.10 Hz) stages were significantly lower than those in thepresaline group (pre-ES: 91.86 4.39 Hz; post-ES: 137.3923.90 Hz), and revealed a dose-dependent suppression man-ner (Figure 3).

3.3. Effect of Lidocaine Pretreatment on NPY and c-Fos Exp-ression in the Cuneate Nucleus. There were little to no NPY-LI fibers in the CN of uninjured control rats, with or withoutelectrical stimulation (control, 0.13 0.01%; control + ES,0.14 0.03%; Figures 4(a), 4(b), and 5). However, in thepresaline group, numerous NPY-LI fibers were detected inthe middle CN four weeks after CCI in both the unstimulated(30.62 1.21%) and stimulated (22.53 4.44%) sides (Figures4(c), 4(d), and 5). The percentage of NPY-LI fibers in thelidocaine pretreatment CCI groups in both the unstimulated(pre-1% lido, 19.81 2.03%; pre-5% lido, 6.04 1.63%) andstimulated (pre-1% lido, 12.12 4.07%; pre-5% lido, 4.260.78%) sides of the CN were significantly decreased in a dose-dependent manner compared with those in the presalinegroup (Figures 4(c)–4(h) and 5). Furthermore, in all CCIgroups the amount of NPY-LI fibers in the unstimulated sideof the CN (Figures 4(c), 4(e), 4(g), and 5) was significantlyhigher than that in the stimulated side of the CN (Figures4(d), 4(f), 4(h), and 5), respectively, except for the pre-5%lido group.

No, or only very few, c-Fos-LI cells were found in theCN of the control rats, the median nerves with or withoutelectrical stimulation, or in CCI rats without electricalstimulation (Figure 6(a)). However, numerous c-Fos-LI cellswere detected when injured median nerves treated withelectrical stimulation in all CCI groups and predominantlydistributed in the ventral portion of the middle CN(Figure 6). Furthermore, quantitative analysis showed thatthe mean number of c-Fos-LI cells in the presaline group(42.9 2.8 cells) was significantly greater than that in othergroups (Figures 7(b) and 8). The mean number of c-Fos-LIcells in the CN was also reduced by lidocaine pretreatmentin a dose-dependent manner (pre-1% lido, 26.6 1.6 cells;pre-5% lido, 18.5 1.4 cells) (Figures 6(c), 6(d), and 7).

In addition, the NPY reduction level was assessed by thepercentage of NPY-LI fibers in the stimulated side of theCN subtracted from that in the unstimulated side of theCN, regarded as an index of the extent of NPY release byelectrical stimulation. Statistical analysis by linear regressiondemonstrated that the mean number of c-Fos-LI cells inthe stimulated side of the CN was significantly correlatedto the NPY reduction level (Figure 8, r 0.64, P 0.01).Finally, linear regression manifested that the mean numberof c-Fos-LI cells in the CN was negatively proportional tothe mechanical withdrawal scale (Figure 9, r 0.80, P0.005).


(a) (b) (c)

(d) (e) (f)

(g) (h)

Figure 4: Photomicrographs showing NPY-LI fibers in the middle region of the ipsilateral CN four weeks after chronic constriction injuryin control (a, b) or four weeks after CCI without (left panel) or with (right panel) electrical stimulation in presaline (c, d), 1% (e, f), and 5%(g, h) lidocaine pre-treatment groups. Bar = 100 μm.

4. Discussion

The results of the present study demonstrate the attenuationof TH and reduction of injury discharges following CCI onmedian nerves by lidocaine pretreatment. Correspondingly,both the level of the injury-induced NPY fibers and the num-ber of injury-induced c-Fos-LI cells in the CN at four weeksafter medina nerve CCI were also dose-dependently reducedby lidocaine pretreatment. These results provide a possiblemechanism in that the suppression of injury discharges bylidocaine pretreatment not only relieves neuropathic painbut also attenuates the NPY and c-Fos expressions in the CNafter CCI.

Following median nerve CCI, signs of mechanical allody-nia were detected three days after CCI and lasted throughout

the experiment period of 28 days in the present study. Similarresults have been reported, where hyperalgesia responsesto noxious radiant heat were observed on the secondpostoperative day and lasted for over two months after sciaticnerve CCI [3]. Another study also indicated that mechanicalallodynia was found three to five days following CCI [28],whereas this neuropathic sign was detected one day after CCIin our recent study [22]. There are discrepancies in the timepoints of neuropathic pain initiating after CCI between vari-ous studies. The reason for these discrepancies may be simplydue to different time points being examined. We focused onthe role of lidocaine pretreatment in the paw withdrawalthreshold of the CCI rats. The reductions in the pawwithdrawal threshold after median nerve CCI were reversedby lidocaine pretreatment in a dose-dependent manner.


∗

∗

∗

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10

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CCICCI + ES

#

#

Are

aoc

cupi

edby

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Y-L

Ifi

bers

inth

em

iddl

ere

gion

ofC

N(%

)

Pre-1%lidocaine

Pre-5%lidocaine

Presaline

Figure 5: Histograms showing morphometric assessments used to quantify intensity of NPY-LI fibers in the middle CN at four weeks afterchronic constriction injury without (CCI) or with electrical stimulation (CCI + ES). It is notable that the intensities of NPY-LI fibers in theCN were significantly lower in rats with electrical stimulation than those without stimulation in the presaline and pre-1% lidocaine groups(#P 0.05 compared with unstimulated side in respective group). The intensity of NPY-LI fibers in the CN was also reduced by lidocainepretreatment in a dose-dependent manner ( , P 0.05 compared with the stimulated and unstimulated side of the presaline group, resp.).

(a) (b)

(c) (d)

Figure 6: Photomicrographs showing c-Fos-LI cells in the middle region of the CN ipsilateral to electrical stimulation four weeks afterchronic constriction injury in control (a), presaline (b), pre-1% lido (c) and pre-5% lido (d) groups. Bar = 100 μm.


Control

0

10

20

30

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Mea

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ofc-

Fos-

LIce

llsin

the

mid

dle

regi

onof

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Pre-1%lidocaine

Pre-5%lidocaine

Presaline

Figure 7: Histograms showing the mean number of c-Fos-LI cellsin the middle region of the CN following electrical stimulation incontrol (a), presaline (b), pre-1% lido (c), and pre-5% lido (d)groups. Note that the mean numbers of c-Fos-LI cells in the pre-1% lido and pre-5% lido groups were significantly less than that inthe presaline group ( P 0.05 compared with the presaline group).

0 5 10 15 200

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50r = 0.64P = 0.0097

NPY reduction level (%)

Mea

nn

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ofc-

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llsin

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regi

onof

CN

Figure 8: Linear regression of the mean number of c-Fos-LI cellsand NPY reduction level in the CN four weeks after chronicconstriction injury (each point represents an individual animal;r 0.64, P 0.01).

A previous study [6] reported that lidocaine pretreatmentrelieved thermal hyperalgesia for a long postoperative period(up to three weeks) after sciatic nerve CCI. However, anotherstudy showed that prior to spinal nerve ligation (SNL), ligno-caine pretreatment increased the paw withdrawal thresholdfor only 24 h [29]. These discrepancies may be related todifferences in the injury models used in the above-mentionedstudies (CCI versus SNL). The lesion site to the DRG in theCCI model was more distal than that in the SNL model. Theinjury level caused by the former was less severe than that bythe latter, so the neuropathic pain induced by the CCI modelcould be prevented by lidocaine pre-treatment.

Furthermore, four weeks after CCI (29 days postinjury),a significant increase in the number of spikes in all CCIgroups, which was regarded as ectopic discharges inducedafter nerve injury. Then, our results also demonstrated that

0 10 20 30 40 50−1.5

−1

−0.5

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1 r = −0.8P = 0.0004

Mean number of c-Fos-LI cells

Mea

nn

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ofc-

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llsin

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regi

onof

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Figure 9: Linear regression of the mean number of c-Fos-LI cellsand mechanical withdrawal scale (presented as log10-gram) fourweeks after chronic constriction injury (each point represents anindividual animal; r 0.80, P 0.005).

the ectopic discharges were suppressed by lidocaine pre-treatment in a dose-dependent manner. The suppression inectopic discharges was considered as one of the contributingfactors in relieving neuropathic pain induced by mediannerve CCI. Our recent study reported that ectopic dischargesevoked by median nerve transection (MNT) were suppressedby pre-treatment with 5% and 10% lidocaine, but not1% lidocaine [15]. However, in the present study, ectopicdischarges induced by CCI were significantly attenuatedby 1% lidocaine pre-treatment. This discrepancy may alsobe explained by the difference in injury model employedbetween these two studies. The injury severity induced byCCI was milder than that by MNT. For this reason, the rateof injury discharges in the CCI rats, but not MNT, couldbe significantly reduced by low-dose (1%) lidocaine pre-treatment.

The present study further demonstrated that a significantincrease in NPY in the CN at four weeks (29 days) post-CCI was also dose-dependently reduced by lidocaine pre-treatment. Previous studies have reported that intense affer-ent discharges and depolarization enhanced NPY induction[30, 31]. Furthermore, the NPY induction in the CN exclu-sively originated from injured DRG neurons, particularlymedium- and large-size neurons, via primary afferent fibers[26]. It is reasonable to infer that the reduction of NPYexpression in the CN would result from the suppressionin injury discharges following CCI with lidocaine pre-treatment. This is consistent with NPY reduction in the CNafter MNT [15] with lidocaine pre-treatment and in thespinal cord laminae 3-4 following sciatic nerve CCI withMK-801 and clonidine pre-treatment [30]. Taken together,these findings suggest that the magnitude of nerve dischargesmay be one of the most important factors to induce NPYsynthesis.

In the rats with bilateral median nerve CCI, c-Fos-LIcells were found only in the CN with electrical stimulation,but not in the unstimulated side of the CN; the level of


NPY-LI fibers in the stimulated side of the CN was alsosignificantly lower than that in the unstimulated side. Onepossible explanation for this is that NPY is released fromthe injured median nerve in the stimulated side of the CNresulting in NPY reduction and induced c-Fos expression inthe same region. This is compatible with previous studieswhere NPY reduction and c-Fos induction were detected inthe stimulated side of the CN following electrical stimulationwith the transected median nerve; injection of an NPYreceptor antagonist into the CN coupled with electricalstimulation to the injured nerve resulted in a dramaticdecrease in the number of c-Fos-LI cells in the ipsilateral CN[15, 22]. In the present study, we also found that the numberof c-Fos-LI cells in the CN after electrical stimulation of theinjured nerve was dose-dependently reduced by lidocainepre-treatment. Statistical analysis further demonstrated thatthe number of c-Fos-LI cells in the stimulated side ofthe CN was significantly correlated to the level of NPYreduction. Taken together, these results suggest that theamount of NPY release (NPY reduction level), followingelectrical stimulation of the injured nerve, directly modulatesc-Fos expression in the CN.

Although the function of c-Fos induction in the CNremains uncertain, the expression of c-Fos immunoreactivityin the spinal cord has been considered as a convincing markerof pain [19, 20]. Our results showed that the number of c-Fos-LI cells in the CN coincided with the reduction in pawwithdrawal thresholds, regarded as mechanical allodynia.This is in agreement with a previous study which reportedthat the number of c-Fos-LI cells was positively associatedwith the magnitude of mechanical allodynia [22]. Earlierstudies have also clarified that after electrical stimulationof the injured median nerve, about 78% of c-Fos-LI cellsin the middle CN were cuneothalamic projection neurons(CTNs) [17, 18]. This study further showed that the numberof c-Fos-LI cells was dose-dependently reduced by lidocainepre-treatment. Injury discharges have been reported tobe implicated in the increase of c-Fos LI cell expressionin the spinal cord dorsal horn [32–34], while lidocainepre-treatment attenuates the discharges to prevent c-Fosinduction [21, 34].

5. Conclusions

Our results suggest that lidocaine pre-treatment dose-dependently suppressed injury discharges development toattenuate NPY expression after median nerve injury. Thisin turn significantly reduces the NPY release to decrease thetransmitting of TH to the thalamus and c-Fos expression inthe CTNs.

Acknowledgment

This study was supported by Research Grants from theNational Science Council (NSC 94-2320-B002-003; NSC 98-2320-B002-033-MY3), Taiwan.

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Review Article

New Formulations of Local Anaesthetics—Part I

Edward A. Shipton

Department of Anaesthesia, University of Otago, Christchurch 8042, New Zealand

Correspondence should be addressed to Edward A. Shipton, [email protected]

Received 26 July 2011; Revised 14 September 2011; Accepted 14 September 2011


Copyright © 2012 Edward A. Shipton. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Part 1 comments on the types of local anaesthetics (LAs); it provides a better understanding of the mechanisms of action ofLAs, and their pharmacokinetics and toxicity. It reviews the newer LAs such as levobupivacaine, ropivacaine, and articaine,and examines the newer structurally different LAs. The addition of adjuvants such as adrenaline, bicarbonate, clonidine, andcorticosteroids is explored. Comment is made on the delivery of topical LAs via bioadhesive plasters and gels and controlled-releaselocal anaesthetic matrices. Encapulation matrices such as liposomes, microemulsions, microspheres and nanospheres, hydrogelsand liquid polymers are discussed as well. New innovations pertaining to LA formulations have indeed led to prolonged actionand to novel delivery approaches.

1. Introduction

Local anaesthetics (LAs) are used clinically for anaesthesiaand analgesia either following surgery or for managementof other acute and chronic pain conditions; they only lasta few hours. Part 1 of this paper deals with the newer LAs,more recent LA formulations, a better understanding of themechanisms of action of LAs, and their pharmacokineticsand toxicity.

Local anaesthesia for a prolonged period of days isbest provided using catheter techniques [1] with disposablepumps [2] or multiple injections [3]. Most attempts toprolong LA action have so far only doubled or tripled theplain drug effect time, using adjuncts to LA agents of readilyavailable agents. These include opioids and clonidine thatdelay local anaesthetic clearance from their site of action[4] and dexamethasone that prolongs peripheral nerve andplexus blocks [5].

2. Types of Local Anaesthetics

Lignocaine is perhaps most commonly used or known localanaesthetic agent; it is used either in local or regional anaes-thesia, or in epidural or spinal blockade; it has a numberof uses in anaesthesia and pain medicine. However, it isalso given parenterally in the management of neuropathic

pain states. EMLA, a eutectic mixture of lignocaine andprilocaine, is an effective topical anaesthetic in preventingpain associated with needle procedures [6].

Local anaesthetics can be classified into two groups basedon the nature of the link, namely, amides [–NH–CO–] andesters [–O–CO–] (Figures 1 and 2). The amide group isthe most commonly used clinically; it includes lignocaine,prilocaine, levobupivacaine, bupivacaine, mepivacaine, andropivacaine.

The ester group is weak bases, solubilised for injectionas strong conjugate acidic hydrochloride salts (pH 3–6); itincludes cocaine, procaine, chloroprocaine, and amethocaine(Figure 3) [3, 7]. Benzocaine and butamben are ester-typelocal anaesthetics mostly used in topical and mucous formu-lations. Anaphylaxis to local anaesthetics is very uncommonand has decreased in frequency because of the decreasinguse of the ester group of local anaesthetics [8]. Most allergicreactions are due to the common metabolic product ofthe ester local anaesthetic, para-amino benzoic acid [8].Cross-reactivity among esters is common. Allergic reactionsto amide local anaesthetics remain anecdotal. Ingredientsincluded in local anaesthetic solutions such as antioxidantsor preservatives including metabisulphite or parabens (alsometabolised to para-amino benzoic acid) may also elicitallergic or adverse reactions [8]. Local anaesthetics (withoutpreservatives or adrenaline) may be skin tested.


3. Pharmacokinetics of Local Anaesthetics

Injectable local anaesthetics are subject to absorption; a largefraction of the injected drug is removed by the systemiccirculation and distributed to distant organs according totheir vascular density [9]. Highly vascular organs (brain,heart, lung, liver, and kidneys) are exposed to unmetabolisedlocal anaesthetic at peak concentration. The local anaestheticis taken up within each organ according to its tissue-plasma partition coefficient. Most absorbed local anaestheticis cleared from the liver. Hepatic clearance is a functionof the hepatic extraction ratio and hepatic blood flow.The hepatic extraction ratio, in turn, is dependent on theratio of free to protein-bound drug. Local anaestheticsbind tightly to plasma proteins greatly limiting the freefraction of available drug. Only the free or unbound fractionthat is bioactive. Like most weak bases, local anaestheticsbind mainly to alpha-1-acid glycoprotein. Lignocaine, beingmoderately protein-bound, has a high hepatic extractionratio (70–75% per pass) [9]. Clearance is therefore flow-limited and is reduced by factors that limit hepatic bloodflow. Conversely, bupivacaine and ropivacaine, being highlyprotein-bound, are cleared <50% per pass; hence, theirclearance depends on free drug concentration [9]. Lowcardiac output states may not greatly affect the plasmaconcentration of the highly protein-bound agents, as theirclearance is not flow limited. Intrinsic hepatic disease mayalter clearance by altering plasma protein content and degreeof protein binding, by decreasing the enzyme activity ofthe liver, and by reducing hepatic blood flow. Patients withliver disease may have single-shot blocks with normal doses.Doses for continuous infusion and repeat blocks need tobe significantly reduced (10–50% relative to the degree ofdysfunction) due to the risk of accumulation of the primarycompound and its metabolites [10]. Patients with mild orcontrolled cardiac failure may not need a dose reduction forsingle-shot blocks. Doses of ropivacaine and bupivacaine forcontinuous infusion and repeat blocks need to be reduced, astheir metabolites will be eliminated slowly. In patients withrenal dysfunction, reduced clearance and faster absorption oflocal anaesthetic lead to an elevation in plasma concentration[10]. Clearance of both bupivacaine and ropivacaine hasbeen shown to be reduced in uraemic patients [9, 10]. Theclearance of one of the main metabolites of ropivacaine, 2,6-pipecoloxylidide (PPX), is also decreased in uraemic patients[9].

4. Newer Local Anaesthetics

4.1. Levobupivacaine. In recent years, levobupivacaine, thepure S (−) enantiomer of bupivacaine, emerged as a saferalternative for regional anaesthesia than its racemic parent(Figure 4). In common to all local anaesthetics, levobupiva-caine reversibly blocks the transmission of action potential insensory, motor, and sympathetic nervous fibres by inhibitingthe passage of sodium through voltage-sensitive ion channelsin the neuronal membrane. Various factors such as siteof administration, duration of continuous infusion, and/oraddition of agents with vasomotor effect may influence thedegree of systemic uptake of levobupivacaine.

Linkage

Lipophilic part Hydrophilic part

N

Figure 1: Structure of all local anaesthetics.

NH-C

O

R

N

C3H6 C4H9R = CH3

Ropivacaine Bupivacaine Mepivacaine

CH3

CH3

Figure 2: Amide local anaesthetics.

In pharmacodynamic studies, levobupivacaine demon-strated less affinity and depressant effects on myocardial andcentral nervous vital centres and a superior pharmacokineticprofile [11]. Clinically, levobupivacaine is well tolerated ina variety of regional anaesthesia techniques both after bolusadministration and continuous postoperative infusion.

The incidence of adverse events with levobupivacainewas similar to that after bupivacaine in comparative trials.These include hypotension, nausea, postoperative pain, fever,vomiting, pruritus, back pain, headache, constipation, dizzi-ness, and foetal distress [11]. The early clinical presentationof toxicity after levobupivacaine appears to consist of cen-tral nervous symptoms (disorientation, drowsiness, slurredspeech), which may culminate with tonic-clonic seizures insome cases. Reports of toxicity with levobupivacaine arescarce; occasional toxic symptoms are usually reversible withminimal treatment with no fatal outcome [11].

Surgical sensory block of similar characteristics and re-covery over equal dose ranges of levobupivacaine and bu-pivacaine has been confirmed in surgical patients [11].The onset of motor block is slower with levobupivacaine,and its quality follows the rank of order bupivacaine >levobupivacaine> ropivacaine [11]. The regression of motorblock was significantly more rapid after levobupivacaine andropivacaine than bupivacaine; this may be advantageous forearly ambulation after day-case surgery.

The effective dose of epidural levobupivacaine for con-tinuous postoperative analgesia approaches 15 mg/hour [11].The addition of adjunctive agents (adrenaline, opioids, orclonidine) to levobupivacaine in epidural anaesthesia andanalgesia may increase the duration and quality of analgesiaand further decrease the risk of toxicity. Traditionally, thedose of levobupivacaine used for spinal anaesthesia is 15 mg


O O

CH3

CH3

NHCCH2N

C2H5 C2H5

C2H5C2H5

H2N COCH2CH2N

Lignocaine Procaine

Figure 3: Amide local anaesthetic (lignocaine) and ester local anaesthetic (procaine).

N

N

O

CH3

H3C H3C

Figure 4: Structure of levobupivacaine.

[11]. Smaller doses (5–10 mg) have been used in ambulatorysurgery and allow a more rapid recovery and subsequentdischarge home.

Current evidence suggests a potency hierarchy of bupiva-caine> levobupivacaine> ropivacaine for epidurals in labour[11]. Using an epidural bolus of 10 mL levobupivacaine0.2%–0.25% followed by epidural infusions or top-ups oflow concentrations levobupivacaine (0.1%–0.125%) pro-vides the same good-quality labour analgesia as bupivacaine,but possibly with less motor block [11]. A combined spinal-epidural technique with intrathecal levobupivacaine 1.2–2.5 mg combined with a small dose of opioid (e.g., fentanyl12.5–25 μg) provides excellent prolonged sensory block withminimum motor blockade [11].

In brachial plexus nerve blocks, a sensory and motorblock of similar onset (6–10 min) and duration (14–16hours) follows the administration of an equal dose oflevobupivacaine 0.5% or bupivacaine 0.5% [11]. Continuingthe administration of levobupivacaine via a peripheralnerve block continuous catheter is associated with excellentpostoperative analgesia as demonstrated by a significantdecline in the postoperative systemic opioids requirements.

4.2. Ropivacaine. Ropivacaine is a long-acting, enantiomer-ically pure (S-enantiomer) amide local anaesthetic regionalanaesthetic with an efficacy broadly similar to that ofbupivacaine (Figure 5). However, it may be a preferredoption because of its reduced central nervous system (CNS)and cardiotoxic potential and its lower propensity for motorblock [12]. It has a high pKa and low lipid solubility that

O

N

CH3

CH3

NH-C-CH

C3H7

S-ropivacaine

(a)

ON

CH3

CH3

NH-C-CH

C3H7

R-ropivacaine

(b)

Figure 5: Structure of S and R enantiomers of ropivacaine(marketed as the S enantiomer).

block nerve fibres involved in pain transmission (A delta andC fibres) to a greater degree than those controlling motorfunction (A beta fibres). The drug is less cardiotoxic thanequal concentrations of racemic bupivacaine but more sothan lignocaine; it has a significantly higher threshold forCNS toxicity than racemic bupivacaine. Extensive clinicaldata have shown that epidural ropivacaine 0.2% is effectivefor the initiation and maintenance of labour analgesia, andprovides pain relief after abdominal or orthopaedic surgeryespecially when given in conjunction with opioids [12].Ropivacaine had an adverse event profile similar to thatof bupivacaine in clinical trials. Comparative data suggestthat higher concentrations of ropivacaine (0.75%) may be


needed to provide the same sensory and motor blockadeas bupivacaine 0.5% [12]. Brachial plexus anaesthesia wasbroadly similar to that achieved with equivalent volumes ofbupivacaine 0.5%, although the time to onset of sensoryblock tended to be faster and the duration of motor blockshorter with ropivacaine [12].

4.3. Articaine. Articaine is a relatively new local anaestheticused now in dentistry in many countries. It is an amide typelocal anaesthetic, and, instead of benzene ring, it containsa thiophene ring that increases its lipid solubility. Unlikeother local anaesthetics, articaine is exceptional in that itcontains an additional ester group that is rapidly metabolisedby plasma esterase to articainic acid [13]. As a result, itshalf-life, about 20 minutes, is also very short comparedto other local anaesthetics. Thus, it can rapidly be clearedfrom the systemic circulation through kidney, minimisingadverse effects [13]. Advantages are low lipid solubility,high plasma protein binding rate, fast metabolism, fastelimination half time, and low blood levels [14]. Articaineseems to be the local anaesthetic of first choice in tissues withsuppurative inflammation, for adults, children (over 4 yearsold), elderly, pregnant women, breastfeeding women, andpatients suffering from hepatic disorders and renal functionimpairment [14]. Articaine solutions must not be used inpersons who are allergic or hypersensitive to sulphite, due tothe content of sodium metabisulphite as the vasoconstrictor’santioxidant in it.

4.4. Newer Structurally Different Local Anaesthetics. Anothergroup of potent LAs includes the basic esters of phenylcar-bamic acid [15]. Basic esters of alkoxy-substituted phenylcar-bamic acid have shown high LA potency, while maintaininga relatively safe toxicity profile [15]. The most potentphenylcarbamic anaesthetics exceed the potency of the mostcommon clinically used local anaesthetics by 100–300 times[15]. Their potency uniquely increases with the decreasingpH of the external medium. This is of importance whenusing LAs in inflamed tissues, where the action of commonLAs is often problematic. Further study of their action isrequired.

5. Mechanisms of Action of Local Anaesthetics

Local anaesthetics directly block transmission of pain fromnociceptive afferents. Local anaesthetic agents are applieddirectly, and their efficacy results from action on thenerve where the inward Na+ current is blocked at thesodium ionophore during depolarisation. LAs not onlyblock Na+ channels but Ca2+ and K+ channels [16–18],transient receptor potential vanniloid-1 receptors [19], andother ligand-gated receptors as well. Local anaesthetics alsodisrupt the coupling between certain G proteins and theirassociated receptors [20]. Through this action, LAs exertpotent anti-inflammatory effects, particularly on neutrophilpriming reactions [21]. Local anaesthetics inhibit localinflammatory response to injury that can sensitise noci-ceptive receptors and contribute to pain and hyperalgesia.

Studies have observed that local anaesthetics reduce therelease of inflammatory mediators from neutrophils, reduceneutrophil adhesion to the endothelium, reduce formationof free oxygen radicals, and decrease oedema formation [22].There are, in addition, a variety of other antithromboticand neuroprotective actions of intravenous LAs [20] that areindependent of Na+ channel blockade but may account formany of the improvements in pain after surgery [16, 22].Local anaesthetics can alleviate some types of neuropathicpain, and part of this effect may be related to sensitisationof the antinociceptive pain pathways that occur in theneuropathic pain state; spinal glial cells have been shown toplay some part in this as well [23].

Lignocaine seems to have some modulatory effect on theNMDA receptor [24]. Intravenous application of lignocainein a rat model of acute and neuropathic pain demonstratedantinociception in both pain models [25]. Several studieshave previously shown that lignocaine at antiarrhythmicdoses or lower doses demonstrates neuroprotective effects[24]. A randomised, double blinded, placebo controlledstudy of neuroprotection with lignocaine in cardiac surgeryshowed a potential protective effect of lower lignocaine dosesin nondiabetic patients. LAs have long been known to inhibitthe growth of different species in vitro [24]. The antibacterialactivity of various LAs and additives used in epiduralinfusions has been tested [26]. Bupivacaine was shown tohave the most efficient activity against microorganisms [26].LAs have been used to enhance bowel function recoveryafter surgery or trauma. Twenty-two patients scheduled forelective bowel surgery randomised into two groups weregiven intravenous lignocaine or placebo to assess differencesin surgical pain, length of postsurgical ileus, and hospitalstay [27]. The lignocaine group showed less pain after24 hours, a faster return of bowel movements, and anearlier discharge from hospital. LAs stimulate the activityof natural killer cells during the perioperative period [24].Perioperative lignocaine has been found to improve imme-diate postoperative pain management and reduce surgery-induced immune alterations [28]. The long-term effect ofanaesthesia/analgesia provided by LAs on cancer recurrenceneeds further investigation.

6. Local Anaesthetic Toxicity

Toxicity primarily involves the central nervous system fol-lowed by the cardiovascular system. More potent agents(bupivacaine, levobupivacaine, ropivacaine) produce car-diotoxic effects at lower blood concentrations and dosesthan less potent LA agents (lignocaine) [29]. The (+)-(R)-enantiomers bind with greater affinity to cardiac Na+

channels than the (−)-(S)-enantiomers do. LA agents causemarked but reversible lesions to skeletal muscle tissue[3]. Myotoxicity seems to be explained by mitochondrialbioenergetics alteration. In the animal model, this toxiceffect was significantly more severe in young rats [30]. Thenitric oxide pathway is involved in the development oftachyphylaxis [31]. In addition, there is a growing amount ofevidence that intra-articular administration of bupivacaine


is chondrotoxic especially at a higher concentration and withprolonged exposure [24].

A lipid emulsion infusion alongside cardiopulmonaryresuscitation appears to be an effective treatment for cardiactoxicity induced by lipophilic medications [32]. The practiceadvisory on LA systemic toxicity of the American Societyof Regional Anesthesia and Pain Medicine suggests that20% lipid emulsion initially be administered as a bolusof 1.5 mL/kg over a minute [33]. Following completion ofthe bolus, a continuous infusion of 0.25 mL/kg/min shouldbe started [33, 34]. If the patient does not respond tothe initial bolus, one to two additional boluses may beadministered. The rate of the infusion may be increasedto 0.5 mL/kg if there is persistent hypotension. The infu-sion should be continued until 10 minutes after thepatient regains haemodynamic stability [33, 34]. Giventhe difficulties of performing clinical trials, further labo-ratory investigation and clinical correlation are needed tobetter define its role in resuscitation. Another potentialtreatment is the use of pegylated anionic liposomes toreduce free drug concentration of LA [35]. In summary,LA cardiotoxicity primarily arises from a blockade ofsodium channels. As for treatment, in addition to ventila-tion, oxygenation, and chest compressions, lipid emulsiontherapy should be a primary element in the treatment[36].

6.1. Prevention of Local Anaesthetic Toxicity. There is no sin-gle measure that can prevent LA toxicity in clinical practice.The lowest effective dose of local anaesthetic should be used(dose = product of volume × concentration). LAs should beinjected incrementally through a catheter [33]. The needle orcatheter should be carefully aspirated before each injectionwith close observation when injecting LA. More diluteLAs should be used. The use of ultrasound guidance mayreduce the frequency of intravascular injection. Intravascularinjection of adrenaline 10–15 microgram/mL in adultsproduces a >10 beat heart rate increase or a >15-mm Hgsystolic blood pressure increase in the absence of beta-blockade, active labour, advanced age, or general/neuraxialanaesthesia [33]. Intravascular injection of adrenaline0.5 microgram/mL in children produces a >15-mm Hgincrease in systolic blood pressure [33]. All these mea-sures have improved morbidity and mortality following LAuse.

7. Adjuvants

Adrenaline induces vasoconstriction, reducing local anaes-thetic clearance from the site of action, thus prolonging theduration of action. Solutions such as 1 : 200000 or 1 : 400000are commonly used [37].

The addition of bicarbonate raises the pH of LA solutionthereby increasing the proportion of unionised LA availableto cross the neuronal phospholipid membrane, increasingspeed of onset. The recommended dose is 1 mL of 8.4% ofsodium bicarbonate per 10 mL of LA. The stability of LAswith added bicarbonate is not well studied; such mixtures

cannot be recommended for continuous perineural infusions[37].

Clonidine is an alpha-2 receptor agonist whose effectmay be mediated by inhibiting action potentials. Its effect isdose dependent, increasing the duration of anaesthesia andanalgesia when used with intermediate acting LAs [37].

Corticosteroids have been shown to specifically inhibit C-fibre transmission [38]. Dexamethasone prolongs peripheralnerve and plexus blocks [5]. It prolongs analgesia frominterscalene blocks using ropivacaine or bupivacaine [39],and prolongs the duration of analgesia after supraclavicularbrachial plexus blockade using mepivacaine [40].

8. Topical Local Anaesthetics

Topical delivery systems for LA are characteristically com-posed by a diversity of formulations (viscosity inducingagents, preservatives, permeation enhancers, emollients,)and presentations such as semisolid (gel, creams, ointments),liquid (emulsions, dispersions), and solid (patches) phar-maceutical forms [41]. The proposed formulations aim toreduce the LA concentration used, increase its permeabilityand absorption, keep the LA at the target site for longer anddecrease the clearance, and limit local and systemic toxicity[41].

8.1. Bioadhesive Plaster and Gels. Different topical localanaesthetics have varying effects on skin blood flow andvascular reactivity. The vasoactive properties of 70 mg ligno-caine/70 mg tetracaine medicated plaster (Rapydan), a newtopical local anaesthetic, were compared with those of tetra-caine base (4.0% w/w or Ametop ) and 2.5% lignocaine/2.5%prilocaine (EMLA ) creams in 20 healthy volunteers [42]. Thetetracaine base produced a greater degree of vasodilatationthan that seen after the application of a lignocaine/tetracainemedicated plaster [42]. The eutectic patch will be discussedfurther on.

In the laboratory, the anaesthetic action of the for-mulated mepivacaine gel containing enhancer and vaso-constrictor was evaluated with the tail-flick analgesimeter[43]. Among the enhancers used, polyoxyethylene 2-oleylether showed the greatest enhancement of permeation.The vasoconstrictor tetrahydrozoline showed prolonged andincreased local anaesthetic action compared to the controlused [43]. Mepivacaine gel is not available commerciallyfor use in humans. Mepivacaine’s spinal use was largelyabandoned in the late 1990s due to a relatively high incidenceof transient neurological symptoms with concentrated mepi-vacaine solutions [44].

8.2. Controlled-Release Local Anaesthetic Matrix. An ab-sorbable, controlled-release lignocaine matrix delivery sys-tem has been developed; it is a suspension of a water-insoluble particulate and a hydrophobic carrier containing16% lignocaine (w/w) (Xybrex ) [45]. It can block the ratsciatic nerve for 1-2 days and suppress postincisional pain[16].


Liposomes

Figure 6: Liposomes.

9. Encapsulation Matrices

A rapidly growing research topic is the use of vesicularcarriers such as liposomes, niosomes, ethosomes (soft lipidvesicles), and elastic and deformable vesicles to provide anefficient dermal delivery system [46]. Encapsulation of localanaesthetic agents allows large doses to be released slowlyand provides analgesia over a prolonged period withouttoxicity [47]. Encapsulating agents include liposomes [48],lipospheres [49], cyclodextrins [50], and microparticles [51].Following injection of a depot of the formulation, much ofthe LA agent is bound or carried inside another agent andis not immediately available. The duration of the analgesiadepends on the release rate of the LA agent from thecarrier agent. Several properties such as hydrophobicity andinternal membrane pH affect encapsulated drug release rates[3]. Some synergistic agents such as dexamethasone andclonidine encapsulated with the main effective agent havebeen formulated; these increased the anaesthesia time forseveral days [3, 52].

9.1. Liposomes. Liposomes act as reservoirs for drugs. Lipidvesicles are sealed sacs containing a lipid bilayer, usuallyphospholipids (Figure 6). There are three types of liposomes,namely, multilamellar vesicles, small unilamellar vesicles,and large unilamellar vesicles [3]. Lipid-soluble drugs canbe carried in the bilayer itself; liposomes may contain oneor more bilayers. Alternatively, aqueous drugs can be carriedinside the aqueous compartment contained inside the bilayer[53].

Liposomes supply both a lipophilic region and an aque-ous “milieu interior” in one system making them suitablefor hydrophobic, aliphatic, and hydrophilic drugs (Figure 7)

aqueous fluid

Lipid

Lipid solubledrug in

Drug crystallized in

bilayerbilayer

Figure 7: Liposome for drug delivery.

[54]. They are biocompatible due to their biodegradabilityand low toxicity. Liposomes help to reduce exposure ofsensitive tissues to toxic drugs. They can be administeredby a variety of routes (topical, intramuscular, subcutaneous,pulmonary, nasal, oral, and intravenous) [54]. Their routeof administration and their lipid composition size canmanipulate their pharmacokinetics and in vivo distribution.Following a single injection at the time of surgery, theyremain in subcutaneous tissues (around the surgical inci-sion) around a neural plexus or in the epidural space for amuch longer period of time compared to the free drug [54].

Liposomes suffer lack of reliability and reproducibilityduring manufacture owing to oxidation and hydrolysis,which results in leaking of the encapsulated drug [3, 55].Liposome metabolite compounds have been found to beneurotoxic. The mechanism for this may be lethicin fattyacid oxidation. Also, uncontrolled leakage of drug may occurfollowing breakdown of the liposomes. Ideally, desirableattributes should include prolonged analgesic action; noneurotoxicity; sterility; physical and chemical stability givinga long shelf life; absence of unwanted side products (e.g.,residues of organic solvents in bilayer); a reproducibleproduction process [54].

Liposomal formulations of various anaesthetics allow anincrease in clinical efficacy in comparison with the plaindrugs [56]. Recently, classical liposomes have evolved to“highly deformable” liposomes, endowed with enhancedskin penetration ability and drug skin delivery [57]. “Highlydeformable” liposomes consist of phospholipids and an edgeactivator that is often a single chain surfactant which desta-bilises the liposomal lipid bilayers, increasing their elasticityand flexibility [58]. Several studies have demonstrated thepenetration across the skin of liposomal vesicles to be directlyrelated with their deformability. The high adaptability ofsuch elastic vesicles enable them to squeeze between the


cells of the stratum corneum to penetrate intact to the deeplayers of the skin; this gives an effect comparable to that of asubcutaneous injection [59].

Limitations of encapsulated local anaesthetic agentsinclude neurotoxicity, myotoxicity, tachyphylaxis, motorblock, and viscosity [3]. Many formulations including poly-mer and liposome carriers have facilitated prolonged localanaesthetic action for several days, although few clinicalstudies have been performed. Many routes of drug admin-istration have been described, including central neuraxialadministration and peripheral nerve administration [3].

Grant et al. [60] described safe and prolonged analgesiafor 48 hours following local anaesthetic infiltration of 2%liposomal lignocaine. Boogaerts et al. [61] demonstrated atwofold increase in the duration of the analgesia followingepidural administration of liposomal bupivacaine in patientsfollowing abdominal surgery. For intraoral topical anaes-thesia, liposome-encapsulated 2% ropivacaine gel was aseffective as 20% benzocaine gel in reducing pain during nee-dle insertion and inducing soft-tissue anaesthesia; neither,however, was able to induce pulpal anaesthesia [62]. In arecent randomised single-blinded, placebo-controlled (2.5%lignocaine/2.5% prilocaine) cross-over study, liposomal-encapsulated ropivacaine formulations (1%, 2%) did notreduce the pain of insertion of a needle into the palatalmucosa [63]. Another blinded cross-over study in volunteersundergoing intraoral injections at four different sessionsevaluated the injection discomfort comparing 2% and 3%liposome-encapsulated mepivacaine with 2% mepivacainewith 1 : 100,000 adrenaline and 3% mepivacaine [64]. Theencapsulation of mepivacaine was found to increase theduration of anaesthesia and reduce the injection discom-fort caused by these vasoconstrictor-associated formulations[64].

The entrapment of hydrophobic drugs in the aqueouscore of liposomes as soluble inclusion complexes withcyclodextrins has been proposed to avoid the use of organicsolvents, giving rise to drug-in cyclodextrin-in liposomesystems [65]. The main types of cyclodextrin are α-, β-,and γ-cyclodextrins, comprising six to eight sugar unitsin the ring. This combined approach that simultaneouslyexploits the cyclodextrin solubilising power towards thedrugs and the liposome carrier function through the skin hasrecently been demonstrated by using both classic [66] anddeformable liposomes [67]. The use of this double-loadingtechnique by preparing liposomes loaded with the plaindrug in the lipophilic phase and its cyclodextrin complex inthe aqueous phase of the vesicles gives rise to a fast onsetaction and a prolonged effect [68]. The composition vesiclescontaining the cationic surfactant allowed a significant (P <0.05) improvement of the drug anaesthetic effect in terms ofintensity and duration of action [68].

9.2. Microemulsions. Microemulsions have penetration-enhancing properties. Local anaesthetics encapsulated inmicroemulsions result in fast transdermal penetration andeffect [39, 69]. Microemulsions contain a large amount ofsurfactants and cosurfactants that have the potential to causehaemolysis or histopathological changes [69].

Microsphere

Liposome

Figure 8: Microspheres (or nanospheres) within liposome.

9.3. Poly(lactic-co-glycolic acid) Microspheres and Nano-spheres. The most commonly used micro- and nanoscalevehicles for drug encapsulation and delivery are micro-spheres and nanospheres. They are usually prepared frombiodegradable synthetic hydrophobic materials such ashomo- or copolymers of polylactic and polyglycolic acids[70].

Microparticles are perfect for drug delivery as theyremain at the depot site for long periods allowing slowprolonged release of the encapsulated drug [3]. Particle sizeand the thickness of thin, free films are factors in drugrelease. The lipospheres are stable structures consisting ofa solid hydrophobic fat core such as triglycerides or fattyacid derivatives, estabilised by a monolayer of phospholipids(Figure 8) [3].

More recently, a nanoliposphere has been developedthat does not gelify and is suitable for injection [3, 71].When poly(dL-lactic acid) microspheres were embeddedinto poloxamer 407-based hydrogel, this microsphere-gelsystem containing lignocaine was easy to inject. In addition,it proved degradable [3]. Clinically, in human intercostalblockade studies, dexamethasone added to microcapsulescontaining bupivacaine showed longer duration of anaesthe-sia affect compared with microcapsules without dexametha-sone [3].

9.4. Hyaluronic Acid-Based Hydrogels. Hyaluronic acid is anonimmunogenic naturally occurring mucopolysaccharideused as a viscous carrier solution to prolong LA action [3].However, addition of cross-linked hyaluronic acid doubledthe length of action of bupivacaine compared with thenoncross-linked hyaluronic acid. It is in an easily injectableliquid form.

9.5. Calcium Phosphate Apatite Loaded with Bupivacaine.Synthetic calcium-deficient apatites are structurally similarto biological apatites; they are chemical precursors of bipha-sic calcium phosphates. Biphasic calcium phosphates aremixtures of hydroxyapatite and beta-tricalcium phosphateand are widely used as bone substitutes in human surgery[72]. In Wistar male rats, bupivacaine has been loaded


on to calcium-deficient apatites using isostatic compaction[72]. This was able to release local anaesthetic in a mannerthat prevented or limited postoperative pain following bonesurgery [72].

9.6. Controlled-Release Local Anaesthetic Matrix. As previ-ously mentioned, the absorbable, controlled-release, localanaesthetic delivery system containing 16% (w/w) ligno-caine (Xybrex) is capable of providing up to several daysof reversible rat sciatic nerve block in a dose- (mass-)dependent fashion [73]. Two sets of lignocaine-containingdrug delivery matrices (OSB-L and OST-R) have been usedin subfascial sciatic nerve blocks in rats as well. The OSB-L formulations consisted of four different concentrationsof lignocaine ranging from 1.875% to 15% (w/w). Theseare denoted as OSB-1.875L, OSB-3.75L, OSB-7.5L, andOSB- 15L [73]. The OST-R formulations consisted of fourdifferent concentrations of the drug release rate modifier,ranging from 5% to 20% (w/w) in 5% increments, withlignocaine concentration kept constant at 16% (w/w). Theseformulations are denoted OST-5R, OST-10R, OST-15R, andOST-20R [73]. All OSB-L formulations produced completeand reversible, dose-dependent blockade of nociceptive andmotor functions [73]. Blockade by OST-R formulationsvaried with the concentration of the release rate modifier.All formulations gave complete, reversible blocks of bothfunctions; importantly, their durations did not changemonotonically with increasing concentrations of the releaserate modifier [73]. Implants of slow-release lignocaineformulations are most effective against postincisional painwhen placed at the ipsilateral nerve innervating the areaof incision [74]. No human studies of its use have beenpublished as yet.

9.7. Injectable Liquid Polymers. There are three types of poly-mers for encapsulation, namely, nondegradable polymers,synthetic polymers, natural biodegradables (that degradeto nontoxic products that are completely eliminated fromthe body), and drug-conjugated polymers (where a drug isattached to water-soluble polymer by a cleavable bond) [3].The drug-polymer conjugate can be directly targeted to thesite of specific action. The use of a 15% bupivacaine lacticacid-co-castor oil copolymer prolonged the in vivo effect to96-hour sensory block [75].

Injectable polymers are simple and reliable to prepare;simple mixing combines the local anaesthetic. The maindisadvantage is the prolonged time these polymer carriersdwell in the injection site, far beyond the time of the effectof the local anaesthetic agent [3]. The safety and tissuecompatibility of biodegradable pasty polymers have beentested and found to be safe with no systemic tissue damageor polymer-related lesions [3, 76].

9.8. Films. One of the key areas of intense research is there-fore to achieve an optimal and desirable controlled and sus-tained drug release from the use of biodegradable films. Thebuccal route has some unique compelling benefits making itworth trying; such benefits include avoiding first pass effect,

easy accessibility, and better patient compliance. Adhesion ofbuccal adhesive drug delivery devices to mucosal membranesleads to an increased drug concentration gradient at theabsorption site and therefore improved bioavailability of sys-temically delivered drugs [77]. Various bioadhesive mucosaldosage forms have been developed as films. An ideal buccalfilm should be flexible, elastic, and soft, with accepted sizeand thickness, yet adequately strong to withstand breakagedue to stress from mouth activities. It must also possessgood bioadhesive strength so that it can be retained in themouth for a desired duration [78]. It should be nonirritant,not cause teeth discoloration, resistant to metabolism, andbe capable of releasing a drug at appropriate rate. Buccalfilms were developed using carbopol 971P as a mucoadhesivepolymer and glycerol as a plasticizer. In testing, a buccalmucoadhesive film using lignocaine and its hydrochloridesalt as a model drug found that drug concentration affectedthe mucoadhesive properties of the films [79].

A slow-release lignocaine sheet has been produced andhas been used for sciatic nerve block in the rat modelof postoperative pain. Single treatment of this controlled-release lignocaine inhibited hyperalgesia and c-fos expressionin the spinal cord dorsal horn for one week without inducinginflammation of the sciatic nerve [80]. Bioadhesive filmscontaining benzocaine have been tested in the rat model forbenzocaine local delivery [81]. Tail-flick tests have shown theduration of benzocaine-induced analgesia to be significantlyprolonged with the films compared to commercial creams[81].

10. Conclusion

Local anaesthetics are widely used to manage acute, chronic,and cancer pain, for anaesthesia, and for diagnostic purposes.Local anaesthetics may have similar chemical structures,but differing pharmacokinetic properties and spectra ofpharmacodynamic effects. This influences the selection ofagents for use in various clinical situations [82]. Newinnovations pertaining to LA formulations lead to prolongedaction or to novel delivery approaches. Decades after theintroduction of local anaesthetics for analgesia/anaesthesia,new properties may still be discovered. New applications ofthis class of drugs may still be anticipated. The use of regionalanaesthesia may affect cancer recurrence rates followingsurgical resection of tumours via immunomodulation [79].The preservation of the body’s immune processes by localanaesthetics needs to be further studied.The development ofnew effective delivery systems should suitably modulate therelease rate of these drugs, extend their anaesthetic effect,and enhance their localisation; this should reduce problemsof systemic toxicity. Part 2 of this paper will deal with newtechniques for the delivery of topical and injectable localanaesthetics.

Disclosure

No benefits in any form have been or will be received from acommercial party related directly or indirectly to the subjectof this paper.


Conflict of Interests

The author declares that there is no conflict of interests.

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Review Article

New Delivery Systems for Local Anaesthetics—Part 2

Edward A. Shipton

Department of Anaesthesia, University of Otago, Christchurch 8042, New Zealand

Correspondence should be addressed to Edward A. Shipton, [email protected]

Received 28 September 2011; Accepted 28 September 2011


Copyright © 2012 Edward A. Shipton. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Part 2 of this paper deals with the techniques for drug delivery of topical and injectable local anaesthetics. The various routesof local anaesthetic delivery (epidural, peripheral, wound catheters, intra-nasal, intra-vesical, intra-articular, intra-osseous) areexplored. To enhance transdermal local anaesthetic permeation, additional methods to the use of an eutectic mixture of localanaesthetics and the use of controlled heat can be used. These methods include iontophoresis, electroporation, sonophoresis, andmagnetophoresis. The potential clinical uses of topical local anaesthetics are elucidated. Iontophoresis, the active transportationof a drug into the skin using a constant low-voltage direct current is discussed. It is desirable to prolong local anaesthetic blockadeby extending its sensory component only. The optimal release and safety of the encapsulated local anaesthetic agents still need tobe determined. The use of different delivery systems should provide the clinician with both an extended range and choice in thedegree of prolongation of action of each agent.

1. Introduction

A drug delivery system should have minimal tissue reaction,a reliable drug release profile, and well-defined degradationrate for biodegradable carrier until all nontoxic products areexcreted [1]. For local anaesthetics (LAs), the development ofnew effective delivery systems intends to suitably modulatethe release rate of these drugs, extend their anaesthetic effect,and enhance their localisation; this reduces problems of sys-temic toxicity. Part 2 of this paper deals with the innovationspertaining to formulations, and techniques for drug deliveryof topical and injectable local anaesthetics.

2. Routes of Local Anaesthetic Delivery

2.1. Epidural. Patient controlled epidural analgesia (PCEA)allows patients to self-administer drug doses according totheir analgesic needs. This route relies on a staff-program-med pump and skilled and qualified members of the hospitalstaff for administration. Both local anaesthetics and opioidsare agents for epidural analgesia. The use of epidural lo-cal anaesthetics is associated with a higher incidence ofhypotension, motor block, and urinary retention, comparedwith use of opioids [2]. However, in a recent meta-analysis,only a continuous infusion of epidural local anaesthetics was

superior to intravenous opioids in improving pain controland reducing adverse effects [3].

2.2. Peripheral. Patient-controlled regional analgesia (PCRA)encompasses a variety of techniques that provide effectivepostoperative pain relief without systemic exposure toopioids. Using PCRA, patients initiate the delivery of smalldoses of local anaesthetics (ropivacaine, bupivacaine) via anindwelling catheter that can be placed in different regions ofthe body depending upon the type of surgery. In some cases,a combination of local anaesthetic and opioid is adminis-tered. Infusions are controlled either by a staff-programmedelectronic pump (Figure 1) or by a disposable elastomericpump [3]. An elastomeric pump is a device that has a dis-tensible bulb inside a protective bulb with a built-in fillingport, delivery tube, and an antibacterial filter. Antibacterialfilters are recommended with blocks involving a nerve plexus(and in neuraxial blocks). Analgesia can be delivered directlyinto a surgical incision (incisional PCRA), the intra-articulartissue (IA PCRA), or the perineural site (perineural PCRA)(Figure 2) [2].

2.3. Wound Catheters. The insertion of wound catheters al-lows for continuous infusions of local anaesthetics into thesurgical wound at the end of the procedure (Figure 3).


Figure 1: Pharmacia Deltec CADD Ambulatory Infusion Pump.

Figure 2: Patient-controlled perineural analgesia via infraclavicularbrachial plexus catheter.

Continuous wound catheters can confer several benefits, in-cluding improved analgesia, reduced opioid use and adverseeffects, increased patient satisfaction, and reduced hospitalstay [4].

The use of continuous wound catheters consistently re-duces the need for opioids (both rescue and total dose). Pa-tients have consistently rated postoperative nausea and vom-iting (PONV) as a primary concern after surgery [5, 6]. Thereduced need for opioids (though an infrequently measuredresult in Randomised Controlled Trials) might contribute toincreased patient satisfaction [4]. Reduced length of hospitalstay has been associated with continuous wound catheters,especially in the cardiothoracic and orthopaedic surgerysubgroups [4]. Meta-analysis suggested the potential savingof one day of hospital stay [4]. Incidences of technical failureand local anaesthetic toxicity from wound catheters are low.Several reports have raised potential concern about woundinfections from the presence of a catheter [7]. However, re-ported wound infection rates were found to be similarbetween active (0.7%) and control groups (1.2%) [4].

2.4. Intranasal Route. The nasal mucosa acts as an anatom-ical obstacle hard to get over, except for compounds with

Figure 3: Elastomeric pump for a wound catheter.

low molecular weight or highly lipophilic compounds. Forthe manipulation of nasal fractures, lignocaine and cocainehave been used in topical local anaesthesia in the form ofa spray, paste, or on cotton wool and pledgets; this appearsto be a safe and effective alternative to general anaesthesia.A systematic review has found no significant differencesbetween local anaesthesia and general anaesthesia as regardspain, cosmesis or nasal patency after nasal fracture manipula-tion performed under topical local anaesthesia [8]. A recentCochrane review showed that nasopharyngeal topical localanaesthetic or vasoconstrictor preparations prior to the useof a fibre-optic nasal endoscope did not demonstrate anyadvantages in using a topical treatment prior to endoscopy[9]. In contrast, the very lipophilic opioids, such as fentanylare rapidly absorbed via intranasal administration (with abioavailability close to 90% for fentanyl) and are used for thetreatment of breakthrough pain [10].

2.5. Intravesical (Bladder) Route. The transport of local an-aesthetics through the urothelium into deeper layers of thebladder has been significantly enhanced by electromotivedrug administration (Figure 4) [11]. It is a cost-effective wayto deliver lignocaine with greatly improved penetration rateinto the bladder wall [12]. Vehicles such as electromotivedrug administration, new in situ delivery systems, and bioad-hesive liposomes make it possible to extend intravesical ther-apy and drug administration to many bladder diseases [11].

2.6. Intra-Articular (IA) Route. For microspheres destinedfor intra-articular delivery, the following properties havebeen identified as important, namely, size (within the rangeof 4-5 μm in diameter), resistance to in vivo degradation,minimal leakage of drug, and biocompatibility [13]. Pro-longing the intra-articular drug residence time of LAs may bemet by formulating microspheres that have been rationallydesigned to optimise uptake by the synovium [13]. However,the causes of 23 cases of postarthroscopic glenohumeralchondrolysis were recently analysed. Several common factorswere found, but no single mechanism was shown. Multiple


Adventitia

Lamina propria

The structure of bladder wall

Urothelium

Glycosaminoglycanlayer bound to water

Uroplakin-coveredumbrella cells

Detrusor muscle

Figure 4: The structure of the urinary bladder wall and urothelium.

factors seemed to be implicated. The use of intra-articularlocal anaesthetics is probably not advisable until the role oflocal anaesthetics in this regard has been clarified, as chon-drolysis has been the subject of many lawsuits [14].

2.7. Intra-Osseous Route. Computer-controlled local anaes-thetic delivery devices (C-CLAD) and systems for intra-osseous injection are important additions to the dental an-aesthesia armamentarium [15]. C-CLAD using slow infu-sion rates can significantly reduce the discomfort of localanaesthetic infusions, especially in palatal tissues; C-CLADfacilitates palatal approaches to pulpal nerve block. It shouldfind special use in cosmetic dentistry, periodontal therapy,and paediatric dentistry [15].

3. Transdermal Route of Local AnaestheticDrug Delivery

Transdermal drug delivery is one of the most patient-compli-ant routes of drug administration. However, the stratumcorneum, the outer most layer of the skin resists the penetra-tion of drugs across the skin (Figure 5). Hydrophilic, ionised,and macromolecular substances are poorly permeable acrossthe skin [16]. To enhance drug permeation in a passivemanner, transdermal drugs should be lipophilic and shouldideally have a molecular weight less than 500 Daltons [17].Alternatively, energy-dependent active measures can be usedto enhance drug delivery across the skin. These includephysical permeabilisation of skin or by driving the drugmolecule across the skin. In addition to the use of an eutecticmixture of local anaesthetics, and the use of controlled heat,other methods such as iontophoresis, electroporation, sono-phoresis, and magnetophoresis can be used [16].

3.1. Magnetophoresis. Magnetophoresis is a method of en-hancement of drug permeation across the biological barriersby the application of a magnetic field (Figure 6). The pre-dominant mechanism responsible for magnetically mediateddrug permeation enhancement is known as “magnetokine-sis” [17]. The octanol/water partition coefficient of drugs

increases when exposed to the magnetic field [17]. Magne-tophoretic patch systems deliver drugs at a higher rate thannonmagnetic patch systems. In the rat model, the dermalbioavailability (Area Under the Curve 0–6 hours) from themagnetophoretic patch system was significantly higher com-pared to a non-magnetic control patch [17].

3.2. Sonophoresis/Phonophoresis. The use of ultrasound forthe delivery of drugs to, or through, the skin is commonlyknown as sonophoresis or phonophoresis (Figure 7). Thefrequency of the ultrasound wave corresponds to the numberof times that the transducer tip is displaced per secondof application time. High-frequency sonophoresis includesfrequencies in the range of 0.7–16 MHz (most commonly 1–3 MHz) [18]. Low-frequency sonophoresis includes frequen-cies in the range of 20–100 kHz and allows transdermal deliv-ery of both hydrophilic and high-molecular mass permeantsat therapeutic levels [19].

The main contributor responsible for skin permeabilityenhancement by sonophoresis is acoustic cavitation. Thiscauses the formation of acoustic microjets on the surface ofthe skin in a nonuniform manner [19]. When surfactant isincluded in the treatment of skin with low-frequency sono-phoresis, a strong synergistic enhancement in skin permea-bility occurs, allowing delivery of hydrophilic permeants. Ad-ditionally, low-frequency sonophoresis-mediated transder-mal delivery can be used to deliver macromolecules, includ-ing liposomes and nanoparticles [19]. This technology is cur-rently approved for use by the Federal Drug Administration(FDA) for local anaesthetics. In volunteers, a transducer hasbeen used to administer an anaesthetic drug transdermally.When 0.5 MHz ultrasound in phonophoresis used for con-duction anaesthesia with lignocaine hydrochloride, it wasfound to be more effective than the 1 MHz widely used inclinical situations (Figure 7) [20].

3.3. Microporation Technologies. Skin microporation may beconsidered a minimally invasive technology that can bebroadly divided into microneedle technology, thermal mi-croporation, and laser ablation [21]. To improve the rate andextent of transdermal lignocaine across porcine ear skin, theapplication of novel laser microporation technology (Pain-less Laser Epidermal System) has been used to create well-defined conduits in the skin [22].

3.4. Electroporation. Electroporation is the application ofshort high voltage pulses that result in formation of transientaqueous pathways for diffusion of molecules across the skin[16]. In case of electroporation, the electrical pulses are ap-plied only for fraction of a second; the interval between sub-sequent pulses allows the skin to depolarise [16]. Therefore,polarisation of skin does not interfere with the current flowor drug diffusion. In the porcine epidermis, the transport oflignocaine hydrochloride in case of low voltage electropulsa-tion was found to be 8-fold more than the control [16]. Theamount of lignocaine hydrochloride present in the epidermiswas found to be 2-fold higher as well.


Paracellular route

Transcellular route

Transappendageal route

Epidermis

Hair shaft

Dermis

Subcutaneous fat

Sweat duct

Fat globules

Blood vessels

Figure 5: Transdermal routes of absorption of local anaesthetics.

Figure 6: Magnetophoresis.

Electrokinesis (electrophoresis and or electro-osmosis)and permeabilisation of membranes are responsible for en-hanced transdermal drug transport by low voltage electro-poration. The total duration of electrical current applicationduring 20 minutes of low voltage electroporation is only oneminute. Low voltage electroporation enhances drug perme-ation relatively more efficiently than constant direct currentiontophoresis [16].

3.5. Eutectic Patches. A new topical local anaesthetic eutecticpatch consisting of a mixture of lignocaine 70 mg and tetra-caine 70 mg (Synera in the United States, Rapydan in Europe)has been developed [23]. This patch has an integrated heat-ing element intended to enhance the flux of the tetracaineand lignocaine leading to more rapid and effective deliveryof the local anaesthetics to the target area. The patch startsheating once removed from the pouch and exposed to at-mospheric oxygen; it may increase skin temperature by upto 5◦C [23].

To study the use of lignocaine/tetracaine-medicated plas-ters in patients undergoing minor dermatological or vascularaccess procedures, patients were randomised in a double-blind clinical trial [24]. Patient-reported median pain scoreswith the use of lignocaine/tetracaine-medicated plasters were

Sonophoresis

Returnelectrode

Figure 7: Sonophoresis—an ultrasonic skin permeation device.

found to be significantly lower than those with an identicalplaster-containing placebo [24].

3.6. Clinical. With the use of topical local anaesthetics fordermal laceration repair, a meta-analysis reviewed 22 trialswith more than 3000 randomised patients; it concluded thattopical tetracaine, bupivacaine, and lignocaine had an equiv-alent or superior analgesic efficacy to the intradermal infil-tration of cocaine-containing anaesthetics. The topical prep-arations proved less expensive and were safer [23, 25]. Inanother recent meta-analysis of 25 trials with more than 2000subjects, three topical anaesthetics, (tetracaine, liposome-encapsulated tetracaine, and liposome-encapsulated ligno-caine) were found to be equally efficacious [26]. Tetracainehad the added advantage of a longer duration and was re-ported not to cause methemoglobinemia [27]. Another studyhas demonstrated that the lignocaine/tetracaine patch pro-vided better local anaesthesia than the control at all applica-tion times under 60 minutes [28].

Potential uses of topical anaesthetics include the follow-ing: for gaining pain-free vascular access; for skin or punch


Donor compartmentand anode

Controller andcurrent source

Receptor compartmentand cathode

Stratum Corneum

Epidermis

Dermis

Blood vessel

+ −

A+ C− B+ C−

B+

B+C−

C−

A+ cationic drug: B+ biological cations, C− biological anions

Figure 8: Iontophoresis. Components of an anodal iontophoreticdevice are a current source; a current control device; anode (donor)reservoir system (with a positively charged drug/ion in solution);cathode reservoir system (on a different skin site). With an electriccurrent, all cations move away from the anode and into the skin, andnegatively charged ions move from the body into donor reservoir.

biopsies; for bone marrow aspiration; for treatment of pos-therpetic neuralgia; for immunisation; for myofascial paindue to trigger points; for nerve entrapment such as carpaltunnel syndrome; for regional block placement; and fordermal procedures requiring laser treatment.

4. Iontophoresis

Iontophoresis involves the active transportation of a druginto the skin using a constant low-voltage direct current.Ions migrate between electrodes of opposite charges, pro-moting ion transport through the skin (Figure 8) [29]. Adirect electrical current facilitates the dermal penetration ofpositively charged lignocaine molecules when placed undera positive electrode for local anaesthesia. Physicochemicalproperties, such as good aqueous solubility, and the presenceof charged groups that render peptides and proteins “difficultto deliver” by other approaches, are ideal for iontophoresis[30] The amount of drug delivered via iontophoresis is de-pendent on the current and the duration of delivery. Thecontrol afforded by constant current iontophoresis overtransport rates means that peptide/protein delivery kineticscould mimic endogenous secretion profiles [30]. Moreover,complex input kinetics can be used to optimise and individ-ualise therapy.

Iontophoresis has been known to cause skin irritation athigher current densities or upon longer application [16, 31,32]. Moreover, when direct current electric field is appliedover longer durations, an electrochemical polarisation occursin the skin which decreases the magnitude of current flowthrough the skin [16]. This in turn could affect the amountof drug ions driven across the skin.

Small, portable iontophoresis devices have been devel-oped. Dermal anaesthesia can be achieved fairly rapidly usinglignocaine iontophoresis without needles [29]. Adrenalineadded to the lignocaine solution enhances the effect and

duration of local anaesthesia during iontophoresis; this is dueto the local vasoconstriction inhibiting lignocaine absorptioninto the systemic circulation.

Delivery can be hastened by using ultrasound. In a Ran-domised Controlled Trial, ultrasound pretreatment plus two-minute low-voltage iontophoresis provided better skin an-aesthesia than sham-ultrasound plus two-minute low-volt-age iontophoresis, and similar to standard, 10-minute high-voltage iontophoresis [33]. Lignocaine HCl 10%/Adrenaline0.1% topical iontophoretic patch (LidoSite) is the first FDA-approved prefilled active anaesthetic patch. In volunteers, itwas found that 2% lidocaine could be delivered up to 5 mmbelow the surface of the skin when the drug compoundcontained adrenaline, and when passive delivery occurred forat least 50 minutes after the active delivery has terminated[34].

5. Future

It is desirable to acquire the ability to prolong local anaes-thetic blockade and, if possible, extend only its sensory com-ponent. This paper portrayed the innovative techniques forthe drug delivery of topical and injectable local anaesthetics.However, the optimal release and safety of the encapsulatedLA agents still need to be determined. Using encapsulationto avoid systemic toxicity, the nonconventional local anaes-thetics (tetrodotoxin, saxitoxin) show promising efficacy [1].Recently, lignocaine-coated microneedles have been devel-oped for rapid, safe, and prolonged local analgesic action[35]. These delivery systems should provide the clinicianwith both an extended range and a choice in the degree ofprolongation of action of each agent [36].

Disclosure

No funds were received in support of this work. No benefitsin any form have been or will be received from a commercialparty related directly or indirectly to the subject of this man-uscript. There is no conflict of interests.

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Local Anesthesia - Hindawi Publishing Corporationdownloads.hindawi.com/journals/focusissues/984893.pdfEditorialBoard Peter Andrews, UK Neal H. Badner, Canada Enrico M. Camporesi, USA