Local Anesthetics: a Century of Progress John A

BRIEF REVIEW

Local Anesthetics: A Century of Progress John A. Yagiela, D.D.S., Ph.D. Section of Oral Biology, UCLA School of Dentistry, Los Angeles, California

Summary One century after the clinical introduction of cocaine, local anesthesia remains the most important method of pain control in dentistry. Many local anesthetics have been marketed since 1884, and it is likely that attempts to produce drugs that enhance anesthetic efficacy, reduce systemic and local toxicity, and increase nociceptive selectivity, will continue. In addition, new methods of drug administration have been and will be developed to achieve these goals. Of fundamental importance to such improvements are investigations into the pharmacology of drugs with local anesthetic activity and anatomical and physiologic studies pertaining to the reasons why local anesthetics sometimes fail to achieve desired results. This paper reviews recent advances in our understanding of these drugs and their clinical use.

Introduction Mechanism of Action This issue of Anesthesia Progress marks the 1 00th The mechanism by which local anesthetics inhibit anniversary of the clinical introduction of cocaine by nerve conduction has proved elusive to investiga- Koller and its subsequent application to nerve block tors. It is firmly established that drugs such as lido- in dentistry by Halsted. Since then, there have been caine and procaine block propagation of the action a number of notable advances, including the addi- potential by interfering with the increase in sodium tion of epinephrine for enhanced anesthesia and conductance normally caused by depolarization of reduced systemic toxicity, the discovery of procaine the axolemma. This effect on membrane permeabil- as a nonaddicting alternative to cocaine, and the ity is rather specific; for example, potassium conduc- synthesis of lidocaine, an amide with improved tance is much less affected by these agents. What anesthetic efficacy and reduced allergenicity. These remains controversial, however, is the manner in achievements have been accompanied by similar which sodium conductance is depressed. progress in administration techniques and equip- For many years it was believed that local anesthet- ment (Table 1). Many of these advances were ics provided pain relief by interfering with a normal prompted by recognized deficiencies of existing regulatory function of calcium ions on sodium con- drugs and methodologies and were made possible ductance.4-6 According to this hypothesis, calcium by fundamental investigations of anatomy, physiol- ions bound to phospholipid molecules on the exteri- ogy, and pharmacology. It is likely that future ad- or side of the neuronal membrane prevented sodi- vances will depend even more heavily on informa- um ions from entering the cell. Nerve depolarization, tion gained from the study of nerve conduction, however, would cause the release of calcium and per- inflammation, and pain mechanisms. mit the explosive, if transient, influx of sodium. Local This paper reviews selectively the pharmacology anesthetics were thought to compete with calcium for and therapeutic use of local anesthetics in dentis- its binding sites; however, the drug molecules would try. Particular attention will be placed on recent in- remain bound during membrane depolarization and formation and on possible future developments; the prevent the sodium-dependent action potential from reader is referred to any of several excellent sources propagating. Several lines of evidence now indicate for a more general survey of local anesthesia.'-3 that this chain of events does not accurately portray the basis of local anesthesia. For example, Narahashi and Frazier7 conclusively showed that local anesthetics work from the inside surface of the nerve mem- Accepted for publication December 28, 1984. Address reprint requests to Dr. John Yagiela, UCLA School brane, and various investigators89 have found that of Dentistry, Center for the Health Sciences, Los Angeles, CA direct competition for binding sites does not occur be- 90024. tween calcium and all local anesthetics (e.g., non-

MARCH/APRIL 1985 47 TABLE 1. Historical Landmarks in Local Anesthesia ionized forms) nor does it seem to be directly involved in local anesthetic block. Although the correspon- Date Event dence between anesthetic potency and calcium dis- 1859 Isolation of cocaine in pure form by Niemann placement from cell membranes remains of in- 1884 Clinical introduction of cocaine Koller terest,10 it is likely that both variables are independent by measures of the ability of anesthetic molecules to 1884 Halsted performs first inferior alveolar nerve block penetrate hydrophobic regions of the nerve 1901 Epinephrine used by Braun as a "chemical membrane. tourniquet" Modern theories of local anesthesia can be divid- 1904 Synthesis of procaine by Einhorn ed into two categories according to the postulated site 1920 Anesthetic cartridge and syringe marketed by Cook of action: membrane lipids or the sodium channel. 1928 Tetracaine synthesized by Eisleb The "lateral phase separation" theory of Trudell'1 is 1943 a prominent example of the former group. The term Lidocaine synthesized by Lofgren "lateral phase separation" refers to the situation 1947 Bjorn and Huldt introduce lidocaine into clinical where highly ordered membrane lipids (gel phase) dentistry coexist with areas of disordered lipids (sol phase). 1947 Novocol Company markets first dental aspirating This arrangement permits easy lateral compression syringe of the membrane through conversion of part of the 1956 Synthesis of mepivacaine by Ekenstam fluid sol phase to the more dense, more compact gel 1957 Synthesis of bupivacaine by Ekenstam organization, a reconfiguration that can then accom- 1957 Cook-Waite Laboratories introduces harpoon modate conformational changes in protein necessary aspirating syringe for opening of the sodium channel (Fig. 1). Local 1959 Prilocaine synthesized by L6fgren anesthetics inhibit sodium conductance according to 1959 Disposable sterile needles this therory by so disordering the membrane lipid marketed bilayer that the sol-to-gel transition cannot occur, and 1971 Etidocaine synthesized by Takman conformational shifts of the sodium channel are 1976 High-pressure syringe developed for intraligamentary precluded. This mechanism of action readily ac- anesthesia counts for the close relationship between anesthet- 1983 Bupivacaine marketed in cartridge form ic potency and lipid solubility; it also provides for the

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SAl la 2a 1- " .

Fig.1-Postulated mechanisms of action of local anesthetics. (1) Resting sodium channel. M = activation gate; H = inactivation gate. (2) Open channel permitting the influx of sodium ions. Lateral compression of the membrane permits translocation of the M gate. (3) Inactivated channel. Closure of the H gate precludes sodium entry, and the channel is refractory to further stimulation. (la) Insertion of a local anesthetic disorders the membrane such that opening of the M gate is prevented. (2a) Cationic local anesthetic crosses the open sodium channel to reach its receptor and prevent sodium influx. Neutral anesthetic molecules (not shown) may also bind but do not require the channel to be open for effective diffusion. (3a) Local anesthetic binding is enhanced when the channel is inactivated, and conversion of the channel to the resting state is impeded. Two separate sites of action are depict- ed. Binding to the receptor on the channel exterior impedes sodium entry by an allosteric mechanism (not illustrated).

48 ANESTHESIA PROGRESS structural diversity of the many unrelated compounds receptor sites has been obtained by Huang and that share in the ability to reversibly depress nerve Ehrenstein,19 who measured local anesthetic binding conduction. Until recently, it was thought that a major to batrachotoxin-activated sodium channels. It may limitation of the theory was that it could not explain be that the future will witness a fusion of current lipid the anesthesia caused by permanently charged and channel receptor theories as more specific infor- hydrophilic molecules, such as some experimental mation is obtained about lipid-protein rplationships analogues of lidocaine. Several studies have recently and their interactions with local anesthetic molecules. shown, however, that even charged anesthetics can interact with lipid bilayers at one or more sites12 and Pharmacology that this interaction may be selective for the inner half Local anesthetics can depress conduction in all ex- of the plasma membrane.13 citable tissues: peripheral nerves, neurons in the The theory that best explains the neurophysiology brain and spinal cord, and cardiac, skeletal, and of conduction block holds that the sodium channel it- mooth muscle. Dosage restrictions and accurate self is the site of action.14 Figure 1 outlines the nor- placement of anesthetic solutions adjacent to the tar- mal cycling of a sodium channel and how a local get nerves, but not some specific property of the anesthetic could potentially disrupt its function. drugs themselves, yield selective regional anesthe- Usually, most sodium channels of a nerve membrane sia. Systemic reactions, usually attributed to the are in the resting state (1). An appropriate stimulus central nervous system and less frequently to the causes the channel (specifically its M gate) to open cardiovascular system, occur when plasma concen- transiently and permit sodium (Na +) to flow inward trations increase beyond safe limits (e.g., 5 ug/ml for down its electrochemical gradient (2). Shortly there- lidocaine). Thus, the processes of absorption, distri- after, a time-dependent barrier to sodium movement bution, and elimination of local anesthetics play vital (the H gate) arises, and the channel is said to be roles in the avoidance of systemic toxicity, along with refractory, inactivated, or, simply, closed (3). Repolar- proper drug and dosage selection and administration ization of the membrane then causes conversion of technique. Drug interactions that affect these the closed channel back to the resting form. Cation- processes may also be important clinically. These is- ic local anesthetics can reach their site of action only sues are broadly discussed elsewhere'-3 and need when the channel is open (2a); hence, the rate of on- not be reviewed here; instead, consideration will be set and the degree of block are highly dependent on limited to those areas that have been the object of re- nervous activity.15 Nonionized anesthetic molecules cent interest and study. may also bind to the channel, but they are not as dependent on the functional state of the channel, hav- Distribution: Influence of Lung and ing the ability to cross hydrophobic barriers to reach Plasma Protein their site of action. All local anesthetics, however, In dentistry, the amounts of local anesthetic nor- show some increase in anesthetic efficacy when neu- mally injected fall well within recommended dosage rons are repeatedly stimulated.16 This phenomenon, limits, and true systemic toxic reactions (other than variously called use-dependent or frequency- in small children) are most likely the result of acciden- dependent conduction block, transition block, or tal intravascular injections. Depositing the drug Wedensky inhibition, arises because local anesthet- directly into the blood stream obviously bypasses ab- ics bind more avidly to the inactivated channel, which sorption, and the brain may then be exposed to very in turn retards conversion of the channel back to the high, if short-lived, concentrations of drug. Studies resting state. Because local anesthetics differ wide- proving that intravascular placement of the needle is ly in their use dependency and because nerve fibers a common occurrence have led at least one dentist characteristically transmit signals at different fre- to voice dire warnings of mortality with routine local quencies, important clinical dissimilarities may arise anesthesia.20 It may be the recently discovered between otherwise similar drugs. For instance, "buffering capacity" of the lung that minimizes such bupivacaine and etidocaine are equipotent ex- concerns. perimentally in preventing the transmission of single Because of its role in the pulmonary circulation, the nervous impulses, but bupivacaine with its much lung is the most highly perfused organ of the body. greater use dependency is significantly more active Local anesthetics injected intravenously reach the clinically in blocking pain signals, which are encod- lung before gaining access to the systemic circula- ed in rapid bursts or trains of impulses.17 tion. A study of human volunteers demonstrated that Recent studies indicate that the binding of the neu- more than 900/o of a bolus injection of lidocaine was tral and ionized forms of local anesthetics occurs, at initially taken up by lung tissue.21 This bound drug least in part, at different sites on the channel (3a). was then released into the blood stream over the next Mrose and Ritchie18 found that benzocaine (non- 30 sec. The net effect of lung uptake was to reduce ionized) and lidocaine (mostly ionized) exhibited the maximal arterial concentration from a calculated supra-additive anesthesia when administered high of 34,g/ml (were the lungs not present) to an ac- together, a result that should not occur if both drugs tual value of 10 ,ug/ml. This finding does not obviate were acting identically. Direct evidence for separate the need for slow injection, however. Two out of the

MARCH/APRIL 1985 49 11 patients studied had an abbreviated dampening heart failure and reduced hepatic blood flow are the effect of the lung on the arterial concentration; iso- most likely to experience lidocaine toxicity from in- lated case reports of cardiopulmonary arrest after bo- adequate drug metabolism.25 lus injections of lidocaine indicate that early lung up- Recently, two commonly used groups of drugs- take may not always occur.22 f3-adrenergic receptor blockers (e.g., propranolol) and Plasma protein binding provides a second distribu- H2-histamine receptor blockers (e.g., cimetidine)- tional buffer against local anesthetics entering the have been shown to interfere with lidocaine blood stream. Inasmuch as the free drug concentra- metabolism. Several mechanisms appear to be tion in the plasma serves as the driving force for diffu- responsible. Propranolol and related drugs decrease sion into the central nervous system, a reduction in splanchnic blood flow, and therefore lidocaine clear- that concentration by plasma protein binding should ance, by virtue of their negative inotropic effect on the lessen the danger of systemic toxicity. Only within the heart. In addition, propranolol apparently competes last few years has the binding of local anesthetics to with lidocaine for uptake by hepatocytes and for plasma proteins been elucidated. metabolism by microsomal enzymes.26 Cimetidine Alpha,-acid glycoprotein is now considered the decreases hepatic blood flow by constricting splanch- primary binding site for local anesthetics in the plas- nic blood vessels.27 It may also competitively inhibit ma. Albumin may provide a secondary, low-affinity lidocaine oxidation in the liver. Such influences by site. Factors that can depress binding, and thus in- themselves would significantly increase lidocaine crease the free fraction and systemic toxicity of a lo- retention, but there are additional effects on drug dis- cal anesthetic include anesthetic overdose, acidosis, tribution that contribute to the more than 50% in- and coadministration of some basic drugs (e.g., quini- creases in plasma lidocaine concentrations record- dine) but not others (e.g., procainamide).23 The plas- ed experimentally. These effects, involving inhibition ma concentration of a1-acid glycoprotein is labile; it of tissue binding and a fall in the volume of distribu- may increase 100% or more in patients with Crohn's tion, are especially noteworthy with cimetidine; in one disease or arthritis or in those who suffer traumatic study in which volunteers were given lidocaine infu- injury or myocardial infarction.24 This increase may sions of 1 mg/kg over a 10-min span, "totally unex- explain why bolus injections of lidocaine are gener- pected" symptoms of lidocaine overdosage were ally well tolerated by cardiac patients. recorded when the subjects were pretreated with the Local anesthetics vary in plasma protein binding cimetidine.28 There is no evidence at this time that in rough correlation with their anesthetic potency. these drug interactions are of relevance to dentistry; Thus, procaine is less than 10% bound, lidocaine however, the injection of multiple cartridges, as from 50 to 70%, and bupivacaine about 95%. Obvi- sometimes occurs in oral surgery, can lead to plas- ously, such factors as drug interactions and acidosis ma concentrations equivalent to those obtained in the are much more likely to significantly increase the free study just referred to. concentration of a drug that is heavily bound than one that is not. Toxicity: Dependence on Hypoxia and Injection Route Elimination: Effect of Drugs and Disease In dentistry, adverse systemic reactions to local It is general knowledge that ester anesthetics like anesthetics (but not to the process of injection) are procaine are hydrolyzed by pseudocholinesterase very uncommon. Almost always a special factor is in- found in the plasma, whereas amide drugs like lido- volved that sensitizes the individual in some way to caine are oxidized by microsomal enzymes in the the drug. One factor that is especially important and liver. It is also not uncommon to read admonishments the subject of current investigation is the influence of against using esters in patients with congenital pseu- hypoxia on anesthetic toxicity. Local anesthetics can docholinesterase deficiency and amides in patients cause hypoxia in two ways: drug-induced convulsions with liver disease, such as hepatitis or cirrhosis. For- may interfere with effective ventilation; medullary tunately, pseudocholinesterase deficiency is of rare depression may depress respiration centrally. Clear- concern in dentistry, since esters are used very infre- ly, antecedent hypoxia would add to the respiratory quently and this enzyme defect exists in only one in deficit, but there is also a more sinister interaction. 3000 individuals. Because of the inducibility of hepat- Hypoxia and the concomitant acidosis conspire to ic drug-metabolizing enzymes, even patients with dramatically alter the distribution of the local pronounced liver disease can usually metabolize anesthetic. The proportion of the cardiac output to the amide anesthetics sufficiently for the dosages con- brain increases under these conditions and, there- ventionally administered in the oral cavity. Indeed, the fore, more anesthetic is delivered to the central ner- major limiting factor in the biotransformation of vous system. As previously mentioned, acidosis im- amides appears to be the hepatic blood flow, or in pairs plasma protein binding, freeing more drug for other words, the rate at which the anesthetic is diffusion into the brain, where it is trapped in- presented to the liver. Ergo, patients with congestive traneuronally by the lowered cytoplasmic pH.

50 ANESTHESIA PROGRESS Together these effects on anesthetic distribution in- and few clinicians purchase it in quantity. Esters as crease anesthetic toxicity by three- to fivefold.29-30 In a class proved less effective for pulpal anesthesia addition, the cardiac toxicity of some local anesthet- than their amide counterparts and were more likely ics (i.e., bupivacaine and etidocaine) may be dis- to cause contact dermatitis in practitioners. There are proportionately enhanced,31 which may complicate only two situations in which esters may be preferred the management of a toxic overdose. over amides: in patients with a history of multiple al- Hypoxia in dentistry may occur as a consequence lergy to amide anesthetics but not to esters, and in of parenteral sedation techniques, especially when patients susceptible to malignant hyperthermia. Even large doses of opioid analgesics are adminstered. A so, their use in these situations is not clearcut. Most review of life-threatening reactions after pedodontic patients with a history of allergy to amide local sedation by Goodson and Moore illustrates the anesthetics are not truly allergic but may have danger of combining drugs with respiratory depres- suffered an adverse response for some other reason sant properties and excessive amounts of local (e.g., anxiety). Well documented cases of allergy to anesthetics.32 more than one amide are rare. In similar fashion, evi- A second factor that may lead to exaggerated lo- dence that it is hazardous to administer amides for cal anesthetic toxicity is the accidental intravascular regional anesthesia in patients with malignant hyper- administration of the drug. As previously indicated, thermia is scanty and almost entirely theoretical in na- the process of absorption is bypassed, and the brain ture. Indeed, many patients have been given nerve may be exposed to high concentrations of drug for a blocks with amide anesthetics for diagnostic muscle short period of time. Deposition into certain branches biopsies without incident (H. Rosenberg, personal of the vascular tree is particularly hazardous. For in- communication); the porcine model for malignant stance, clinical incidents have shown that as little as hyperthermia does not respond to even toxic 2.5 mg of bupivacaine (about 1/4 of the contents of a amounts of lidocaine.37 dental cartridge) injected into the vertebral artery can If amides are the preferred group of local anesthet- cause loss of consciousness and grand mal sei- ics, what is the amide of choice? Table 2 provides a zures.33 This event can occur during a stellate gan- comparison of the conventional amides currently glion block or perhaps during a trigger point injection available in the United States. These data were ob- for myofascial pain. tained from 12 studies in which infiltration (including To account for fatalities attributed to small amounts supraperiosteal injections) and nerve block anesthe- of local anesthetics administered intraorally, Aldrete sia (mainly inferior alveolar/lingual injections) were and colleagues34 have postulated that drugs inject- assessed separately and 20/o lidocaine with ed into a branch of the external carotid artery could 1:100,000 epinephrine was one of the drugs test- travel against the normal blood flow down to the in- ed.38-49 The lidocaine values listed in Table 2 ternal carotid artery and then directly to the brain. respresent the mean results from these studies; While there is evidence that this phenomenon can oc- values for the other drugs were adjusted to depict cur and that it may lead to convulsions,35 a compan- relative differences with respect to lidocaine, so that ion paper in this journal36 argues strongly against this all preparations could be compared against the same route as being unduly lethal. standard. Although variations in study design complicate matters, Table 2 accurately reflects the majori- ty of clinical trials involving these drugs. It is appar- Drug Selection ent that none of the anesthetic preparations stands The selection of a local anesthetic for dental use out with regard to anesthetic efficacy or onset time. is deceptively simple. Choose the preparation with (The slow onset of nerve block with 30/o mepivacaine the highest efficacy, the lowest toxicity, and the most is probably an exception to the aformentioned veraci- suitable duration of action for the contemplated ty of Table 2; it includes findings of one study that are procedure. All of these attributes are difficult to as- at variance with several clinical trials that could not sess, however, and may be unpredictable in a given be included there.50'51) Two variables, though, are patient. Nevertheless, only with a sound understand- significant: the presence of a vasoconstrictor in the ing of the drugs currently available and a careful formulation and the duration of action. evaluation of the patient's medical history and phys- ical status is it possible to select a local anesthetic on Vasoconstrictors a rational basis. Epinephrine and related drugs are often combined with local anesthetics to improve anesthetic efficacy, Esters Versus Amides to increase the duration of anesthesia, and to lessen One consideration in choosing a local anesthetic systemic toxicity. Nowhere are the benefits of for use is whether the drug is an ester or an amide. vasoconstrictor inclusion more evident than with the The marketplace has manifested the clinical superi- addition of epinephrine to lidocaine. Without ority of the amides for local anesthesia of the oral epinephrine, lidocaine is a poor drug for pulpal cavity. Ravocaine (propoxycaine and procaine) is the anesthesia, not worthy of being listed in Table 2 as only ester preparation still available in cartridge form, a conventional dental anesthetic.

MARCH/APRIL 1985 51 TABLE 2. Comparison of Conventional Amide Dental Anesthetic Solutions* Lidocaine Mepivacaine Prilocaine with epinephrine alone with vasoconstrictors alone with epinephrine Infiltration Onset of action 105 129 154 140 123 (sec) (7) (5) (5) (1) (1) Duration of soft tissue 167 91 131 106 140 anesthesia (min) (1 1) (5) (5) (5) (3) Frequency of successful 94 90 87 88 87 anesthesia (%) (12) (5) (5) (6) (3) Nerve block Onset of action 169 252 177 154 154 (sec) (5) (2) (2) (1) (1) Duration of soft-tissue 187 163 183 191 222 anesthesia (min) (9) (3) (4) (4) (3) Frequency of successful 87 86 86 90 89 anesthesia (0) (10) (3) (4) (5) (3) *Values compiled from human trials.38-49 The number of studies used for each entry is given in parentheses. Drugs included are 2% lidocaine with 1:80,000 to 1:100,000 epinephrine, 3% mepivacaine, 2% mepivacaine with 1:100,000 epinephrine or 1:20,000 levonordefrin, 4% prilocaine, and 4% prilocaine with 1:200,000 epinephrine.

Although epinephrine improves anesthetic efficien- equally active as 2% lidocaine with epinephrine; cy generally, the effect is much less evident with however, pulpal anesthesia begins to regress within drugs, such as mepivacaine and prilocaine, that are 10 min after injection such that half of the patients not potent vasodilators and do not benefit as much were no longer pain free after 25 min. Thus, the time from local vasoconstriction. Moreover, the influence of evaluation is critically important in measuring the of vasoconstrictors on toxicity remains in question. anesthetic efficacy of plain anesthetic solutions. Prilo- The benefit of retarding absorption and limiting the caine may be a drug of choice for a simple tooth ex- amount of local anesthetic that must be injected for traction, but it is inferior to lidocaine with epinephrine adequate anesthesia must be weighed against infor quadrant dentistry. creased local tissue irritation, potential adverse effects of the vasoconstrictor itself, and a possible potentiation of local anesthetic toxicity. Inasmuch as bI R 1. these questions have been reviewed elsewhere,52 they need not be discussed here, with the exception of the effect of vasoconstrictors on the duration of 98- anesthesia.

Duration of Anesthesia e 84-

For most patients receiving restorative dentistry, - ~0 the ideal anesthetic would provide anesthesia of the C teeth and supporting structures for the entire proce- 4_ 50- dure and then cease to be active as quickly as pos- 0) sible thereafter. Obviously, with soft-tissue anesthe- C 0a.) sia lasting much longer than pulpal anesthesia, this 'a 16- ideal cannot be obtained with current methodologies. c) Many clinicians now use 3% mepivacaine or 4% .j .\ 0\ prilocaine without vasoconstrictor, which provides a 2- \ shorter duration of soft-tissue anesthesia, at least af- C. ter infiltration (Table 2). Other practitioners eschew because of a clinical that they these drugs impression I T II 1I are less effective, in spite of human trials to the con- 12.5 25 50 100 trary (as summarized in Table 2). It is possible to reconcile these diverse results and conclusions if the Duration of anesthesia (min.) evanescent nature of pupal anesthesia with plain for- Fig. 2-Linear relationship between the incidence of anesthesia mulations is kept in mind. Figure 2, taken from a study (probit scale) and the time after injection (log scale). N.B. by Brown and Ward,46 shows that 4% prilocaine is = nerve block; I = infiltration.

52 ANESTHESIA PROGRESS The recent application of bupivacaine and etido- known to affect the quality of anesthesia. Some of caine to dental practice has significantly broadened these factors are obvious and under the control of the the spectrum of available drugs. These highly clinician; others are only poorly understood and/or lipophilic amides have durations of action two to four not amenable to alteration. While a complete deline- times their conventional counterparts. A spate of ar- ation of the variables affecting local anesthesia awaits ticles in this53-55 and other56 57journals document that the future, it is clear that a number of avenues can the clinical efficacy and safety of these drugs is com- be explored at this time to improve on current parable to existing anesthetics. There are several standards. specific indications for their use. First, in oral and Although beyond the scope of this paper, the evo- maxillofacial surgery, the 6-8 hours of pain relief lution of intraligamentary anesthesia and alternatives covers the patient at a time when postoperative pain to the inferior alveolar block injection have been of is at its zenith, thus reducing the need for and use of great importance, and the reader is referred to ap- analgesic medications. Second, they may obviate the propriate descriptions of these techniques.58-62 need for reinjection of patients receiving full mouth Another approach that relies on existing drugs in- reconstructive dentistry. Third, these agents are volves their reformulation for increased efficacy. In sometimes effective in patients for whom traditional an attempt to anesthetize "hypersensitive" teeth, preparations yield anesthesia that is abnormally short Rood tested the ability of 5% lidocaine with 1:80,000 in duration. The formulations most suitable for den- epinephrine to achieve pulpal analgesia. A double- tistry are 0.50/0 bupivacaine and 1.50/% etidocaine, blind comparison with 2% lidocaine and epinephrine both with 1:200,000 epinephrine (although the revealed that the more concentrated preparation suc- bupivacaine, at least, is also highly active as a plain ceeded 85% of the time whereas the conventional solution). Selection between these preparations may agent was successful in only 110% of cases.63 Certain- be somewhat arbitrary: etidocaine has a faster onset ly the 5% solution is more likely to cause local irrita- (by 1-2 min); bupivacaine is currently marketed in tion and is commensurately more toxic systemical- dental cartridges and has enjoyed more widespread ly, but these risks are worth assuming when use. inflammation negates the action of lower- concentration drugs. New Developments A third innovation using currently marketed drugs Clinical studies and personal experiences dictate is the discovery of a new topical anesthetic called that existing drugs and administration techniques are EMLA, the acronym for eutectic mixture of local not completely effective. Even in experienced hands anesthetics. Researchers at Astra Lakemedel in there seems to be some irreducible percentage of in- Sweden found that a eutectic mixture of prilocaine stances in which patients are not adequately anesthe- and lidocaine could be produced yielding an emul- tized. Table 3 lists a number of variables that are sion that is 80% anesthetic by weight (H. Evers, personal communication). A recent test of this formulation showed that EMLA applied to the intact skin could reduce the discomfort of venipuncture in chil- TABLE 3. Factors Influencing the Quality of Local Anesthesia dren.64 Although no studies have as yet been pub- lished on the intraoral use of EMLA, there is every Choice of local anesthetic reason to expect it will make a highly effective prepa- Concentration and volume used ration. Inclusion of a vasoconstrictor and its concentration New drugs with local anesthetic activity continue Administration technique (e.g., supraperiosteal injection to be isolated and synthesized. Many of these agents versus nerve block) are "me too" drugs with little to offer, but some have Accuracy of needle placement unique properties that advance our understanding of neurophysiology and may prove to be useful clinical- pH and ionic content of the tissue environment ly. Tetrodotoxin is an example of the latter category Products of inflammation and tissue breakdown (Fig. 3). Tetrodotoxin is a naturally occurring marine Binding capacity of local tissues biotoxin and one of the most potent local anesthet- Tissue barriers to diffusion ics known. The drug binds specifically to the exter- Microvasculature and local blood flow nal surface of the sodium channel and is used to Neuroanatomy of the area of interest selectively tag these channels in a variety of experimental studies. A high degree of systemic toxic- Microanatomy of the nerve of interest ity and limited lipid solubility preclude the clinical ap- Metabolic state of the nerve plication of tetrodotoxin. However, tests in vivo Accessory innervation suggest that tetrodotoxin acts synergistically with Degree of nociceptive stimulation conventional local anesthetics to provide intense Pain tolerance and anxiety level of the patient anesthesia of long duration.65 It may be that a future derivative of tetrodotoxin will find clinical use for some Adjuvent medications (opioids, antianxiety drugs, etc.) forms of regional anesthesia.

MARCH/APRIL 1985 53 OH irritation for about an hour in laboratory animals. This HO H o initial period is followed by a protracted (months long), 0- H H,Nt--(C H, 1,-C H, *Cl- modality-specific loss of nociception.69 A disappear- H. OH NH ol ance of substance P from the dorsal horn of the spi- N N nal cord and from the periphery may account for this H H,OH HO~~~~CHOH effect. No measurable depletion of substance P oc- H H Centbucridine curs if much smaller amounts of capsaicin are ad- Tetrodotoxin ministered for regional analgesia, yet significant in- 0 sensitivity to heat or noxious chemicals develops II C,H, CH,-NH-C-(CH,).-CH=CH-CH-(CH,I, * Br around the injection site within 2 hours and lasts for H,C,-Nt--(CH,I),-CH, at leasts 10 days.70 Combining the capsaicin with a local anesthetic prevented the acute painful OCH, Triethyidodecyl response; it did not otherwise alter drug effects. The OH ammonium Capsaicin bromide possible clinical introduction of capsaicin, or some derivation thereof, may not occur for many years, but Fig. 3-Structural formulas of some experimental local the desirability of selectively relieving chronic pain will anesthetics. ensure continued research in this area. Centbucridine represents a new class of quinoline derivatives synthesized in India (Fig. 3). It is current- Conclusion ly undergoing human trials and appears to be quite The field of local anesthesia has burgeoned in its similar to lidocaine in its clinical profile.66 Animal first century. Techniques and drugs have blossomed studies indicate that centbucridine has some anti- that can ease suffering and support operative proce- histaminic properties and is about four times as po- dures that might otherwise have been impossible tent as lidocaine.67 Unlike other local anesthetics, without rendering the patient unconscious. Investiga- centbucridine is a true central nervous system tions of the pharmacology and physiology of local stimulant; therefore, in overdose it tends to stimulate anesthesia is providing a rational basis for drug use respiration and increase blood pressure. These and will serve as the soil from which new advances characteristics raise the question of whether an ap- will sprout. There is little doubt that exciting discov- propriate combination of centbucridine and lidocaine eries and impressive advances in the regional con- could be developed with a higher margin of safety trol of pain are in store for the next 100 years. than either agent enjoys alone. For many years tetraethylammonium (TEA +) salts have been used to block potassium channels in tissue one of the References preparations. By replacing ethyl 1. Cousins MJ and Bridenbaugh P: Neural Blockade in Clinical groups with extended hydrocarbon chains, a family Anesthesia and Management of Pain, Philadelphia, J.B. Lip- of local anesthetics has been produced with unusual- pincott Co., 1980. ly long durations of action (Fig. 3).68 The C12 deriva- 2. Covino BG: New developments in the field of local anesthet- tive, triethyldodecyl ammonium, has an onset time of ics and the scientific basis for their clinical use. Acta 3 min in the rat (infraorbital block) but a duration of Anaesthesiol Scand 26:242-249, 1982. action of 18 days. Electron microscopy refutes the 3. Jastak JT and Yagiela JA: Regional Anesthesia of the Oral possibility that the anesthetic duration is caused by Cavity, St. Louis, C.V. Mosby Co., 1981. 4. Aceves J and Machne X: The action of calcium and of local a neurolytic action. Instead, it is hypothesized that the anesthetics on nerve cells and their interaction during exci- binding of the drug to the axolemma is so strong that tation. J Pharmacol Exp Ther 140:138-148, 1963. anesthesia abates only with the synthesis of new 5. Feinstein MB: Reaction of local anesthetics with phos- membrane components. The permanent charge of pholipids: A possible chemical basis for anesthesia. J Gen the nitrogen moiety limits diffusion of TEA + deriva- Physiol 48:357-374, 1964. tives across tissue barriers, such as the nerve sheath. 6. Blaustein MP and Goldman DE: Competitive action of calci- On the other hand the drug is also excluded from the um and procaine on lobster axon. J. Gen Physiol 49:1043- central nervous these 1063, 1966. system. Should agents prove 7. Narahashi T and Frazier DT: Site of action and active form clinically suitable, it may be possible to tailor these of local anesthetics. In: Ehrenpreis S and Solnitzky OC, eds., compounds for a whole spectrum of durations, that Neurosciences Research, vol. 4, New York, Academic Press, is, from 6 hours to 3 weeks. In dentistry, such agents pp 65-99, 1971. would be useful for oral surgical procedures and for 8. Narahashi T, Frazier DT, Takeno K: Effects of calcium on the chronic pain states. local anesthetic suppression of ionic conductances in squid A final agent, capsaicin, is especially interesting axon membranes. J Pharmacol Exp Ther 197:426-438,1976. 9. Marquis JK and Deschenes RJ: A reevaluation of calcium- because it is a natural substance with selective an- local anesthetic antagonism. Exp Neurol 76:547-552, 1982. tinociceptive properties. Capsaicin is the primary 10. Low PS, Lloyd DH, Stein TM, Rogers JA IlIl: Calcium displace- pungent constitutent of the red pepper (Fig. 3). Injec- ment by local anesthetics: Dependence on pH and anesthetic tion of large amounts of this amide causes extreme charge. J Biol Chem 254:4119-4125, 1979.

54 ANESTHESIA PROGRESS 11. Trudell JR: A unitary theory of anesthesia based on lateral 32. Goodson JM and Moore PA: Life-threatening reactions after phase separations in nerve membranes. Anesthesiology 46:5- pedodontic sedation: An assessment of narcotic, local 10, 1977. anesthetic, and antiemetic drug interaction. JADA 107:239- 12. Boulanger Y, Schreier S, Leitch LC, Smith ICP: Multiple bind- 245, 1983. ing sites for local anesthetics in membranes: Characteriza- 33. Kozody R, Ready LB, Barsa JE, Murphy TM: Dose require- tion of the sites and their equilibria by deuterium NMR of spe- ment of local anaesthetic to produce grand mal seizure dur- cifically deuterated procaine and tetracaine. Can J Biochem ing stellate ganglion block. Can Anaesth Soc J 29:489-491, 58:986-995, 1980. 1982. 13. Houslay MD, Dipple I, Rawal S, Sauerheber RD, Esgate JA, 34. Aldrete JA, Narang R, Sada T, Liem ST, Miller GP: Reverse Gordon LM: Glucagon-stimulated adenylate cyclase detects carotid blood flow-a possible explanation for some reactions a selective perturbation of the inner half of the liver plasma- to local anesthetics. JADA 94:1142-1145, 1977. membrane bilayer achieved by the local anaesthetic prilo- 35. Brown LL: Local anesthetic reactions: Prevention, diagnosis, caine. Biochem J 190:131-137, 1980. treatment. J SC Med Assoc 70:359-365, 1974. 14. Hille B: Local anesthetics: Hydrophilic and hydrophobic path- 36. Yagiela JA: Intravascular lidocaine toxicity: Influence of ways for the drug-receptor reaction. J Gen Physiol 69:497- epinephrine and route of administration. Anesth Prog 32:57- 515, 1977. 61, 1985. 15. Strichartz GR: The inhibition of sodium currents in myelinat- 37. Wingard DW and Bobko S: Failure of lidocaine to trigger por- ed nerve by quarternary derivatives of lidocaine. J Gen Physiol cine malignant hyperthermia. Anesth Analg 58:99-103, 1979. 62:37-57, 1973. 38. Berling C: Carbocain in local anaesthesia in the oral cavity: 16. Schwarz W, Palade PT, Hille B: Local anesthetics: Effect of An experimental and clinical investigation comprising 1046 pH on use-dependent block of sodium channels in frog mus- dental local anaesthesias. Odont Rev 9:254-267, 1958. cle. Biophys J 20:343-368, 1977. 39. Berling C and Bjorn H: L 67-a new local anaesthetic of anilide 17. Scurlock JE, Meymaris E, Gregus J: The clinical character type: Experimental determination of its efficacy in dental of local anesthetics: A function of frequency-dependent con- plexus anaesthesia in man. Sver Tandlakaforb Tidn 52:511 - duction block. Acta Anaesthesiol Scand 22:601-608, 1978. 522, 1960. 18. Mrose HE and Ritchie JM: Local anesthetics: Do benzocaine 40. Mumford JM and Geddes IC: Trial of carbocaine in conser- and lidocaine act at the same site? J Gen Physiol 71:223-225, vative dentistry. Br Dent J 110:92-94, 1961. 1978. 41. Goldman V and Gray W: A clinical trial of a new local analgesic agent. Br Dent J 1 1 5:59-65,1963. 19. Huang LM and Ehrenstein G: Local anesthetics OX 572 and benzocaine act at separate sites on the batrachotoxin- 42. Cowan A: Minimum dosage technique in the clinical compar- activated sodium ison of representative modern local anesthetic agents. J Dent channel. J Gen Physiol 77:137-153, 1981. Res 43:1228-1249, 1964. 20. Malmin 0: The "Shot" that Kills: Deaths in the Dental Chair, 43. Stibbs GD and Korn JH: An evaluation of the local anesthet- Hicksville, NY, Exposition Press, 1974. ic, mepivacaine hydrochloride, in operative dentistry. J Prosth 21. Jorfeldt L, Lewis DH, Lofstrom JB, Post C: Lun uptake of lido- Dent 14:355-364, 1964. caine in healthy volunteers. Acta Anaesthesiol Scand 23:567- 44. Cowan A: Further clinical evaluation of prilocaine (Citanest), 574, 1979. with and without epinephrine. Oral Surg 26:304-311, 1968. 22. Grenadier E, Alpan G, Keidar S, Palant A: Respiratory and 45. Bradley DJ and Martin ND: Clinical evaluation of mepivacaine cardiac arrest after the administration of lidocaine into the cen- and lidocaine. Aust Dent J 14:377-381, 1969. tral venous sytem. Eur Heart J 2:235-237, 1981. 46. Brown G and Ward NL: Prilocaine and lignocaine plus adrena- 23. McNamara PJ, Slaughter RL, Pieper JA, Wyman MG, Lalka line. Br Dent J 126:557-562, 1969. D: Factors influencing serum protein binding of lidocaine in 47. Epstein S: Clinical study of prilocaine with varying concen- humans. Anesth Analg 60:395-400, 1981. trations of epinephrine. JADA 78:85-90, 1969. 24. Edwards DJ, Lalka D, Cerra F, Slaughter RL: Alpha,-acid 48. Chilton NW: Clinical evaluation of prilocaine hydrochloride 4% glycoprotein concentration and protein binding in trauma. Clin solution with and without epinephrine. JADA 83:149-154, Pharmacol Ther 31:62-67, 1982. 1971. 25. Thomson PD, Melmon KL, Richardson JA, Cohn K, Stein- 49. Petersen JK, Luck H, Kristensen F, Mikkelsen L: A compari- brunn W, Cudihee R, Rowland M: Lidocaine pharmacokinet- son of four commonly used local analgesics. Int J Oral Surg ics in advanced heart failure, liver disease, and renal failure 6:51-59, 1977. in humans. Ann Intern Med 78:499-508, 1973. 50. Dobbs EC and Ross N: The new local anesthetic carbocaine. 26. Conrad KA, Byers JM ll, Finley PR, Burnham L: Lidocaine NY State Dent J 27:453-457, 1961. elimination: Effects of metoprolol and of propranolol. Clin 51. Ross NM and Dobbs EC: Mepivacaine HCI (carbocaine) Pharmacol Ther 33:133-138, 1983. without vasoconstrictor. J Oral Surg 21:215-218, 1983. 27. Knapp AB, Maguire W, Keren G, Karmen A, Levitt B, Miura 52. Jastak JT and Yagiela JA: Vasoconstrictors and local anesthe- DS, Somberg JC: The cimetidine-lidocaine interaction. Ann sia: A review and rationale for use. JADA 107:623-630,1983. Intern Med 98:174-177, 1983. 53. Babst CR and Gilling BN: Bupivacaine: A review. Anesth Prog 28. Feely J, Wilkinson GR, McAllister CB, Wood AJJ: Increased 25:87-91, 1978. toxicity and reduced clearance of lidocaine by cimetidine. Ann 54. Trieger N and Gillen GH: Bupivacaine anesthesia and post- Intern Med 96:592-594, 1982. operative analgesia in oral surgery. Anesth Prog 26:20.23, 29. Englesson S: The influence of acid-base changes on cehtral 1978. nervous system toxicity of local anaesthetic agents. Acta 55. Davis, WM Jr, Oakley J, Smith E: Comparison of the effec- Anaesthesiol Scand 18:79-87, 1974. tiveness of etidocaine and lidocaine as local anesthetic agents 30. Morishima HO and Covino BG: Toxicity and distribution of lido- during oral surgery. Anesth Prog 31:159-164, 1984. caine in nonasphyxiated and asphyxiated baboon fetuses. 56. Nespeca JA: Clinical trials with bupivacaine in oral surgery. Anesthesiology 54:182-186, 1981. Oral Surg 42:301-307, 1976. 31. Sage DJ, Feldman HS, Arthur GR, Datta S, Ferretti AM, Nor- 57. Giovannitti JA and Bennett CR: The effectiveness of 1.5% way SB, Covino BG: Influence of lidocaine and bupivacaine etidocaine HCI with epinephrine 1:200,000 and 2% lidocaine on isolated guinea pig atria in the presence of acidosis and HCI with epinephrine 1:100,000 in oral surgery: A clinical com- hypoxia. Anesth Analg 63:1-7, 1984. parison. JADA 107:616-618, 1983

MARCH/APRIL 1985 55 58. Smith GN, Walton RE, Abbott BJ: Clincal evaluation of perio- tivity of tetrodotoxin alone and in combination with vasocon- dontal ligament anesthesia using a pressure syringe. JADA strictors and local anesthetics. Anesth Analg 55:568-573, 107:953-956, 1983. 1976. 59. Council on Dental Materials, Instruments, and Equipment: 66. Samsi AB, Bhalerao RA, Shah SC, Mody BB, Paul T, Satoskar Status report: The periodontal ligament injection. JADA RS: Evaluation of centbucridine as a local anesthetic. Anesth 106:222-224, 1983. Analg 62:109-111, 1983. 60. Gow-Gates GAE: Mandibular conduction anesthesia: A new 67. Patnaik GK and Dhawan BN: Pharmacological study of 4-N- technique using extraoral landmarks. Oral Surg 36:321-328, butylamino-1,2,3,4-tetrahydroacridine hydrochloride (cent- 1973. bucridine)-a new local anaesthetic agent. Ind J Exp Biol 61. Akinosi JO: A new approach to the mandibular nerve block. 20:330-333, 1982. Br J Oral Surg 15:83-87, 1977. 68. Scurlock JE and Curtis BM: Tetraethylammonium derivatives: 62. Garber JG and Cohen JS: Newer approaches to mandibular Ultralong-acting local anesthetics? Anesthesiology 54:265- block anesthesia. Compend Cont Educ Dent 3:17-21, 1982. 269, 1981. 63. Eldridge DJ and Rood JP: A double-blind trial of 5 per cent 69. Hayes AG and Tyers MB: Effects of capsaicin on nociceptive lignocaine solution. Br Dent J 142:129-130, 1977. heat, pressure and chemical thresholds and on substance P 64. Ehrenstrom Reiz GME and Reiz SLA: EMLA-a eutectic mix- levels in the rat. Brain Res 189:561-564, 1980. ture of local anaesthetics for topical anaesthesia. Acta 70. Burks TF, Miller MS, Buck SH, Hameroff SR, Sipes IG: Cap- Anaesthesiol Scand 26:596-598, 1982. saicin: A long acting pain fiber specific local anesthetic. 65. Adams HJ, Blair MR Jr, Takman BH: The local anesthetic ac- Anesthesiology 57:A213, 1982.

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