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Advances in local anesthesia
Advances in Local Anesthesia CHRISTOPHER J. ARPEY, MD WILLIAM S. LYNCH, MD
T
he ability to alleviate pain has been an important factor in the progress of medicine over the last century. The development of anesthesia has revolutionized surgery, and the use of local anesthesia, in particular, has greatly facilitated the performance of dermatologic surgery. Local anesthesia may be defined as the reversible circumscribed loss of sensation resulting from inhibition of nerve conduction. Local anesthetics are pharmacologic agents that block action potential transmission in nerves.im5 Local anesthesia for dermatologic use has continued to evolve. Refinements of well-known methods, as well as the development of novel agents and approaches, have contributed to advances in cutaneous anesthesia over the past decade.
Mechanisms of Nerve Transmission and Blockade
History Clinical use of local anesthesia began in 1884 with the topical application of cocaine for ophthalmologic procedures by Koller and Freud.6*7 Cocaine subsequently gained acceptance worldwide. In the United States, Halsted employed cocaine in hundreds of cases.‘,s With increasing use, however, came an appreciation of the toxicity of the drug and a search for less toxic anesthetics. Einhorn synthesized procaine, an ester of paru-aminobenzoic acid (PABA), in 1905.‘*’ Tetracaine and chloroprocaine, longer-acting ester derivatives, were developed subsequently. Though efficacious and less toxic than cocaine, these ester derivatives of PABA were noted for their allergenic properties. From 1943 to 1948, lidocaine was developed by LofFrom the Department of Dermatology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Address correspondence to Christopher J. Arpey, MD, Department of Dermatology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, lowa 52242.
0
1992
by Elsevier
gren.9 It was the first of a new class of anesthetics, the amino amides, which had a much lower propensity for causing allergic reactions. Over the next 30 years, several more agents in this class were developed, with variable duration and potency (Table l).lm3 Most recently, a variety of approaches have further modified cutaneous anesthesia. Some examples include the mixing of agents, altering the vehicles for delivery of anesthetic compounds, and the topical application of anesthetics in novel ways. In addition, more information is available with respect to the influence of anesthetics on procedures such as skin grafting and liposuction, along with new findings regarding anesthetic toxicity. These developments are discussed here.
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Transmission of nerve impulses depends on the phospholipid bilayer surrounding axons, the axolemma.1° This membrane houses the molecular “gates” responsible for the Na+ and K+ ionic flux which creates a resting potential.3 Subsequent nerve stimulation may then result in action potentials and signal propagation.3J1 Schwann cells surround all nerve fibers; however, about one third of nerve fibers are wrapped with multiple layers of a lipid-protein mixture called myelin, formed by the Schwann cell. lo Myelin forms a type of discontinuous insulation with small, intervening unmyelinated segments called nodes of Ranvier. Myelinated nerves transmit impulses more quickly than unmyelinated nerves because of saltatory conduction of the action potential between nodes of Ranvier. At least 15 types of afferent nerves have been identified,12 many of which contribute to the complex sensory innervation of the skin. Small, lightly-myelinated A fibers and tiny, unmyelinated C fibers are believed to be responsible for the sensation of pain (nociception).5 The
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Table 1. Classification Name
and Clinical Class
Clinics in Dermatology 1992:10:275-283 Pharmacology
of
Local Anesthetics
Relative Potency
Pk
Onset
Duration
Metabolism
Procaine Chloroprocaine Tetracaine
Ester Ester Ester
1 l-4 8-16
8.9 8.7 8.5
Slow Fast Slow
Short Short Long
Plasma Plasma Plasma
Lidocaine Mepivacaine Prilocaine Etidocaine Bupivacaine
Amide Amide Amide Amide Amide
l-2 l-2 l-2 4-6 4-8
7.9 7.6 7.9 7.7 8.1
Fast Fast Fast Fast Moderate
Moderate Moderate Moderate Long Long
Liver Liver Liver Liver Liver
A fibers carry sharp pain; the C fibers carry dull pain.” As a result of their myelin insulation, A fibers are more difficult to anesthetize. The largest, most heavily myelinated A fibers, which transmit the sensations of pressure, touch, and proprioception, as well as motor function, are the most difficult to anesthetize, hence the ability of most patients to feel pressure and movement during local anesthesia.6 Current evidence suggests that local anesthetics operate by reversibly binding to specific receptors in the axolemma,2~3~5J3-15 within or adjacent to the internal opening of the sodium channel (Fig 1). The receptor conformation is altered and sodium influx ceases. Nerve depolarization and impulse transmission are thus pre-
vented. A second, nonspecific mechanism may also be operative, whereby the anesthetic is absorbed into the axolemma, resulting in temporary expansion of the phospholipid bilayer and closure of the sodium channels. Reaching the internal opening of the sodium channel requires passage through the hydrophobic axolemmal membrane. Local anesthetics are administered in their water-soluble, acidic, ionized form. Conversion to the nonionized base is required to traverse the membrane. Finally, once inside the axoplasm, reequilibration with the acid form occurs- this cation is the active channelblocking moiety.3J5 Many characteristics contribute to the efficacy of local anesthetics (Table 1).lm3 The most important of these are
Figure 2. Cross section of nerve and sodium channel. The channel is believed to span the entire thickness of the axonal membrane, with a gating mechanism located closer to the inner aspect. The sodium gate is closed when the nerve is at rest, preventing sodium influx and action potential generation. An open channel allows an inward rush of sodium, axonal depolarization, and subsequent impulse transmission. Binding of local anesthetics to a specific receptor within or nearby the internal aspect of the channel perpetuates closure of the gate. (From Savarese I], Covino BG. Basic and clinical pharmacology of local anesthetic drugs. In: Miller RD, editor. Anesthesia. 2nd ed. New York: Churchill Livingstone, 1986:994, with permission.)
ARPEY AND LYNCH LOCAL ANESTHESIA
Clinics in Dermatology 1992;10:275-283 lipid solubility, protein binding, and pK, .3,5These intrinsic properties clinically affect potency, duration, and onset of anesthesia, respectively. Anesthetic potency is defined in terms of the minimum concentration required to produce conduction blockade. Highly lipophilic anesthetics are more potent agents as a result of the high lipid content of the axolemma. Just as nonionized forms cross the nonpolar membrane more quickly, highly lipophilic compounds reach the axoplasma faster.5 Duration of anesthesia results mainly from the protein-binding capacity of the anesthetic. The axolemmal receptor site is believed to be composed of protein. Thus, agents with higher binding affinity are longer-acting.3,5 Onset of anesthetic action is affected principally by its method of delivery, its diffusion rate through tissue, and its pK,. Injected agents have a faster onset when compared with topical agents. Clearly, compounds that diffuse more quickly reach the nerve faster, and onset occurs sooner; however, the variation in diffusion times for anesthetics is not well understood. The pK, becomes important once the drug reaches the axolemma.5,16 The pKp, or dissociation constant, is the pH at which the cationic form is in equilibrium with the nonionized base form. Recall that although the cationic form is the active moiety at the receptor site, it is the base form that diffuses through the axolemmal lipid bilayer. The pK, of virtually all local anesthetics is higher than tissue pH (7.4). Therefore, a drug such as lidocaine (pK, 7.7) has a more rapid onset than procaine (pK, 8.9) because it creates more base at physiologic pH. In general, the lower the pK,, the faster the onset. Systemic absorption and subsequent inactivation of the tissue reservoir of anesthetic also play a role in determining efficacy. Except for cocaine, all local anesthetics possess variable intrinsic vasodilating capacity. Increased blood flow from vasodilation results in more rapid absorption and metabolism. The common practice of adding a vasoconstrictor, such as epinephrine, to local anesthetics partially counteracts this process and prolongs the duration of action.’
Classification Local anesthetics are typically classified by the two types of chemical bonds between the aromatic and amine portions of the compounds. lj3 In general, most of them have the following basic structure: Ester Amide
Aromatic Aromatic
portion- COO-R-amine portion portion - NHCO - R-amine portion
The aromatic portion is lipophilic,
the amine portion is
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hydrophilic, and R corresponds to a variable-length hydrocarbon intermediate chain. Variations in these three regions of anesthetics determine their physiologic properties. Anesthetics with an amide linkage are much less likely to elicit allergic reactions than ester-containing compounds. Esters are metabolized in plasma by pseudocholinesterase, whereas amides undergo enzymatic degradation in the liver. A summary of the properties of the most commonly used anesthetics may be found in Table 1.
Clinical
Use
Three methods for establishing local anesthesia of the skin have been in widespread use: topical anesthesia, infiltration anesthesia, and peripheral nerve blockade. Recent advances in cutaneous anesthesia have evolved from these techniques. Standard topical anesthesia involves the use of amide or ester derivatives in various vehicles applied to the skin or the use of skin refrigerants.‘Intact skin, however, often greatly impairs the penetration of topical anesthetics, restricting their use mainly to procedures involving the mucous membranes. As discussed later, improving topical anesthesia has been an area of great interest over the past decade. Refrigerants are rapid-onset, short-acting agents useful for minor procedures and dermabrasion. Some investigators *’ have, however, suggested that this technique may alter the morphology of skin, potentially increasing the difficulty of establishing an accurate histopathologic diagnosis. Modifications of standard techniques of infiltrative anesthesia have been attempted in recent years with some success in improving cutaneous anesthesia, and these are discussed later. General methods for infiltrative anesthesia and peripheral nerve blockade have been well reviewed elsewhere,s,18 and are not described here.
Advances
in Topical
Anesthesia
Local anesthetics have been available in topical formulations for many years, but because of poor penetration of intact skin their use has been limited mainly to mucosal regions.’ Formulations have included creams, ointments, aerosols, solutions, and suppositories. Several anesthetic ingredients have been used, namely, the esters cocaine, benzocaine, dibucaine, and tetracaine, as well as the amide lidocaine. A variety of investigators have attempted to improve the epidermal penetration of topical anesthetics. In 1957, Monash used the water-soluble salts of six different agents, under occlusion, without achieving anesthesia19;
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however, he found moderate success with higher concentrations of the base form of anesthetics in a petrolatum or hydrophilic ointment vehicle, under occlusion. Subsequent investigators found that such formulations neither penetrated sufficiently nor lasted long enough for clinical use 20.21 In the 1960s and 197Os, the potent solvents dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA) greatly improved the penetration of topical anesthetics, but resulted in unacceptable reactions,22 including edema, erythema, pruritus, burning, and stinging. At the same time, an amino ether compound, ketocaine, was extensively investigated. This highly lipophilic agent was effective, but it caused local irritation and blister formation.22*23 The search for more efficacious topical anesthetic formulations continued over the next decade, with the emergence of EMLA (eutectic mixture of local anesthetics, Astra Pharmaceuticals) as a useful agent for local anesthesia. EMLA was developed in the late 1970s and early 1980s by Juhlin, Evers, and Broberg.24-27 The eutectic phenomenon is the spontaneous lowering of the melting point of two substances when their solid forms are mixed together, far lower than the melting point of either ingredient alone.27-29 This phenomenon occurs with the two amide anesthetics, lidocaine and prilocaine, at room temperature. EMLA cream 5% consists of 25 mg/mL each of lidocaine and prilocaine base, with an emulsifier, viscosity-increasing agent, and water as the vehicle.30,31 The oil-in-water emulsion created by the eutectic effect obviates the need to dissolve the anesthetic base in an oi1.27 The result is a lidocaine-prilocaine concentration of 80% in the emulsion droplets, even though the total concentration is only 5%. Numerous clinical trials have been performed with EMLA in Europe, though the drug is still investigational in the United States. Most trials have studied its efficacy in venipuncture, 27,30-40skin graft harvesting,22*29,41 curettage of molluscum contagiosum,42*43 cautery of genital warts,44 and pulsed-dye treatment of port-wine stains.45 Most studies used a visual analog scale (VAS) to assess patient perception of pain to pinprick or to the procedure being performed. Some studies obtained additional subjective assessments of pain by patients and observers. Arendt-Nielsen and Bjerring, however, used the argon laser to elicit a pain response, citing its increased specificity for nociceptors when compared with pinprick.46 They also quantitated the degree of sensory blockade after EMLA application by eliciting cortical-evoked responses to low-energy, short argon-laser pulses, believing this technique more accurately simulates surgical pain. Regardless of method of pain assessment, a review of
Clinics in Dermatology 1992:10:275-283
these series reveals that EMLA was effective in attaining analgesia in about 60 to 75% of patients, though in some studies absent or mild pain was observed in over 90%.41,42 Conversely, effective analgesia was observed in only 40% of women treated for vaginal warts in a study by Hallen et a1.44 They theorized that mucosal absorption over the 50-minute application time may have inactivated the drug. Indeed, in the same study, EMLA was efficacious in 96% of the men with genital warts. EMLA has been found far superior to placebo and about as effective as infiltrated lidocaine when applied for at least 60 minutes. Application times appear to be important. Ehrenstrom Reiz et al recommend at least a 45minute application time, though success appears to be greater with over 60 minutes.32 In addition, most investigators recommend the use of a relatively thick layer of EMLA under an occlusive dressing. Application periods of at least 120 minutes were used for harvesting of skin grafts.29,41 The shortest effective application time cited for cutting skin grafts was 90 minutes,22 though the mean time in that series was 3 hours 20 minutes. Interestingly, however, after 3 hours EMLA may lose its efficacy, by way of depletion of lidocaine - prilocaine droplets in the EMLA layer nearest the skin.22 Gentle massage of the cream while under the occlusive dressing may replete the “reservoir” of droplets during prolonged applications. Studies of systemic absorption have been performed on both norma122*27,47*48and diseased48 skin. In adults, even with the application of large quantities of EMLA, plasma concentrations were far below toxic levels. Enberg et al used EMLA for venipuncture in infants 3 to 12 months old.47 They found that 2 mL of the substance applied for under 4 hours yielded subtoxic plasma levels of both anesthetics in all 22 patients. In addition, only minor elevations in methemoglobin were seen (prilocaine may result in methemoglobinemia when administered systemically). Nearly all studies reported occasional mild local reactions, including pallor, erythema (especially if left on for several hours), and edema. No long-term sequelae have been noted, and no delayed-type hypersensitivity has been observed, despite repeated administration at the same site.27 More recently, a group of investigators from Northern Ireland has studied a 4% amethocaine gel for local anesthesia.5,49-51 This highly lipophilic agent was found to be far better than placebo in achieving anesthesia. In addition, its onset was 30 to 45 minutes instead of the 60 to 70 minutes required for EMLA, its duration was typically twice as long as that of EMLA, and it appears to be much more potent on a per-gram basis50 No adverse reactions were noted in the 20 volunteers studied; however, it might be of interest to search for adverse or allergic
ARPEY AND LYNCH LOCAL ANESTHESIA
Clinics in Dermatology 1992;10:275-283 reactions on reexposure given its membership in the ester class of anesthetics. The same agent was found to be an effective anesthetic in 80% of 80 patients undergoing skin graft harvesting. 51 Although still under investigation, it has many potential benefits and may prove to be clinically useful. Other methods of increasing the penetration of topical anesthetics have been attempted, including ultrasound52-54 and iontophoresis.55-57 Many past reports of the efficacy of ultrasound in improving penetration of the skin by various drugs have been anecdotal reports or uncontrolled studies.52-54 Indeed, McElnay et al found insignificant improvement in anesthesia in a doubleblind, crossover trial comparing ultrasound plus 25% lidocaine with lidocaine cream alone.52 Bezzant et al employed salt-free 4% lidocaine delivered by means of a painless low-level electric current prior to cauterization of spider veins.55 Using this technique, iontophoresis, they were able to achieve adequate anesthesia in 15 of 16 patients, though no control group was employed. Further controlled studies may be helpful in assessing the usefulness of both ultrasound and iontophoresis in cutaneous anesthesia. Even if proven efficacious, the need for ultrasound equipment or a battery-operated iontophoresis device may limit the widespread use of these modalities. Finally, a mixture of tetracaine 0.5%, adrenaline 1: 2000, and cocaine 11.8% in solution (“TAC”) was used widely in the 1980s for suturing minor lacerations, particularly in children. 5s,59Typically, a gauze pad soaked in the solution is applied for 10 to 20 minutes to a laceration. The anesthesia achieved is comparable to that of infiltrated lidocaine, but the lack of an injection improves patient acceptance and suturing may be completed more efficiently; however, several toxic reactions have been well described, particularly in small children and when the mixture is applied to mucosal surfaces.@-62 High plasma levels of cocaine and tetracaine have been suspected as the cause of seizures, respiratory compromise, and cardiovascular toxicity. Tipton et al recommend further investigation to establish guidelines for the clinical use of TAC.60
Advances in Infiltrative
Anesthesia
Current pharmacologic agents for infiltrative anesthesia have changed little over the past decade, although a variety of modifications have been made in an attempt to lessen the pain of infiltration and to improve efficacy. Before some of these modifications are discussed, however, mention should be made of an investigational agent
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in the amide class of anesthetics. This drug, ropivacaine, is structurally similar to mepivacaine and bupivacaine.3 Its onset is similar to that of bupivacaine, but its potency and duration of blockade are slightly less. Ropivacaine has a shorter elimination half-life and depresses the myocardium less than bupivacaine. It may become a useful alternative to mepivacaine and bupivacaine among the longer-acting amide anesthetics. Minimizing the pain of administering local anesthesia has been of great interest recently. Amdt et aP studied the assessment of pain by 15 volunteers using 2% lidoCaine. They examined the influence of depth of injection, rate of administration, and temperature on the perception of pain, using a 30-gauge needle. Degree of anesthesia was subsequently assessed by pricking the skin with a 30-gauge needle, as well. Not surprisingly, they found that superficial wheal-producing injections were much more painful than subcutaneous injections. In addition, although onset of anesthesia was delayed several minutes in those receiving deeper injections, duration was similar to those receiving intradermal injections. As one might expect, more slowly administered injections were significantly less painful than those given rapidly. Interestingly, no difference in pain sensation was noted when comparing lidocaine at 21 “C with lidocaine warmed to 37°C. Perhaps the most significant advance has been the discovery that alkalinizinganesthetics before theiradministration markedly diminishes the pain of injection, without compromising efficacy. Commercial preparations of local anesthetics are acidified to promote solubility and stability. 6L Moore tested the pH of a variety of commercially prepared ester and amide anesthetics, and found that all had pH values less than 6.6.65 The pH range for solutions containing epinephrine was 3.5 to 4.2. For plain anesthetics the pH range was 2.8 to 6.6, with most agents, including lidocaine, between 5.5 and 6.5. As a result of acidification, local anesthetics retain their stability for many months.66 Several groups have tested the theory that the acid pH is mainly responsible for the pain during infiltration and that alkalinizing local anesthetics would ameliorate the discomfort.64*67-69 A pH of about 7.3 can be attained by the addition of 1 mL of sodium bicarbonate (1 mEq/mL) to 10 mL of anesthetic. 64*6*This yields a final bicarbonate concentration of 0.1 mEq/mL. In all studies reviewed, this concentration significantly reduced pain when compared with anesthetic alone. Results were less impressive with anesthetics containing epinephrine, but the attenuation of pain persisted. Stewart et al found that the use of an equal volume of bicarbonate at a concentration of 0.4 mEq/mL, yielding a pH of 7.0, was nearly as effective.68 The addition of 0.1 mEq/mL (resultant pH of 6.5) was, however, insufficient; in fact, pain scores were
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nearly identical to those produced by injection of anesthetic alone. The mechanism of action of sodium bicarbonate in this setting may be more complex than a simple elevation of PH.~ For instance, a shift in equilibrium of the anesthetic to its nonionized form occurs with increasing pH, and it is possible that nociceptors are less sensitive to this form. It is also conceivable that the markedly increased concentration of nonionized anesthetic allows much more rapid diffusion through the tissue and axolemma, resulting in nearly instant inhibition of impulse transmission. Regardless of mechanism, alkalinization of local anesthetics, including lidocaine and mepivacaine among others, reduces the pain of infiltrative anesthesia. Fortunately it has been shown that onset of action is not prolonged, and the duration not shortened, by the addition of sodium bicarbonate.‘O Moreover, some studies cite a beneficial effect of alkalinization, namely, that onset may be shortened and duration prolonged.71-73 Other authors contend that this issue remains unsettled.‘O Finally, Larson et al made the observation that batch quantities of buffered lidocaine with epinephrine maintained greater than 90% of the original concentration of each constituent when stored at 0 to 4”C, up to 2 weeks after initial mixing.74 Lidocaine remained at greater than 90% of its initial concentration and epinephrine greater than SO%, under the same conditions after 4 weeks. At room temperature, lidocaine falls to nearly half, and epinephrine to less than 2%, of their original concentrations.6**74 The simple technique of refrigeration, then, permits batch buffering of lidocaine in an office setting without loss of efficacy. Another technique for minimizing the pain of establishing local anesthesia, the “ice-saline - xylocaine techThis pronique, ” was recently suggested by Swinehart. cess involves the use of small ice packs applied to the skin for several minutes, followed by a slow injection of normal saline with 0.9% benzyl alcohol (which is typically present in commercially available bacteriostatic saline), and finally an injection of buffered anesthetic with or without epinephrine. The injection of saline is painless and the benzyl alcohol may have intrinsic anesthetic properties. Swinehart reports excellent results in an uncontrolled series of 762 patients undergoing a variety of procedures, including hair transplantation and dermabrasion. Further studies may confirm the usefulness of this method in achieving local anesthesia. Finally, a method for safely administering large quantities of local anesthetic for liposuction has been developed. 76-78This method, the “tumescent technique,” involves the injection of large volumes of dilute lidocaine with epinephrine into subcutaneous fat prior to liposuction. A typical buffered 0.1% solution can be formed by
adding 100 mL of 1% lidocaine, 1 mL of 1: 1000 epinephrine, and 12.5 mL of sodium bicarbonate (1 mEq/mL) to a 1-L bag of normal saline. ” Modified blunt-tipped spinal needles”,‘s can be used to instill the solution which is attached to the syringe via intravenous tubing. Instillation of fluid is begun through a 20-gauge needle, followed by a longer la-gauge needle. General anesthesia and intravenous sedation are not required. Klein recommends either no sedation or small intramuscular injections of midazolam (2.5-5 mg) every 2 to 3 hours for larger procedures.” The amount of fluid instilled ranges from as little as 100 mL in the submental region to 2000 mL for the abdomen. The needle is inserted in multiple directions through the same entrance site, with subcutaneous induration as the goal. Anesthesia obtained in this fashion appears to be excellent, and liposuction may be performed easily and completely. Considerable blood-tinged drainage occurs for up to 18 hours, but actual whole-blood loss is minimal. Significantly, up to 35 mg/kg lidocaine may be safely given instead of the “standard” maximum of 7 mg/kg. Dilution both delays and diminishes the peak plasma lidocaine levels. By measuring plasma levels repeatedly over 24 to 36 hours in patients undergoing tumescent anesthesia, Klein found that none had levels greater than 2.7 pg/mL at any time. No patients experienced subjective toxicity and the minimal toxic level of 3 pg/mL was not broached. 79Peak levels were often seen 10 to 14 hours after the start of the procedure. Corresponding anesthesia was prolonged as well, improving postoperative pain management. The tumescent technique for liposuction appears to offer many benefits, and may become more widely used in the near future.
Adverse Reactions Adverse reactions to local anesthetics are uncommon. Several recent articles have reviewed this subject,8*18*80 and it is discussed briefly here in the context of recent findings and recommendations for approaching the patient with suspected anesthetic allergy. Reactions to local anesthetics may be regional or systemic. Local reactions include edema, pain, ecchymosis, and rarely gangrene or nerve damage. Systemic reactions may be toxic (ie, central nervous system excitability followed by coma, hypotension and myocardial depression from elevated blood levels), allergic (IgE-mediated), or idiosyncratic. Tachycardia, hypertension, angina, and dysrhythmias can result from high plasma levels of epinephrine. Many systemic reactions are vasovagal responses, averted by placing the patient in a supine position prior to injection. Toxic reactions are best avoided by limiting the dose and by reaffirming an extravascular in-
Clinics in Dermatology 1992;10:275-283
ARPEY AND LYNCH LOCAL ANESTHESIA
jection site. Possible drug interactions, in particular those occurring with monoamine oxidase inhibitors (hypertension), phenothiazines (hypotension), and beta blockers (hypertension, if epinephrine is in the solution), should be kept in mind.7*1* Type I (immediate or IgE-mediated) allergy is more common with ester-type anesthetics than amides.1,3,8 Type IV reactions (delayed, cell-mediated) are not as well documented,s’ except in the setting of contact dermatitis to topical anesthetics. so Type I reactions are the most feared, because angioedema, bronchospasm, and anaphylaxis may occur. Although well-documented type I reactions have occurred with lidocaine and other amide anesthetics,s2 occasionally it is unclear whether the anesthetic itself or a preservative is the offending agent. Parabens have been implicated in some instances,W,*3 and more recently bisulfites and related compounds have been demonstrated to play a role.W,85 The use of singledose, preservative-free anesthetics may be helpful in treating such individuals. Finally, Glinert and Zachary have recently suggested an overall approach to “Caine-sensitive” patients.@ This approach includes a detailed history including past medical history and specific information regarding agents administered. The dose, route, presence of preservatives, other medications taken concurrently, type of reaction, and temporal relationship to anesthetic administration are also important. Highly suggestive of anaphylaxis are urticaria, angioedema, and wheezing within 2 hours of administration. For this group of patients, as well as for those having a borderline history or incomplete history, they recommend skin testing and challenge, preferably by an allergist in a setting where preparations for possible resuscitation have been made. A prick or scratch test to a minute amount of the drug is attempted first. The amount is then gradually increased and injected intradermally or subcutaneously over a l- to 2-hour period. Evidence of a local urticarial, or systemic reaction is sought. Epinephrine is excluded because it may blunt the wheal-and-flare response. Preservative-containing solutions may be tested separately. False-negative tests are fortunately quite rare, s2 whereas false-positive results occur in about 15% of patients tested.80 An organized approach to patients with suspected anesthetic allergy and judicious use of skin testing and incremental challenge improve physician confidence and patient safety during local anesthesia.
Conclusions Local anesthesia has been of critical evolution of cutaneous surgery over
Further refinements,
importance in the the past 50 years.
including EMLA and similar topical
agents, buffered anesthetics, technique, and a more detailed
modifications framework
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of injection for investigat-
ing adverse reactions, have allowed continued progress in cutaneous anesthesia over the past decade.
References 1. Covino BG, Vassallo HG. Local anesthetics. Mechanisms of action and clinical use. New York: Grune & Stratton, 1976:1-11,13-39,57-75,89-121. 2. Strichartz GR, Covino BG. Local anesthetics. In: Miller RD, ed. Anesthesia. 3rd ed. New York: Churchill Livingstone, 1990:437-470. of local anesthet3. Covino BG, Lambert DM. Pharmacology ics. In: Longnecker DE, Murphy FL, editors. Introduction to anesthesia. 8th ed. Philadelphia: WB Saunders, 1992:195 212. 4. Stoelting RK, Miller RD. Basics of anesthesia. 2nd ed. New York: Churchill Livingstone, 1989:81-9. 5. Woolfson AD, McCafferty DF. Local anaesthesia of the skin. J Clin Pharmacol Ther 1989;14:103-9. 6. Koller C. Historical notes on the beginning of local anaesthesia. JAMA 1941;90:1742-3. 7. Lynch WS. Local anesthetics. In: Epstein E, Epstein E, Jr, eds. Skin surgery, 6th ed. Philadelphia: WB Saunders, 1987:25-35. 8. Grekin RC, Auletta MJ. Local anesthesia in dennatologic surgery. J Am Acad Dermatol 1988;19:599-614. 9. Lafgren N. Studies on local anesthetics. Xylocaine: A new synthetic drug. Stockholm: Haeggstroms, 1948. 10. Schmidt RF. The structure of the nervous system. In: Schmidt RF, editor. Fundamentals of neurophysiology. 2nd ed. New York: Springer-Verlag, 1978:1- 18. 11. Dude1 J. Excitation of nerve and muscle. In: Schmidt RF, editor. Fundamentals of neurophysiology. 2nd ed. New York: Springer-Verlag, 1978:19- 71. 12. Iggo A. Cutaneous sensory mechanisms. In: Barlow HB, Mollon JD, editors. The senses. Cambridge: Cambridge University Press, 1982:369-406. 13. Strichartz GR. Molecular mechanisms of nerve block by local anesthetics. Anesthesiology 1976;45:421-38. 14. Singer MA, Jain MK. Interaction of four local anesthetics with phospholipid bilayer membranes: Permeability effects and possible mechanisms. Can J Biochem 1980;58:815 - 21. 15. Covino BG. New developments in the field of local anesthetics and the scientific basis for their clinical use. Acta Anaesthesiol Stand 1982;26:242-9. 16. Covino BG. Local anesthetic agents for peripheral nerve blocks. Anaesthetist 1980;29:33-7. 17. Serup J. Punch biopsy of the skin: Effect of temperature and local anesthesia with ethyl chloride freezing. J Dermatol Surg Oncol 1983;9:558-61. 18. Winton GB. Anesthesia for dermatologic surgery. J Dermato1 Surg Oncol 1988;14:41-54.
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19. Monash S. Topical anesthesia of the unbroken skin. Arch Dermatol 1957;76:752-6. 20. Adriani G, Dalili H. Penetration of local anesthetics through epithelial barriers. Anesth Analg 1971;50:834-41. 21. Dalili H, Adriani G. The efficacy of local anesthetics in blocking the sensations of itch, burning, and pain in normal and “sunburned” skin. Clin Pharmacol Ther 1971;12: 913-9.
36. Hallen B, Ohlsson GL, Uppfeldt A. Pain-free venipuncture. Effect of timing of application of local anaesthetic cream. Anaesthesia 1984;39:969 - 72.
22. OhlsPn L, Englesson S, Evers H. An anaesthetic lidocaine/ prilocaine cream (EMLA) for epicutaneous application tested for cutting split skin grafts. Stand J Plast Reconstr Surg 1985;19:201-9. 23. Ponten B, Ohlsen L. Skin surface application of ketocaine to provide local anaesthesia for cutting split skin grafts. Br J Plast Surg 1977;30:251-4. of hyperhidrosis by 24. Juhlin L, Evers H, Broberg F. Inhibition topical application of a local anesthetic composition. Acta Den-n Venereol (Stockh) 1979;59:556-9. 25. Juhlin L, Evers H, Broberg F. A lidocaine-prilocaine cream for superficial skin surgery and painful lesions. Acta Derm Venereol (Stockh) 1980;60:544-6. 26. Broberg F, Evers H. European Patent 0002425 (1981). 27. Evers H, Von Dardel 0, Juhlin L, et al. Dermal effects of compositions based on the eutectic mixture of lignocaine and prilocaine (EMLA). Studies in volunteers. Br J Anaesth 1985;57:997-1005. A, Wadsten I, et al. Phase dia28. Brodin A, Nyqvist-Mayer gram and aqueous solubility of the lidocaine-prilocaine binary system. J Pharm Sci 1984;73:481-4. 29. Goodacre TEE, Sanders R, Watts DA, et al. Split skin grafting using topical local anaesthesia (EMLA): A comparison with infiltrated anaesthesia. Br J Plast Surg 1988;41:533-8. 30. Ehrenstrijm Reiz GME, Reiz SLA. EMLA - A eutectic mixture of local anaesthetics for topical anaesthesia. Acta Anaesthesiol Stand 1982;26:596-8. 31. Hallen B, Carlsson P, Uppfeldt A. Clinical study of a lignocaine-prilocaine cream to relieve the pain of venepuncture. Br J Anaesth 1985;57:326-8. 32. Ehrenstriim Reiz G, Reiz S, Stockman 0. Topical anaesthesia with EMLA, a new lidocaine - prilocaine cream, and the Cusum technique for detection of minimal application time. Acta Anaesthesiol Stand 1983;27:510-2. 33. Maunuksela E-L, Korpela R. Double-blind evaluation of a lignocaine - prilocaine cream (EMLA) in children. Effect on the pain associated with venous cannulation. Br J Anaesth 1986;58:1242-5. 34. Manner T, Kanto J, Iisalo E, et al. Reduction of pain at venous cannulation in children with a eutectic mixture of lidocaine and prilocaine (EMLA cream): Comparison with placebo cream and no local premeditation. Acta Anaesthesiol Stand 1987;131:735-9. A. Does lidocaine-prilocaine cream 35. Hallen 8, Uppfeldt permit painfree insertion of IV catheters in children? Anesthesiology 1982;57:340-2.
39. Hopkins CS, Buckley CJ, Bush GH. Pain-free injection in infants. Use of a lignocaine-prilocaine cream to prevent pain at intravenous induction of general anaesthesia in l-5-year-old children. Anaesthesia 1988;43:198-201.
37. Moller C. A lignocaine-prilocaine cream reduces puncture pain. Ups J Med Sci 1985;90:293-8. 38. Cooper CM, Gerrish SP, Hardwick reduces the pain of venipuncture aesthesiol 1987;4:441-8.
veni-
M, et al. EMLA cream in children. Eur J An-
40. Watson AR, Szymkin P, Morgan AG. Topical anaesthesia for fistula cannulation in hemodialysis patients. Nephrol Dial Transplant 1988;3:800-2. 41. LIhteenm&i T, Lillieborg S, Ohlsen L, et al. Topical analgesia for the cutting of split-skin grafts: A multicenter comparison of two doses of a lidocaine/prilocaine cream. Plast Reconstr Surg 1988;82:458-62. 42. Rosdahl I, Edmar B, Gisslen H, et al. Currettage of molluscum contagiosum in children: Analgesia by topical application of a lidocaine/prilocaine cream (EMLA). Acta Derm Venereol (Stockh) 1988;68:149-53. 43. de Waard-van der Spek FB, Oranje AP, Lillieborg S, et al. Treatment of molluscum contagiosum using a Iidocaine/ prilocaine cream (EMLA) for analgesia. J Am Acad Dermato1 1990;23:685-8. 44. Hallen A, Ljunghall K, Wallin J. Topical anaesthesia with local anaesthetic (lidocaine and prilocaine, EMLA) cream for cautery of genital warts. Genitourin Med 1987;63: 316-9. 45. Ashinoff R, Geronemus RG. Effect of the topical anesthetic EMLA on the efficacy of pulsed dye laser treatment of portwine stains. J Dermatol Surg Oncol 1990;16:1008-11. 46. Arendt-Nielsen L, Bjerring P. Laser-induced pain for evaluation of local analgesia: A comparison of topical application (EMLA) and local injection (lidocaine). Anesth Analg 1988;67:115-23. 47. Enberg G, Danielson K, Henneberg S, et al. Plasma concentrations of prilocaine and lidocaine and methaemoglobin formation in infants after epicutaneous application of a 5% lidocaine-prilocaine cream (EMLA). Acta Anaesthesiol Stand 1987;31:624-8. 48. Juhlin L, Hagglund G, Evers H. Absorption of lidocaine and prilocaine after application of a eutectic mixture of local anesthetics (EMLA) on normal and diseased skin. Acta Derm Venereol (Stockh) 1989;69:18-22. 49. Woolfson AD, McCafferty DF, McClelland KH, et al. Concentration-response analysis of percutaneous local anaesthetic formulations. Br J Anaesth 1988;61:589-92. 50. McCafferty DF, Woolfson AD, Boston V. In viva assessment of percutaneous local anaesthetic preparations. Br J Anaesth 1989;62:17-21.
Clinics in Dermatology
1992;10:275-283 51. Small J, Wallace RG, Millar R, et al: Pain-free cutting of split skin grafts by application of a percutaneous local anaesthetic cream. Br J Plast Surg 1988;41:539-43. 52. McElnay JC, Matthews MP, Harland R, et al. The effect of ultrasound on the percutaneous absorption of lignocaine. Br J Clin Pharmacol 1985;20:421-4. 53. Cameroy BM. Ultrasound enhanced local anaesthesia. Am J Orthop 1966;8:47. 54. Novak EJ. Experimental transmission of lidocaine through intact skin by ultrasound. Arch Phys Med Rehabil 1964; 64:331-2. 55. Bezzant JL, Stephen RL, Petelenz TJ, et al. Painless cauterization of spider veins with the use of iontophoretic local anesthesia. J Am Acad Dermatol 1988;19:869-75. 56. Sloan JB, Soltani K. Iontophoresis in dermatology: A review. J Am Acad Dermatol 1986;15:671-84. 57. Gangarosa LP, Sr. Defining a practical solution for iontophoretic local anesthesia of skin. Methods Find Exp Clin Pharmacol 1981;3:83-94. 58. Pryor GJ, Kilpatrick WR, Opp DR. Local anesthesia in minor lacerations: Topical TAC vs lidocaine infiltration, Ann Emerg Med 1980:9:568 - 71. 59. Schaffer DJ. Clinical comparisons of TAC anesthetic solutions with and without cocaine. Ann Emerg Med 1985; 14:1077-80. 60. Tipton GA, Dewitt GW, Eisenstein SJ. Topical TAC (tetraCaine, adrenaline, cocaine) solution for local anesthesia in children: Prescribing inconsistency and acute toxicity. South Med J 1989;82:1344-6. 61. Dailey RH. Fatality secondary to misuse of TAC solution. Ann Emerg Med 1988;17:159-60. 62. Schou H, Krosh B, Knudsen F. Unexpected cocaine intoxication in a 14 month old child following topical exposure. J Toxic01 Clin Toxic01 1987;25:419-22. 63. Amdt KA, Burton C, Noe JM. Minimizing the pain of local anesthesia. Plast Reconstr Surg 1983;72:676-9. 64. McKay W, Morris R, Mushlin P. Sodium bicarbonate attenuates pain on skin infiltration with lidocaine, with or without epinephrine. Anesth Analg 1987;66:572-4. 65. Moore DC. The pH of local anesthetic solutions. Anesth Analg 1981;60:833-4. 66. Kirchhoefer RD, Allgire JF, Juenge EC. Stability of sterile aqueous lidocaine hydrochloride and epinephrine injections submitted by US hospitals. Am J Hosp Pharm 1986;43:1736-41. 67. Christoph RA, Buchanan L, Begalla K, et al. Pain reduction in local anesthetic administration through pH buffering. Ann Emerg Med 1988;17:117-20.
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68. Stewart JH, Cole GW, Klein JA. Neutralized lidocaine with epinephrine for local anesthesia. J Dermatol Surg Oncol 1989;15:1081-3. 69. Stewart JH, Chinn SE, Cole GW, et al. Neutralized lidocaine with epinephrine for local anesthesia-II. J Dermatol Surg Oncol 1990;16:842-5. 70. Buckley FP, Neto GD, Fink BR. Acid and alkaline solutions of local anesthetics: Duration of nerve block and tissue pH. Anesth Analg 1985;64:477-82. 71. DiFazio CA, Canon H, Grosslight KR, et al. Comparison of pH-adjusted lidocaine solutions for epidural anesthesia. Anesth Analg 1986;65:760-4. 72. Hilgier H. Alkalinization of bupivacaine for brachial plexus block. Region Anesth 1985;10:59-61. 73. Galindo A. pH-adjusted local anesthetics: Clinical experience. Region Anesth 1983;8:35 - 6. 74. Larson PO, Gangaram R, Swandby M, et al. Stability of buffered lidocaine and epinephrine used for local anesthesia. J Dermatol Surg Oncol 1991;17:411-4. 75. Swinehart JM. The ice-saline-xylocaine technique. A simple method for minimizing pain in obtaining local anesthesia. J Dermatol Surg Oncol 1992;18:28-30. 76. Klein JA. The tumescent technique for lipo-suction surgery. Am J Cosmet Surg 1987;4:263-267. 77. Klein JA. Tumescent technique for regional anesthesia permits lidocaine doses of 35 mg/kg for liposuction. J Dermato1 Surg Oncol 1990;16:248-263. 78. Coleman WP III, Badame A, Phillips JH III. A new technique for injection of tumescent anesthetic mixtures. J Dermat01 Surg Oncol 1991;17:535-7. 79. Benowitz NL, Meister W. Clinical pharmacokinetics of lidocaine. Clin Pharmacokinet 1978;3:177-201. 80. Glinert RJ, Zachary CB. Local anesthetic allergy. Its recognition and avoidance. J Dermatol Surg Oncol1991;17:491-6. 81. Ruzicka T, Gerstmeier M, Przybilla B, et al. Allergy to local anesthetics: Comparison of patch test with prick and intradermal test results. J Am Acad Dermatol 1987;16:1202-8. 82. Shatz M, Fung DL. Anaphylactic and anaphylactoid reactions due to anesthetic agents. Clin Rev Allergy 1986; 4:215-27. 83. Fisher DA. Local anesthesia in dermatologic surgery (letter). J Am Acad Dermatol 1990;22:139-41. 84. Schwartz HJ, Gilbert IA, Lenner KA, et al. Metabisulfite sensitivity and local anesthesia. Ann Allergy 1989;62: 83-6. 85. Schwartz HJ, Scher TH. Bisulfite sensitivity manifesting as allergy to local dental anesthesia. J Allergy Clin Immunol 1985;75:525 - 7.
T
he ability to alleviate pain has been an important factor in the progress of medicine over the last century. The development of anesthesia has revolutionized surgery, and the use of local anesthesia, in particular, has greatly facilitated the performance of dermatologic surgery. Local anesthesia may be defined as the reversible circumscribed loss of sensation resulting from inhibition of nerve conduction. Local anesthetics are pharmacologic agents that block action potential transmission in nerves.im5 Local anesthesia for dermatologic use has continued to evolve. Refinements of well-known methods, as well as the development of novel agents and approaches, have contributed to advances in cutaneous anesthesia over the past decade.
Mechanisms of Nerve Transmission and Blockade
History Clinical use of local anesthesia began in 1884 with the topical application of cocaine for ophthalmologic procedures by Koller and Freud.6*7 Cocaine subsequently gained acceptance worldwide. In the United States, Halsted employed cocaine in hundreds of cases.‘,s With increasing use, however, came an appreciation of the toxicity of the drug and a search for less toxic anesthetics. Einhorn synthesized procaine, an ester of paru-aminobenzoic acid (PABA), in 1905.‘*’ Tetracaine and chloroprocaine, longer-acting ester derivatives, were developed subsequently. Though efficacious and less toxic than cocaine, these ester derivatives of PABA were noted for their allergenic properties. From 1943 to 1948, lidocaine was developed by LofFrom the Department of Dermatology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Address correspondence to Christopher J. Arpey, MD, Department of Dermatology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, lowa 52242.
0
1992
by Elsevier
gren.9 It was the first of a new class of anesthetics, the amino amides, which had a much lower propensity for causing allergic reactions. Over the next 30 years, several more agents in this class were developed, with variable duration and potency (Table l).lm3 Most recently, a variety of approaches have further modified cutaneous anesthesia. Some examples include the mixing of agents, altering the vehicles for delivery of anesthetic compounds, and the topical application of anesthetics in novel ways. In addition, more information is available with respect to the influence of anesthetics on procedures such as skin grafting and liposuction, along with new findings regarding anesthetic toxicity. These developments are discussed here.
Science
Publishing
Co., Inc.
l
0738-081x/92/$5.00
Transmission of nerve impulses depends on the phospholipid bilayer surrounding axons, the axolemma.1° This membrane houses the molecular “gates” responsible for the Na+ and K+ ionic flux which creates a resting potential.3 Subsequent nerve stimulation may then result in action potentials and signal propagation.3J1 Schwann cells surround all nerve fibers; however, about one third of nerve fibers are wrapped with multiple layers of a lipid-protein mixture called myelin, formed by the Schwann cell. lo Myelin forms a type of discontinuous insulation with small, intervening unmyelinated segments called nodes of Ranvier. Myelinated nerves transmit impulses more quickly than unmyelinated nerves because of saltatory conduction of the action potential between nodes of Ranvier. At least 15 types of afferent nerves have been identified,12 many of which contribute to the complex sensory innervation of the skin. Small, lightly-myelinated A fibers and tiny, unmyelinated C fibers are believed to be responsible for the sensation of pain (nociception).5 The
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Table 1. Classification Name
and Clinical Class
Clinics in Dermatology 1992:10:275-283 Pharmacology
of
Local Anesthetics
Relative Potency
Pk
Onset
Duration
Metabolism
Procaine Chloroprocaine Tetracaine
Ester Ester Ester
1 l-4 8-16
8.9 8.7 8.5
Slow Fast Slow
Short Short Long
Plasma Plasma Plasma
Lidocaine Mepivacaine Prilocaine Etidocaine Bupivacaine
Amide Amide Amide Amide Amide
l-2 l-2 l-2 4-6 4-8
7.9 7.6 7.9 7.7 8.1
Fast Fast Fast Fast Moderate
Moderate Moderate Moderate Long Long
Liver Liver Liver Liver Liver
A fibers carry sharp pain; the C fibers carry dull pain.” As a result of their myelin insulation, A fibers are more difficult to anesthetize. The largest, most heavily myelinated A fibers, which transmit the sensations of pressure, touch, and proprioception, as well as motor function, are the most difficult to anesthetize, hence the ability of most patients to feel pressure and movement during local anesthesia.6 Current evidence suggests that local anesthetics operate by reversibly binding to specific receptors in the axolemma,2~3~5J3-15 within or adjacent to the internal opening of the sodium channel (Fig 1). The receptor conformation is altered and sodium influx ceases. Nerve depolarization and impulse transmission are thus pre-
vented. A second, nonspecific mechanism may also be operative, whereby the anesthetic is absorbed into the axolemma, resulting in temporary expansion of the phospholipid bilayer and closure of the sodium channels. Reaching the internal opening of the sodium channel requires passage through the hydrophobic axolemmal membrane. Local anesthetics are administered in their water-soluble, acidic, ionized form. Conversion to the nonionized base is required to traverse the membrane. Finally, once inside the axoplasm, reequilibration with the acid form occurs- this cation is the active channelblocking moiety.3J5 Many characteristics contribute to the efficacy of local anesthetics (Table 1).lm3 The most important of these are
Figure 2. Cross section of nerve and sodium channel. The channel is believed to span the entire thickness of the axonal membrane, with a gating mechanism located closer to the inner aspect. The sodium gate is closed when the nerve is at rest, preventing sodium influx and action potential generation. An open channel allows an inward rush of sodium, axonal depolarization, and subsequent impulse transmission. Binding of local anesthetics to a specific receptor within or nearby the internal aspect of the channel perpetuates closure of the gate. (From Savarese I], Covino BG. Basic and clinical pharmacology of local anesthetic drugs. In: Miller RD, editor. Anesthesia. 2nd ed. New York: Churchill Livingstone, 1986:994, with permission.)
ARPEY AND LYNCH LOCAL ANESTHESIA
Clinics in Dermatology 1992;10:275-283 lipid solubility, protein binding, and pK, .3,5These intrinsic properties clinically affect potency, duration, and onset of anesthesia, respectively. Anesthetic potency is defined in terms of the minimum concentration required to produce conduction blockade. Highly lipophilic anesthetics are more potent agents as a result of the high lipid content of the axolemma. Just as nonionized forms cross the nonpolar membrane more quickly, highly lipophilic compounds reach the axoplasma faster.5 Duration of anesthesia results mainly from the protein-binding capacity of the anesthetic. The axolemmal receptor site is believed to be composed of protein. Thus, agents with higher binding affinity are longer-acting.3,5 Onset of anesthetic action is affected principally by its method of delivery, its diffusion rate through tissue, and its pK,. Injected agents have a faster onset when compared with topical agents. Clearly, compounds that diffuse more quickly reach the nerve faster, and onset occurs sooner; however, the variation in diffusion times for anesthetics is not well understood. The pK, becomes important once the drug reaches the axolemma.5,16 The pKp, or dissociation constant, is the pH at which the cationic form is in equilibrium with the nonionized base form. Recall that although the cationic form is the active moiety at the receptor site, it is the base form that diffuses through the axolemmal lipid bilayer. The pK, of virtually all local anesthetics is higher than tissue pH (7.4). Therefore, a drug such as lidocaine (pK, 7.7) has a more rapid onset than procaine (pK, 8.9) because it creates more base at physiologic pH. In general, the lower the pK,, the faster the onset. Systemic absorption and subsequent inactivation of the tissue reservoir of anesthetic also play a role in determining efficacy. Except for cocaine, all local anesthetics possess variable intrinsic vasodilating capacity. Increased blood flow from vasodilation results in more rapid absorption and metabolism. The common practice of adding a vasoconstrictor, such as epinephrine, to local anesthetics partially counteracts this process and prolongs the duration of action.’
Classification Local anesthetics are typically classified by the two types of chemical bonds between the aromatic and amine portions of the compounds. lj3 In general, most of them have the following basic structure: Ester Amide
Aromatic Aromatic
portion- COO-R-amine portion portion - NHCO - R-amine portion
The aromatic portion is lipophilic,
the amine portion is
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hydrophilic, and R corresponds to a variable-length hydrocarbon intermediate chain. Variations in these three regions of anesthetics determine their physiologic properties. Anesthetics with an amide linkage are much less likely to elicit allergic reactions than ester-containing compounds. Esters are metabolized in plasma by pseudocholinesterase, whereas amides undergo enzymatic degradation in the liver. A summary of the properties of the most commonly used anesthetics may be found in Table 1.
Clinical
Use
Three methods for establishing local anesthesia of the skin have been in widespread use: topical anesthesia, infiltration anesthesia, and peripheral nerve blockade. Recent advances in cutaneous anesthesia have evolved from these techniques. Standard topical anesthesia involves the use of amide or ester derivatives in various vehicles applied to the skin or the use of skin refrigerants.‘Intact skin, however, often greatly impairs the penetration of topical anesthetics, restricting their use mainly to procedures involving the mucous membranes. As discussed later, improving topical anesthesia has been an area of great interest over the past decade. Refrigerants are rapid-onset, short-acting agents useful for minor procedures and dermabrasion. Some investigators *’ have, however, suggested that this technique may alter the morphology of skin, potentially increasing the difficulty of establishing an accurate histopathologic diagnosis. Modifications of standard techniques of infiltrative anesthesia have been attempted in recent years with some success in improving cutaneous anesthesia, and these are discussed later. General methods for infiltrative anesthesia and peripheral nerve blockade have been well reviewed elsewhere,s,18 and are not described here.
Advances
in Topical
Anesthesia
Local anesthetics have been available in topical formulations for many years, but because of poor penetration of intact skin their use has been limited mainly to mucosal regions.’ Formulations have included creams, ointments, aerosols, solutions, and suppositories. Several anesthetic ingredients have been used, namely, the esters cocaine, benzocaine, dibucaine, and tetracaine, as well as the amide lidocaine. A variety of investigators have attempted to improve the epidermal penetration of topical anesthetics. In 1957, Monash used the water-soluble salts of six different agents, under occlusion, without achieving anesthesia19;
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however, he found moderate success with higher concentrations of the base form of anesthetics in a petrolatum or hydrophilic ointment vehicle, under occlusion. Subsequent investigators found that such formulations neither penetrated sufficiently nor lasted long enough for clinical use 20.21 In the 1960s and 197Os, the potent solvents dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA) greatly improved the penetration of topical anesthetics, but resulted in unacceptable reactions,22 including edema, erythema, pruritus, burning, and stinging. At the same time, an amino ether compound, ketocaine, was extensively investigated. This highly lipophilic agent was effective, but it caused local irritation and blister formation.22*23 The search for more efficacious topical anesthetic formulations continued over the next decade, with the emergence of EMLA (eutectic mixture of local anesthetics, Astra Pharmaceuticals) as a useful agent for local anesthesia. EMLA was developed in the late 1970s and early 1980s by Juhlin, Evers, and Broberg.24-27 The eutectic phenomenon is the spontaneous lowering of the melting point of two substances when their solid forms are mixed together, far lower than the melting point of either ingredient alone.27-29 This phenomenon occurs with the two amide anesthetics, lidocaine and prilocaine, at room temperature. EMLA cream 5% consists of 25 mg/mL each of lidocaine and prilocaine base, with an emulsifier, viscosity-increasing agent, and water as the vehicle.30,31 The oil-in-water emulsion created by the eutectic effect obviates the need to dissolve the anesthetic base in an oi1.27 The result is a lidocaine-prilocaine concentration of 80% in the emulsion droplets, even though the total concentration is only 5%. Numerous clinical trials have been performed with EMLA in Europe, though the drug is still investigational in the United States. Most trials have studied its efficacy in venipuncture, 27,30-40skin graft harvesting,22*29,41 curettage of molluscum contagiosum,42*43 cautery of genital warts,44 and pulsed-dye treatment of port-wine stains.45 Most studies used a visual analog scale (VAS) to assess patient perception of pain to pinprick or to the procedure being performed. Some studies obtained additional subjective assessments of pain by patients and observers. Arendt-Nielsen and Bjerring, however, used the argon laser to elicit a pain response, citing its increased specificity for nociceptors when compared with pinprick.46 They also quantitated the degree of sensory blockade after EMLA application by eliciting cortical-evoked responses to low-energy, short argon-laser pulses, believing this technique more accurately simulates surgical pain. Regardless of method of pain assessment, a review of
Clinics in Dermatology 1992:10:275-283
these series reveals that EMLA was effective in attaining analgesia in about 60 to 75% of patients, though in some studies absent or mild pain was observed in over 90%.41,42 Conversely, effective analgesia was observed in only 40% of women treated for vaginal warts in a study by Hallen et a1.44 They theorized that mucosal absorption over the 50-minute application time may have inactivated the drug. Indeed, in the same study, EMLA was efficacious in 96% of the men with genital warts. EMLA has been found far superior to placebo and about as effective as infiltrated lidocaine when applied for at least 60 minutes. Application times appear to be important. Ehrenstrom Reiz et al recommend at least a 45minute application time, though success appears to be greater with over 60 minutes.32 In addition, most investigators recommend the use of a relatively thick layer of EMLA under an occlusive dressing. Application periods of at least 120 minutes were used for harvesting of skin grafts.29,41 The shortest effective application time cited for cutting skin grafts was 90 minutes,22 though the mean time in that series was 3 hours 20 minutes. Interestingly, however, after 3 hours EMLA may lose its efficacy, by way of depletion of lidocaine - prilocaine droplets in the EMLA layer nearest the skin.22 Gentle massage of the cream while under the occlusive dressing may replete the “reservoir” of droplets during prolonged applications. Studies of systemic absorption have been performed on both norma122*27,47*48and diseased48 skin. In adults, even with the application of large quantities of EMLA, plasma concentrations were far below toxic levels. Enberg et al used EMLA for venipuncture in infants 3 to 12 months old.47 They found that 2 mL of the substance applied for under 4 hours yielded subtoxic plasma levels of both anesthetics in all 22 patients. In addition, only minor elevations in methemoglobin were seen (prilocaine may result in methemoglobinemia when administered systemically). Nearly all studies reported occasional mild local reactions, including pallor, erythema (especially if left on for several hours), and edema. No long-term sequelae have been noted, and no delayed-type hypersensitivity has been observed, despite repeated administration at the same site.27 More recently, a group of investigators from Northern Ireland has studied a 4% amethocaine gel for local anesthesia.5,49-51 This highly lipophilic agent was found to be far better than placebo in achieving anesthesia. In addition, its onset was 30 to 45 minutes instead of the 60 to 70 minutes required for EMLA, its duration was typically twice as long as that of EMLA, and it appears to be much more potent on a per-gram basis50 No adverse reactions were noted in the 20 volunteers studied; however, it might be of interest to search for adverse or allergic
ARPEY AND LYNCH LOCAL ANESTHESIA
Clinics in Dermatology 1992;10:275-283 reactions on reexposure given its membership in the ester class of anesthetics. The same agent was found to be an effective anesthetic in 80% of 80 patients undergoing skin graft harvesting. 51 Although still under investigation, it has many potential benefits and may prove to be clinically useful. Other methods of increasing the penetration of topical anesthetics have been attempted, including ultrasound52-54 and iontophoresis.55-57 Many past reports of the efficacy of ultrasound in improving penetration of the skin by various drugs have been anecdotal reports or uncontrolled studies.52-54 Indeed, McElnay et al found insignificant improvement in anesthesia in a doubleblind, crossover trial comparing ultrasound plus 25% lidocaine with lidocaine cream alone.52 Bezzant et al employed salt-free 4% lidocaine delivered by means of a painless low-level electric current prior to cauterization of spider veins.55 Using this technique, iontophoresis, they were able to achieve adequate anesthesia in 15 of 16 patients, though no control group was employed. Further controlled studies may be helpful in assessing the usefulness of both ultrasound and iontophoresis in cutaneous anesthesia. Even if proven efficacious, the need for ultrasound equipment or a battery-operated iontophoresis device may limit the widespread use of these modalities. Finally, a mixture of tetracaine 0.5%, adrenaline 1: 2000, and cocaine 11.8% in solution (“TAC”) was used widely in the 1980s for suturing minor lacerations, particularly in children. 5s,59Typically, a gauze pad soaked in the solution is applied for 10 to 20 minutes to a laceration. The anesthesia achieved is comparable to that of infiltrated lidocaine, but the lack of an injection improves patient acceptance and suturing may be completed more efficiently; however, several toxic reactions have been well described, particularly in small children and when the mixture is applied to mucosal surfaces.@-62 High plasma levels of cocaine and tetracaine have been suspected as the cause of seizures, respiratory compromise, and cardiovascular toxicity. Tipton et al recommend further investigation to establish guidelines for the clinical use of TAC.60
Advances in Infiltrative
Anesthesia
Current pharmacologic agents for infiltrative anesthesia have changed little over the past decade, although a variety of modifications have been made in an attempt to lessen the pain of infiltration and to improve efficacy. Before some of these modifications are discussed, however, mention should be made of an investigational agent
279
in the amide class of anesthetics. This drug, ropivacaine, is structurally similar to mepivacaine and bupivacaine.3 Its onset is similar to that of bupivacaine, but its potency and duration of blockade are slightly less. Ropivacaine has a shorter elimination half-life and depresses the myocardium less than bupivacaine. It may become a useful alternative to mepivacaine and bupivacaine among the longer-acting amide anesthetics. Minimizing the pain of administering local anesthesia has been of great interest recently. Amdt et aP studied the assessment of pain by 15 volunteers using 2% lidoCaine. They examined the influence of depth of injection, rate of administration, and temperature on the perception of pain, using a 30-gauge needle. Degree of anesthesia was subsequently assessed by pricking the skin with a 30-gauge needle, as well. Not surprisingly, they found that superficial wheal-producing injections were much more painful than subcutaneous injections. In addition, although onset of anesthesia was delayed several minutes in those receiving deeper injections, duration was similar to those receiving intradermal injections. As one might expect, more slowly administered injections were significantly less painful than those given rapidly. Interestingly, no difference in pain sensation was noted when comparing lidocaine at 21 “C with lidocaine warmed to 37°C. Perhaps the most significant advance has been the discovery that alkalinizinganesthetics before theiradministration markedly diminishes the pain of injection, without compromising efficacy. Commercial preparations of local anesthetics are acidified to promote solubility and stability. 6L Moore tested the pH of a variety of commercially prepared ester and amide anesthetics, and found that all had pH values less than 6.6.65 The pH range for solutions containing epinephrine was 3.5 to 4.2. For plain anesthetics the pH range was 2.8 to 6.6, with most agents, including lidocaine, between 5.5 and 6.5. As a result of acidification, local anesthetics retain their stability for many months.66 Several groups have tested the theory that the acid pH is mainly responsible for the pain during infiltration and that alkalinizing local anesthetics would ameliorate the discomfort.64*67-69 A pH of about 7.3 can be attained by the addition of 1 mL of sodium bicarbonate (1 mEq/mL) to 10 mL of anesthetic. 64*6*This yields a final bicarbonate concentration of 0.1 mEq/mL. In all studies reviewed, this concentration significantly reduced pain when compared with anesthetic alone. Results were less impressive with anesthetics containing epinephrine, but the attenuation of pain persisted. Stewart et al found that the use of an equal volume of bicarbonate at a concentration of 0.4 mEq/mL, yielding a pH of 7.0, was nearly as effective.68 The addition of 0.1 mEq/mL (resultant pH of 6.5) was, however, insufficient; in fact, pain scores were
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LYNCH
nearly identical to those produced by injection of anesthetic alone. The mechanism of action of sodium bicarbonate in this setting may be more complex than a simple elevation of PH.~ For instance, a shift in equilibrium of the anesthetic to its nonionized form occurs with increasing pH, and it is possible that nociceptors are less sensitive to this form. It is also conceivable that the markedly increased concentration of nonionized anesthetic allows much more rapid diffusion through the tissue and axolemma, resulting in nearly instant inhibition of impulse transmission. Regardless of mechanism, alkalinization of local anesthetics, including lidocaine and mepivacaine among others, reduces the pain of infiltrative anesthesia. Fortunately it has been shown that onset of action is not prolonged, and the duration not shortened, by the addition of sodium bicarbonate.‘O Moreover, some studies cite a beneficial effect of alkalinization, namely, that onset may be shortened and duration prolonged.71-73 Other authors contend that this issue remains unsettled.‘O Finally, Larson et al made the observation that batch quantities of buffered lidocaine with epinephrine maintained greater than 90% of the original concentration of each constituent when stored at 0 to 4”C, up to 2 weeks after initial mixing.74 Lidocaine remained at greater than 90% of its initial concentration and epinephrine greater than SO%, under the same conditions after 4 weeks. At room temperature, lidocaine falls to nearly half, and epinephrine to less than 2%, of their original concentrations.6**74 The simple technique of refrigeration, then, permits batch buffering of lidocaine in an office setting without loss of efficacy. Another technique for minimizing the pain of establishing local anesthesia, the “ice-saline - xylocaine techThis pronique, ” was recently suggested by Swinehart. cess involves the use of small ice packs applied to the skin for several minutes, followed by a slow injection of normal saline with 0.9% benzyl alcohol (which is typically present in commercially available bacteriostatic saline), and finally an injection of buffered anesthetic with or without epinephrine. The injection of saline is painless and the benzyl alcohol may have intrinsic anesthetic properties. Swinehart reports excellent results in an uncontrolled series of 762 patients undergoing a variety of procedures, including hair transplantation and dermabrasion. Further studies may confirm the usefulness of this method in achieving local anesthesia. Finally, a method for safely administering large quantities of local anesthetic for liposuction has been developed. 76-78This method, the “tumescent technique,” involves the injection of large volumes of dilute lidocaine with epinephrine into subcutaneous fat prior to liposuction. A typical buffered 0.1% solution can be formed by
adding 100 mL of 1% lidocaine, 1 mL of 1: 1000 epinephrine, and 12.5 mL of sodium bicarbonate (1 mEq/mL) to a 1-L bag of normal saline. ” Modified blunt-tipped spinal needles”,‘s can be used to instill the solution which is attached to the syringe via intravenous tubing. Instillation of fluid is begun through a 20-gauge needle, followed by a longer la-gauge needle. General anesthesia and intravenous sedation are not required. Klein recommends either no sedation or small intramuscular injections of midazolam (2.5-5 mg) every 2 to 3 hours for larger procedures.” The amount of fluid instilled ranges from as little as 100 mL in the submental region to 2000 mL for the abdomen. The needle is inserted in multiple directions through the same entrance site, with subcutaneous induration as the goal. Anesthesia obtained in this fashion appears to be excellent, and liposuction may be performed easily and completely. Considerable blood-tinged drainage occurs for up to 18 hours, but actual whole-blood loss is minimal. Significantly, up to 35 mg/kg lidocaine may be safely given instead of the “standard” maximum of 7 mg/kg. Dilution both delays and diminishes the peak plasma lidocaine levels. By measuring plasma levels repeatedly over 24 to 36 hours in patients undergoing tumescent anesthesia, Klein found that none had levels greater than 2.7 pg/mL at any time. No patients experienced subjective toxicity and the minimal toxic level of 3 pg/mL was not broached. 79Peak levels were often seen 10 to 14 hours after the start of the procedure. Corresponding anesthesia was prolonged as well, improving postoperative pain management. The tumescent technique for liposuction appears to offer many benefits, and may become more widely used in the near future.
Adverse Reactions Adverse reactions to local anesthetics are uncommon. Several recent articles have reviewed this subject,8*18*80 and it is discussed briefly here in the context of recent findings and recommendations for approaching the patient with suspected anesthetic allergy. Reactions to local anesthetics may be regional or systemic. Local reactions include edema, pain, ecchymosis, and rarely gangrene or nerve damage. Systemic reactions may be toxic (ie, central nervous system excitability followed by coma, hypotension and myocardial depression from elevated blood levels), allergic (IgE-mediated), or idiosyncratic. Tachycardia, hypertension, angina, and dysrhythmias can result from high plasma levels of epinephrine. Many systemic reactions are vasovagal responses, averted by placing the patient in a supine position prior to injection. Toxic reactions are best avoided by limiting the dose and by reaffirming an extravascular in-
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ARPEY AND LYNCH LOCAL ANESTHESIA
jection site. Possible drug interactions, in particular those occurring with monoamine oxidase inhibitors (hypertension), phenothiazines (hypotension), and beta blockers (hypertension, if epinephrine is in the solution), should be kept in mind.7*1* Type I (immediate or IgE-mediated) allergy is more common with ester-type anesthetics than amides.1,3,8 Type IV reactions (delayed, cell-mediated) are not as well documented,s’ except in the setting of contact dermatitis to topical anesthetics. so Type I reactions are the most feared, because angioedema, bronchospasm, and anaphylaxis may occur. Although well-documented type I reactions have occurred with lidocaine and other amide anesthetics,s2 occasionally it is unclear whether the anesthetic itself or a preservative is the offending agent. Parabens have been implicated in some instances,W,*3 and more recently bisulfites and related compounds have been demonstrated to play a role.W,85 The use of singledose, preservative-free anesthetics may be helpful in treating such individuals. Finally, Glinert and Zachary have recently suggested an overall approach to “Caine-sensitive” patients.@ This approach includes a detailed history including past medical history and specific information regarding agents administered. The dose, route, presence of preservatives, other medications taken concurrently, type of reaction, and temporal relationship to anesthetic administration are also important. Highly suggestive of anaphylaxis are urticaria, angioedema, and wheezing within 2 hours of administration. For this group of patients, as well as for those having a borderline history or incomplete history, they recommend skin testing and challenge, preferably by an allergist in a setting where preparations for possible resuscitation have been made. A prick or scratch test to a minute amount of the drug is attempted first. The amount is then gradually increased and injected intradermally or subcutaneously over a l- to 2-hour period. Evidence of a local urticarial, or systemic reaction is sought. Epinephrine is excluded because it may blunt the wheal-and-flare response. Preservative-containing solutions may be tested separately. False-negative tests are fortunately quite rare, s2 whereas false-positive results occur in about 15% of patients tested.80 An organized approach to patients with suspected anesthetic allergy and judicious use of skin testing and incremental challenge improve physician confidence and patient safety during local anesthesia.
Conclusions Local anesthesia has been of critical evolution of cutaneous surgery over
Further refinements,
importance in the the past 50 years.
including EMLA and similar topical
agents, buffered anesthetics, technique, and a more detailed
modifications framework
281
of injection for investigat-
ing adverse reactions, have allowed continued progress in cutaneous anesthesia over the past decade.
References 1. Covino BG, Vassallo HG. Local anesthetics. Mechanisms of action and clinical use. New York: Grune & Stratton, 1976:1-11,13-39,57-75,89-121. 2. Strichartz GR, Covino BG. Local anesthetics. In: Miller RD, ed. Anesthesia. 3rd ed. New York: Churchill Livingstone, 1990:437-470. of local anesthet3. Covino BG, Lambert DM. Pharmacology ics. In: Longnecker DE, Murphy FL, editors. Introduction to anesthesia. 8th ed. Philadelphia: WB Saunders, 1992:195 212. 4. Stoelting RK, Miller RD. Basics of anesthesia. 2nd ed. New York: Churchill Livingstone, 1989:81-9. 5. Woolfson AD, McCafferty DF. Local anaesthesia of the skin. J Clin Pharmacol Ther 1989;14:103-9. 6. Koller C. Historical notes on the beginning of local anaesthesia. JAMA 1941;90:1742-3. 7. Lynch WS. Local anesthetics. In: Epstein E, Epstein E, Jr, eds. Skin surgery, 6th ed. Philadelphia: WB Saunders, 1987:25-35. 8. Grekin RC, Auletta MJ. Local anesthesia in dennatologic surgery. J Am Acad Dermatol 1988;19:599-614. 9. Lafgren N. Studies on local anesthetics. Xylocaine: A new synthetic drug. Stockholm: Haeggstroms, 1948. 10. Schmidt RF. The structure of the nervous system. In: Schmidt RF, editor. Fundamentals of neurophysiology. 2nd ed. New York: Springer-Verlag, 1978:1- 18. 11. Dude1 J. Excitation of nerve and muscle. In: Schmidt RF, editor. Fundamentals of neurophysiology. 2nd ed. New York: Springer-Verlag, 1978:19- 71. 12. Iggo A. Cutaneous sensory mechanisms. In: Barlow HB, Mollon JD, editors. The senses. Cambridge: Cambridge University Press, 1982:369-406. 13. Strichartz GR. Molecular mechanisms of nerve block by local anesthetics. Anesthesiology 1976;45:421-38. 14. Singer MA, Jain MK. Interaction of four local anesthetics with phospholipid bilayer membranes: Permeability effects and possible mechanisms. Can J Biochem 1980;58:815 - 21. 15. Covino BG. New developments in the field of local anesthetics and the scientific basis for their clinical use. Acta Anaesthesiol Stand 1982;26:242-9. 16. Covino BG. Local anesthetic agents for peripheral nerve blocks. Anaesthetist 1980;29:33-7. 17. Serup J. Punch biopsy of the skin: Effect of temperature and local anesthesia with ethyl chloride freezing. J Dermatol Surg Oncol 1983;9:558-61. 18. Winton GB. Anesthesia for dermatologic surgery. J Dermato1 Surg Oncol 1988;14:41-54.
282
ARPEY
AND
LYNCH
Clinics in Dermatology 1992;10:275-283
19. Monash S. Topical anesthesia of the unbroken skin. Arch Dermatol 1957;76:752-6. 20. Adriani G, Dalili H. Penetration of local anesthetics through epithelial barriers. Anesth Analg 1971;50:834-41. 21. Dalili H, Adriani G. The efficacy of local anesthetics in blocking the sensations of itch, burning, and pain in normal and “sunburned” skin. Clin Pharmacol Ther 1971;12: 913-9.
36. Hallen B, Ohlsson GL, Uppfeldt A. Pain-free venipuncture. Effect of timing of application of local anaesthetic cream. Anaesthesia 1984;39:969 - 72.
22. OhlsPn L, Englesson S, Evers H. An anaesthetic lidocaine/ prilocaine cream (EMLA) for epicutaneous application tested for cutting split skin grafts. Stand J Plast Reconstr Surg 1985;19:201-9. 23. Ponten B, Ohlsen L. Skin surface application of ketocaine to provide local anaesthesia for cutting split skin grafts. Br J Plast Surg 1977;30:251-4. of hyperhidrosis by 24. Juhlin L, Evers H, Broberg F. Inhibition topical application of a local anesthetic composition. Acta Den-n Venereol (Stockh) 1979;59:556-9. 25. Juhlin L, Evers H, Broberg F. A lidocaine-prilocaine cream for superficial skin surgery and painful lesions. Acta Derm Venereol (Stockh) 1980;60:544-6. 26. Broberg F, Evers H. European Patent 0002425 (1981). 27. Evers H, Von Dardel 0, Juhlin L, et al. Dermal effects of compositions based on the eutectic mixture of lignocaine and prilocaine (EMLA). Studies in volunteers. Br J Anaesth 1985;57:997-1005. A, Wadsten I, et al. Phase dia28. Brodin A, Nyqvist-Mayer gram and aqueous solubility of the lidocaine-prilocaine binary system. J Pharm Sci 1984;73:481-4. 29. Goodacre TEE, Sanders R, Watts DA, et al. Split skin grafting using topical local anaesthesia (EMLA): A comparison with infiltrated anaesthesia. Br J Plast Surg 1988;41:533-8. 30. Ehrenstrijm Reiz GME, Reiz SLA. EMLA - A eutectic mixture of local anaesthetics for topical anaesthesia. Acta Anaesthesiol Stand 1982;26:596-8. 31. Hallen B, Carlsson P, Uppfeldt A. Clinical study of a lignocaine-prilocaine cream to relieve the pain of venepuncture. Br J Anaesth 1985;57:326-8. 32. Ehrenstriim Reiz G, Reiz S, Stockman 0. Topical anaesthesia with EMLA, a new lidocaine - prilocaine cream, and the Cusum technique for detection of minimal application time. Acta Anaesthesiol Stand 1983;27:510-2. 33. Maunuksela E-L, Korpela R. Double-blind evaluation of a lignocaine - prilocaine cream (EMLA) in children. Effect on the pain associated with venous cannulation. Br J Anaesth 1986;58:1242-5. 34. Manner T, Kanto J, Iisalo E, et al. Reduction of pain at venous cannulation in children with a eutectic mixture of lidocaine and prilocaine (EMLA cream): Comparison with placebo cream and no local premeditation. Acta Anaesthesiol Stand 1987;131:735-9. A. Does lidocaine-prilocaine cream 35. Hallen 8, Uppfeldt permit painfree insertion of IV catheters in children? Anesthesiology 1982;57:340-2.
39. Hopkins CS, Buckley CJ, Bush GH. Pain-free injection in infants. Use of a lignocaine-prilocaine cream to prevent pain at intravenous induction of general anaesthesia in l-5-year-old children. Anaesthesia 1988;43:198-201.
37. Moller C. A lignocaine-prilocaine cream reduces puncture pain. Ups J Med Sci 1985;90:293-8. 38. Cooper CM, Gerrish SP, Hardwick reduces the pain of venipuncture aesthesiol 1987;4:441-8.
veni-
M, et al. EMLA cream in children. Eur J An-
40. Watson AR, Szymkin P, Morgan AG. Topical anaesthesia for fistula cannulation in hemodialysis patients. Nephrol Dial Transplant 1988;3:800-2. 41. LIhteenm&i T, Lillieborg S, Ohlsen L, et al. Topical analgesia for the cutting of split-skin grafts: A multicenter comparison of two doses of a lidocaine/prilocaine cream. Plast Reconstr Surg 1988;82:458-62. 42. Rosdahl I, Edmar B, Gisslen H, et al. Currettage of molluscum contagiosum in children: Analgesia by topical application of a lidocaine/prilocaine cream (EMLA). Acta Derm Venereol (Stockh) 1988;68:149-53. 43. de Waard-van der Spek FB, Oranje AP, Lillieborg S, et al. Treatment of molluscum contagiosum using a Iidocaine/ prilocaine cream (EMLA) for analgesia. J Am Acad Dermato1 1990;23:685-8. 44. Hallen A, Ljunghall K, Wallin J. Topical anaesthesia with local anaesthetic (lidocaine and prilocaine, EMLA) cream for cautery of genital warts. Genitourin Med 1987;63: 316-9. 45. Ashinoff R, Geronemus RG. Effect of the topical anesthetic EMLA on the efficacy of pulsed dye laser treatment of portwine stains. J Dermatol Surg Oncol 1990;16:1008-11. 46. Arendt-Nielsen L, Bjerring P. Laser-induced pain for evaluation of local analgesia: A comparison of topical application (EMLA) and local injection (lidocaine). Anesth Analg 1988;67:115-23. 47. Enberg G, Danielson K, Henneberg S, et al. Plasma concentrations of prilocaine and lidocaine and methaemoglobin formation in infants after epicutaneous application of a 5% lidocaine-prilocaine cream (EMLA). Acta Anaesthesiol Stand 1987;31:624-8. 48. Juhlin L, Hagglund G, Evers H. Absorption of lidocaine and prilocaine after application of a eutectic mixture of local anesthetics (EMLA) on normal and diseased skin. Acta Derm Venereol (Stockh) 1989;69:18-22. 49. Woolfson AD, McCafferty DF, McClelland KH, et al. Concentration-response analysis of percutaneous local anaesthetic formulations. Br J Anaesth 1988;61:589-92. 50. McCafferty DF, Woolfson AD, Boston V. In viva assessment of percutaneous local anaesthetic preparations. Br J Anaesth 1989;62:17-21.
Clinics in Dermatology
1992;10:275-283 51. Small J, Wallace RG, Millar R, et al: Pain-free cutting of split skin grafts by application of a percutaneous local anaesthetic cream. Br J Plast Surg 1988;41:539-43. 52. McElnay JC, Matthews MP, Harland R, et al. The effect of ultrasound on the percutaneous absorption of lignocaine. Br J Clin Pharmacol 1985;20:421-4. 53. Cameroy BM. Ultrasound enhanced local anaesthesia. Am J Orthop 1966;8:47. 54. Novak EJ. Experimental transmission of lidocaine through intact skin by ultrasound. Arch Phys Med Rehabil 1964; 64:331-2. 55. Bezzant JL, Stephen RL, Petelenz TJ, et al. Painless cauterization of spider veins with the use of iontophoretic local anesthesia. J Am Acad Dermatol 1988;19:869-75. 56. Sloan JB, Soltani K. Iontophoresis in dermatology: A review. J Am Acad Dermatol 1986;15:671-84. 57. Gangarosa LP, Sr. Defining a practical solution for iontophoretic local anesthesia of skin. Methods Find Exp Clin Pharmacol 1981;3:83-94. 58. Pryor GJ, Kilpatrick WR, Opp DR. Local anesthesia in minor lacerations: Topical TAC vs lidocaine infiltration, Ann Emerg Med 1980:9:568 - 71. 59. Schaffer DJ. Clinical comparisons of TAC anesthetic solutions with and without cocaine. Ann Emerg Med 1985; 14:1077-80. 60. Tipton GA, Dewitt GW, Eisenstein SJ. Topical TAC (tetraCaine, adrenaline, cocaine) solution for local anesthesia in children: Prescribing inconsistency and acute toxicity. South Med J 1989;82:1344-6. 61. Dailey RH. Fatality secondary to misuse of TAC solution. Ann Emerg Med 1988;17:159-60. 62. Schou H, Krosh B, Knudsen F. Unexpected cocaine intoxication in a 14 month old child following topical exposure. J Toxic01 Clin Toxic01 1987;25:419-22. 63. Amdt KA, Burton C, Noe JM. Minimizing the pain of local anesthesia. Plast Reconstr Surg 1983;72:676-9. 64. McKay W, Morris R, Mushlin P. Sodium bicarbonate attenuates pain on skin infiltration with lidocaine, with or without epinephrine. Anesth Analg 1987;66:572-4. 65. Moore DC. The pH of local anesthetic solutions. Anesth Analg 1981;60:833-4. 66. Kirchhoefer RD, Allgire JF, Juenge EC. Stability of sterile aqueous lidocaine hydrochloride and epinephrine injections submitted by US hospitals. Am J Hosp Pharm 1986;43:1736-41. 67. Christoph RA, Buchanan L, Begalla K, et al. Pain reduction in local anesthetic administration through pH buffering. Ann Emerg Med 1988;17:117-20.
ARPEY AND LYNCH LOCAL ANESTHESIA
283
68. Stewart JH, Cole GW, Klein JA. Neutralized lidocaine with epinephrine for local anesthesia. J Dermatol Surg Oncol 1989;15:1081-3. 69. Stewart JH, Chinn SE, Cole GW, et al. Neutralized lidocaine with epinephrine for local anesthesia-II. J Dermatol Surg Oncol 1990;16:842-5. 70. Buckley FP, Neto GD, Fink BR. Acid and alkaline solutions of local anesthetics: Duration of nerve block and tissue pH. Anesth Analg 1985;64:477-82. 71. DiFazio CA, Canon H, Grosslight KR, et al. Comparison of pH-adjusted lidocaine solutions for epidural anesthesia. Anesth Analg 1986;65:760-4. 72. Hilgier H. Alkalinization of bupivacaine for brachial plexus block. Region Anesth 1985;10:59-61. 73. Galindo A. pH-adjusted local anesthetics: Clinical experience. Region Anesth 1983;8:35 - 6. 74. Larson PO, Gangaram R, Swandby M, et al. Stability of buffered lidocaine and epinephrine used for local anesthesia. J Dermatol Surg Oncol 1991;17:411-4. 75. Swinehart JM. The ice-saline-xylocaine technique. A simple method for minimizing pain in obtaining local anesthesia. J Dermatol Surg Oncol 1992;18:28-30. 76. Klein JA. The tumescent technique for lipo-suction surgery. Am J Cosmet Surg 1987;4:263-267. 77. Klein JA. Tumescent technique for regional anesthesia permits lidocaine doses of 35 mg/kg for liposuction. J Dermato1 Surg Oncol 1990;16:248-263. 78. Coleman WP III, Badame A, Phillips JH III. A new technique for injection of tumescent anesthetic mixtures. J Dermat01 Surg Oncol 1991;17:535-7. 79. Benowitz NL, Meister W. Clinical pharmacokinetics of lidocaine. Clin Pharmacokinet 1978;3:177-201. 80. Glinert RJ, Zachary CB. Local anesthetic allergy. Its recognition and avoidance. J Dermatol Surg Oncol1991;17:491-6. 81. Ruzicka T, Gerstmeier M, Przybilla B, et al. Allergy to local anesthetics: Comparison of patch test with prick and intradermal test results. J Am Acad Dermatol 1987;16:1202-8. 82. Shatz M, Fung DL. Anaphylactic and anaphylactoid reactions due to anesthetic agents. Clin Rev Allergy 1986; 4:215-27. 83. Fisher DA. Local anesthesia in dermatologic surgery (letter). J Am Acad Dermatol 1990;22:139-41. 84. Schwartz HJ, Gilbert IA, Lenner KA, et al. Metabisulfite sensitivity and local anesthesia. Ann Allergy 1989;62: 83-6. 85. Schwartz HJ, Scher TH. Bisulfite sensitivity manifesting as allergy to local dental anesthesia. J Allergy Clin Immunol 1985;75:525 - 7.