Periodontology 2000, Vol. 46, 2008, 5679 Printed in Singapore.

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2008 The Author. Journal compilation 2008 Blackwell Munksgaard

PERIODONTOLOGY 2000

Intraoral topical anesthesia

J O H N G. M E E C H A N

Local anesthesia is the mainstay of pain control during intraoral operative procedures. A number of advances have occurred in relation to drugs and delivery systems since cocaine was isolated as the active anesthetic component of cocoa leaves by Albert Niemann in the middle of the 19th century (18, 104). Although the main role for local anesthetic drugs in the mouth is by injection they can also be applied topically. Topical intraoral application can be used to reduce the discomfort of intraoral local anesthetic injections; to provide anesthesia for intraoral operative procedures; to provide symptomatic relief from the pain of supercial mucosal lesions (such as ulcers); or to treat toothache and postextraction pain. The earliest recorded anesthetic effect of isolated cocaine was topical anesthesia of the tongue, reported by Niemann in 1860 (18). We have come full circle in that the latest local anesthetic formulation designed specically for periodontal treatments (Oraqix) is a topical application (45). This paper will consider the use and effectiveness of topical anesthesia in the mouth before local anesthetic injections, as the sole means of anesthesia for intraoral procedures, and as a treatment for toothache and postoperative pain.

Pharmacology of local anesthetic drugs

Those local anesthetics that are injected for the control of pain during intraoral operative procedures are classied by their chemical structure into esters and amides. Ester local anesthetics, such as procaine, are no longer in routine use as injectable agents because of the superior qualities of the amide type; however, esters such as benzocaine and amethocaine (tetracaine) are employed topically. Ester and amide anesthetics differ in two important respects. First, in

their potential to produce allergic reactions; second, in the way they are metabolized. Ester allergy has been recognized for some time (114). One study reported that the ester agent benzocaine produced contact sensitivity in 5% of a sample of 1200 eczematous patients (134). On the other hand, allergy to amides is thought to be rare (30, 38) and many so-called allergic reactions are probably toxic or vaso-vagal (30). This is supported by the fact that a number of patients reported to be allergic do not suffer reactions when challenged with the supposed antigen (32). Nevertheless, a number of allergic reactions to the amide lidocaine have been reported (30, 58, 74, 87, 118, 127, 132). These have ranged from mucosal reactions after topical use (58) to anaphylaxis (74, 85). Cross reactivity between different amide agents has been reported (30) and it is pertinent to point out that other components of dental local anesthetic carpules, such as preservatives, reducing agents and latex, could cause allergy (5, 91). Fortunately most modern local anesthetics are preservative-free and latex-free carpules are available. Ester local anesthetics are metabolized in the plasma by pseudocholinesterases and thus have a relatively short plasma half-life. Amide metabolism is more complex and takes place mainly in the liver, but not all amides are metabolized in an identical fashion. The metabolism of the archetypal amide lidocaine is shown in Fig. 1. Variations to the plan shown in Fig. 1 are experienced by prilocaine and articaine. Prilocaine undergoes some biotransformation in the lungs (9, 13). Articaine, although an amide, undergoes initial metabolism in plasma by a pseudocholinesterase (120). These differences in metabolism explain why prilocaine and articaine are available in higher concentrations than lidocaine for injection in dentistry. Although the higher concentrations may be more effective (82) there is some concern over problems of localized toxicity (nerve damage such as

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CH3 C2H5 NH CH3 CH3 NH CH3 C O CH3 NH2 CH3 HO NH2 CH3 CH3 Hydroxylation 4-hydroxy-2,6-xylidine 2,6-xylidine C O CH2 N C2H5 N-dealkylation C2H5 CH2 N H Hydrolysis Monoethylglycinexylidide Lidocaine

Fig. 1. The metabolism of lidocaine.

paresthesia) when injected around nerve trunks (59, 72). It is important to understand the mechanism of action of clinically useful local anesthetics. Notwithstanding their chemical differences, ester and amide local anesthetics have the same mode of action; they inuence the voltage-gated sodium channel. The structure of the voltage-dependent sodium channel is well characterized (25, 26); it is a complex structure composed of three subunits named a, b1, and b2. The b units are concerned with modulation of channel gating and are important in intercellular interactions (25) while the pore itself is contained in the a unit. Simplied diagrammatic representations of the a subunit and its congurational changes from rest through activation to inactivation are shown in Fig. 2AC. The a unit comprises four very similar protein domains (IIV), each of which has six helical segments (S1S6) that traverse the width of the cell membrane. S1S3 are negatively charged, S4 is positively charged, mainly arising from arginine and lysine residues (146). Activation of the channel occurs when the S4 segment moves outwards in a spiral path to open up the channel. A loop between domains III and IV acts as the inactivation gate (25), demonstrated by the fact that antibodies directed against this loop block inactivation (146). The S6 segment is the proposed site of local anesthetic binding (see below). When binding occurs, a physical blockade to sodium entry is created. In simple terms local anesthetics act as chemical roadblocks to the entry of sodium into the nerve cell, although they also prevent leakage of potassium. By blocking sodium entry, local

anesthetics inhibit nerve cell depolarization and thus prevent the propagation of nerve cell impulses along the nerve. There are two theories of local anesthetic action. These are the membrane expansion theory and the specic binding theory. The membrane expansion theory dictates that the incorporation of the local anesthetic into the nerve cell membrane causes a degree of expansion of the membrane and this physical distortion prevents sodium entry. There may be some effect of this non-specic action but the specic binding theory (71) is the method that is generally accepted as the main mode of action; in this model the local anesthetic binds to a receptor on the sodium channel. Good support for this theory is provided by the fact that different racemic forms of the same molecule show different pharmacological activities (146) and that binding ability is directly related to anesthetic potency (88). Two critical amino acid residues for local anesthetic binding (Phe 1764 and Tyr 1771) have been located on the S6 segment of domain 4 in the a subunit (25). Access to the binding site is from within the cell (25) and entry into the cell requires a lipophilic uncharged moiety to enter the nerve cell. Access to the binding site is easiest when the nerve cell is in the inactivated conguration (63, 146). It has been suggested that the binding of local anesthetic molecules is 17 times lower for resting channels than for inactivated channels (146). The more regularly a nerve res the more times it adopts the inactivated form so rapidly ring neurons are the most susceptible to the action of local anesthetics. This gives rise to the phenomenon known as use-

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Meechan Fig. 2. (A) The resting state of the a unit of the sodium channel showing the pore surrounded by the four domains each containing six protein segments that traverse the membrane. The entry of the S4 segments into the channel prevents sodium entry and thus maintains the resting potential. (B) The channel during the activation phase when the obstruction to sodium entry has been removed by movement of the S4 segments into the body of the membrane. (C) The inactivated conguration when a loop between domains III and IV blocks sodium entry. This is the conguration that is maintained with local anesthetic binding.

III

1 4 5

2 3

IV

II I

III

1 4 5

2 3

IV

II I

III

1 4 5

2 3

IV

II

phase of the nerve ring cycle (Fig. 2C). In this formation any further stimulation will not result in depolarization. Specic binding is achieved by charged molecules, so the anesthetic must be in the charged form to be active. The ability of local anesthetics to exist as both charged and uncharged portions is possible because they are weak bases. The portion that is present as an uncharged base is governed by the pH of the medium and the pKa of the molecule. The uncharged part traverses the nerve cell membrane and re-equilibrates to release the charged portion within the cell and this gains access to the binding site. Sodium channels are not all identical in structure. At present, nine different voltage-gated sodium channels have been identied (24). These are susceptible to different pharmacological actions and this, together with the fact that drug-binding sites are being characterized (41), suggests that it should be possible to develop drugs that are highly specic, for example it should be possible to increase afnity for peripheral nerves rather than cardiac tissue. In this way, local anesthetic drugs with less cardiotoxicity (see below) could be developed. The heterogeneity of sodium channels means that there is a variation in the efcacy of local anesthetics and is one explanation as to why the presence of inammation, which encourages the development of neural tissue into areas of inammation, reduces the effectiveness of local anesthetics as these new nociceptors have sodium channels that are less sensitive to the action of local anesthetics (63).

Adverse effects of local anesthetics

The problem of allergy was discussed above. Other unwanted effects are toxicity and drug interactions. The topic of drug interactions is covered in the paper by Hersh & Moore in this volume (69). Toxicity may be systemic or localized. Localized toxicity presents as nerve damage. This adverse effect of local anes-

dependent (or frequency-dependent) block. This act of binding maintains the sodium channel in the conguration that it adopts during the refractory

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thetics on nerves is concentration-dependent and has been demonstrated in vivo with differing concentrations of lidocaine (79). This has clinical implications because there is some evidence that more concentrated solutions, such as 4% articaine and 4% prilocaine, cause a greater prevalence of long-lasting paresthesia, especially of the lingual nerve. (59, 72). Some have criticized these ndings (99), noting that large-scale studies have shown no difference in the production of paresthesias following the intraoral injection of 2% lidocaine and 4% articaine (100). The jury is still out on this debate and undoubtedly more work will be performed in this important area. Local anesthetics are not specic in their action. They will affect tissues other than peripheral sensory nerves, thus adverse effects in other areas can ensue. Toxic effects of local anesthetics occur mainly in the central nervous and cardiovascular systems. The central nervous system is particularly sensitive to local anesthetics; plasma concentrations that do not affect transmission in peripheral nerves can affect the central nervous system. A study that investigated the levels of lidocaine required to produce central nervous system toxicity in humans concluded that the critical plasma level was 5 lg ml (40). At low doses the toxic effect is excitatory as a result of the anesthetic blocking inhibitory activity; at higher doses the effect is depressant, for example unconsciousness. Fatalities as a result of local anesthetic overdose are a result of the effect on the central nervous system, namely respiratory arrest (92). Any effect on the central nervous system will be determined by a number of factors, such as the concurrent use of other central nervous active agents, for example the convulsive threshold of lidocaine is raised by concurrent use of diazepam (31). The effects of local anesthetics on the cardiovascular system can be direct or indirect. The latter occurs as a result of inhibition of the autonomic bers that regulate cardiovascular function. Early signs of cardiovascular toxicity are a slowing of the pulse. Further inhibition of conduction leads to varying degrees of block, arrhythmias, and ventricular brillation (90). Toxicity is avoided by using sensible doses and ensuring that intravascular injection is avoided. The maximum doses of the local anesthetics used for injection in dentistry are shown in Table 1. These doses are those recommended when vasoconstrictorfree solutions are used. Although the addition of a vasoconstrictor, such as epinephrine, will reduce systemic uptake of local anesthetics, the downside is that epinephrine has been shown to reduce the

concentration of lidocaine needed to produce central nervous system effects (145, 154). Thus the doses given in Table 1 are suggested as a wise maximum. As a working rule of thumb one-tenth of a cartridge per kilogram of patient body weight approximates to the safe maximum dose for most formulations. The treatment of local anesthetic overdose is outlined in Table 2. Methemoglobinemia Methemoglobinemia is an unwanted effect of a number of local anesthetics, but is mainly associated with prilocaine and benzocaine (2, 62). Methemoglobinemia can cause cyanosis. It is a consequence of the oxidation of hemoglobin from the ferrous to the ferric state, leading to an inability to transport oxygen. Kreutz & Kinni (89) reported a case of methemoglobinemia in a healthy adult who received 632 mg of prilocaine with epinephrine. Crawford (29)

Table 1. Maximum recommended doses for the injectable local anesthetics used in dentistry
Recommended maximum dose (mg kg) (Ceiling in mg) 1.3 (90) 8.0 (400) 4.4 (300) 4.4 (300) 4.4 (300) 4.4 (300) 6.0 (400) 6.0 (400) 7.0 (500) Amount (mg) in 1.8-ml (2.2-ml) carpule 9 (11) 27 (33) 36 (44) 54 (66) 36 (44) 54 (66) 54 (66) 72 (88) 72 (88)

Drug and concentration 0.5% Bupivacaine 1.5% Etidocaine 2% Lidocaine 3% Lidocaine 2% Mepivacaine 3% Mepivacaine 3% Prilocaine 4% Prilocaine 4% Articaine

Table 2. Management of local anesthetic overdose

Stop the procedure Reassure the patient Lie the patient at Monitor and record vital signs Administer oxygen Give intravenous uids Give intravenous anticonvulsants Perform basic life support

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reported that the injection of the maximum recommended dose of prilocaine (400 mg) resulted in <1% of the total hemoglobin being converted to methemoglobin at 90 minutes post injection; this is considered a physiological level (95). Methemoglobinemia has been reported after topical application of prilocaine and benzocaine (see below); the management of methemoglobinemia is the intravenous infusion of methylene blue at a dose of 12 mg kg over a 5- to 10-minute period (62).

stimulation as the test method. These workers reported that the longest-acting drugs were those with the slowest onset. When different drugs were combined (lidocaine and tetracaine) the duration of anesthesia was determined by the longer-lasting drug, and no benet was derived. This nding is in contrast to later work, which has shown increasing efcacy with certain combinations such as lidocaine and prilocaine (see below). In order of decreasing duration the clinically useful drugs tested were amethocaine, cocaine, dibucaine, dyclonine, and lidocaine.

Pharmacology of topical application of local anesthetics

When applied topically, anesthetic agents must cross tissue barriers to get to their site of action. To achieve suitable amounts of drug at the site of action it is necessary to use concentrations that are higher than those normally injected. This has an impact on the production of systemic toxicity, as rapid and extensive absorption can occur. Animal experiments have demonstrated the transfer of lidocaine and prilocaine across oral mucosa within 2.5 minutes of application (11). Not all local anesthetics are active when applied to surface tissues, procaine for example does not achieve topical anesthesia at clinically acceptable concentrations (4, 11, 12). Both amide and ester local anesthetic agents can be active when applied topically. In addition non-ester, non-amide agents are used as topical anesthetics, for example dyclonine is a ketone. The agents that are most effective topically are those that are potentially most toxic systemically (4), this limits the choice. The duration of anesthesia following topical application is less than that of the same dose deposited intracutaneously. Adriani et al. (4) reported that the duration of action of 1% tetracaine was 53 minutes after topical application compared with 120 minutes after subcutaneous injection.

Concentration
The study of Adriani et al. (4) showed that although the onset and duration of local anesthetic action were concentration-dependent, there was a ceiling dose above which these factors did not vary. An in vivo study in dogs (11) showed that the plasma level of lidocaine, not surprisingly, was raised with increasing concentration of the topical agent. When a concentration of 12.5% was applied to lingual mucosa the average rate of transfer into plasma was 0.0017 mg% minute; this increased to 0.007 mg% minute when the concentration was doubled. A dose response has been shown by a number of workers. Giddon et al. (54) used electrical stimulation of the attached gingiva in the maxillary premolar region of human volunteers to assess the efcacy of different concentrations of lidocaine in lm strips in a placebo-controlled single-blinded study. They found a positive dose response for both depth and duration of anesthesia. Hersh et al. (67) compared the efcacies of intraoral patches containing 10% and 20% lidocaine or placebo placed on the mandibular buccal gingiva in human volunteers and noted that the more concentrated material was signicantly more effective than placebo after a 2.5minute application. The 10% patch took 5 minutes to achieve a similar result. They demonstrated a positive dose response throughout the 45 minutes of that trial.

Factors affecting efcacy

A number of in vitro and in vivo studies in both animals and humans have shown that a variety of factors inuence the action of topical anesthetics.

pH
As it is the un-ionized form of the drug that diffuses across tissues to get to the site of action and local anesthetics are weak bases, then an increase in pH should increase the rate of diffusion by increasing the amount of un-ionized base. In an in vitro experiment using dogs (11) the rate of transfer of 1%

The drug
Adriani et al. (4) studied a number of different topical anesthetics in human volunteers. They used electrical

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lidocaine across the oral mucosa increased from 0.05 mg 5 minutes at pH 5.9 to 0.07 mg 5 minutes at pH 8.6. Similar results were reported for prilocaine.

Site
Studies in human volunteers (4) have shown that the site of intraoral application governs the onset time and duration of anesthetic action after topical application. Anesthesia to electrical stimulation was apparent on the tongue after a 30-second application. This was not improved by extending the time of application up to 3 minutes. Duration of intraoral anesthesia increased from tip of tongue to lip to palate, although these were all less than the duration after conjunctival application. One aspect that makes intraoral sites vary in their susceptibility to topical anesthetics is the degree of keratinization of the mucosa. The palatal mucosa is much more keratinized than the buccal sulcus. Regimens that produce anesthesia of buccal sulcus mucosa have no effect on the palate (74, 76). It is not only the extent of keratinization that governs efcacy. One study has shown that the mandibular buccal sulcus is more rapidly anesthetized following topical application compared with the equivalent zone in the maxilla (67). The results of a retrospective study of 703 dental patients receiving maxillary inltration injections with or without 20% benzocaine topical anesthetic applied for 1 minute suggested that the topical anesthetic was effective in reducing the discomfort of needle penetration in the maxillary lateral incisor region, but had no inuence in this regard in the maxillary molar buccal sulcus (119).

Additives
Adriani et al. (4) reported that the addition of catecholamine and peptide vasoconstrictors did not inuence the activity of topical anesthetics. The addition of 1:10,000 epinephrine or vasopressin did not affect the duration, onset or depth of topical anesthesia provided by cocaine or tetracaine. The addition of detergents has been shown to both increase and decrease the onset of anesthesia when combined with topical anesthetics. Some studies have shown a decrease in onset time (4), while others (11) demonstrated that detergents inhibited onset. Bergman et al. (11) noted that the effect of the detergent cetylpyridinium chloride was concentration-dependent. At low concentrations of cetylpyridinium chloride (0.1%) the anesthetic action was enhanced and with higher concentrations (1%) anesthesia was inhibited. Other workers (83) have noted benets by adding absorption-enhancing agents to topical anesthetic formulations; they found that the addition of the glycyrrhiza derivative glycerrhetinic acid monohemiphthalate disodium increased the efcacy of 10% lidocaine in reducing the discomfort of skin pin-prick sensation in humans. A later study (136) showed that this enhanced lidocaine preparation was as effective as EMLA (eutectic mixture of local anesthetics; see below) in reducing skin pin-prick pain in humans.

Formulations
There are a number of different formulations of topical anesthetic for intraoral use. The anesthetic may be present: as a water-soluble salt; dissolved in organic solvents; as an oilwater emulsion; as a eutectic mixture; incorporated into patches and controlled-release devices; or incorporated into liposomes. The type of preparation affects it efcacy. A human volunteer study showed that less lidocaine needed to be incorporated into a lm-strip compared with the doses in a spray or ointment to achieve a similar anesthetic effect on attached gingiva (54). In addition, incorporation into lm strips increased the duration of topical anesthetic action when compared with ointments and sprays (54). As mentioned above, local anesthetics achieve their effect by binding to specic receptors in the sodium channel in nerve cells. This requires the agent to be in a charged form; however, it is the uncharged (base)

Duration of application
The duration of application of the anesthetic inuences the amount of penetration. This has been shown in a volunteer study (12) using needle insertion into skin in which workers measured the depth of penetration of an 18-gauge needle through skin at which pain was reported following the application of a mixture of lidocaine and prilocaine (EMLA) or placebo. They noted that increasing the time of application increased the depth at which pain perception began. Another human study (67) using an intraoral application of 10% or 20% lidocaine in a bioadhesive patch showed increasing relief from pinprick pain with increased time of application. The authors of that study suggested that the duration of residual anesthesia was dependent upon the duration of application.

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form that gains access to the inside of the nerve cell (the site from which the anesthetic gains access to its site of action). Water possesses the good penetrative properties that are important in the diffusion of topical preparations; however, the uncharged local anesthetic molecule is poorly soluble in water. This is overcome by using oilwater emulsions, which effectively increase the concentration of base in the water. The anesthetic is dissolved in oil and then emulsied in an aqueous vehicle. The maximum concentration of lidocaine that can be obtained in oil droplets is 20%; however, when lidocaine and prilocaine are combined they produce a eutectic form that achieves an anesthetic concentration of 80%. This is known as EMLA (eutectic mixture of local anesthetics) (37). When applied as ointments or creams the local anesthetic is released from all surfaces of the applied load. The amount entering the mucosa is therefore uncontrolled. To overcome this, controlled release devices (16) have been designed to discharge the agent from one surface at a predetermined rate. These devices have been used intraorally in a number of studies (15, 67, 144). Another method used to increase penetration after application of topical anesthetics is incorporation of the drug into liposomes (93). These are articial membranes consisting of uni- or multilamellar concentric bilayers that are formed when phospholipids are suspended in aqueous solution (10). Thus they are similar in composition to biological membranes. Liposome structure can be varied, depending upon the function required, by altering the number of layers. They can be used to deliver both water and lipid-soluble drugs. Delivery of a hydrophobic drug is best served by a unilamellar structure; a multilamellar construction with more aqueous phases is better for the incorporation of hydrophilic drugs. In addition to offering increased penetration, other advantages of liposomes include decreasing the effective dose, prolonging the action of drugs as they protect the drug from metabolism (34, 138) and decreased systemic toxicity (14). They have been investigated in medicine both as injectable forms (34) and as topical applications to skin (112) and cornea (137). They have been investigated intraorally as a means of delivering corticosteroids in animal models (64). The use of liposomes to deliver local anesthetics has been investigated by a number of authors. The increased efcacy afforded by liposomes has been demonstrated in skin where a standard application of amethocaine has been shown to be ineffective

whereas the drug incorporated into liposomes provided anesthesia (53). Similarly, lidocaine (17, 23) and amethocaine (75) incorporated into liposomes produce anesthesia of the skin that is as effective as EMLA (see below). The use of liposomes for the delivery of local anesthetics intraorally has been reported in two studies. One (155) compared liposomes containing 5% amethocaine with 20% benzocaine in a double-blind split-mouth trial as a means of disguising intraoral local anesthetic injection pain. These workers reported that the liposome formulation signicantly reduced the discomfort of needle penetration and inltration of anesthesia. The other study (42) compared 1% ropivacaine incorporated into liposomes with plain 1% ropivacaine, EMLA and 20% benzocaine in combating intraoral pin-prick discomfort. The liposome preparation produced longer-lasting anesthesia than the plain ropivacaine and 20% benzocaine and was similar in effect to EMLA.

Iontophoresis and phonophoresis

Another method of directing the diffusion of anesthetics after topical application is the use of iontophoresis (50). Iontophoresis employs an electrical charge to increase transportation of ionized materials across membranes. Local anesthetics such as lidocaine have a positive charge so penetration into tissue can be encouraged using iontophoresis. The method has been employed in dentistry and medicine to improve topical anesthesia, for example iontophoretically applied 4% lidocaine was more effective than topical lidocaine in reducing the discomfort of venous cannulation and the injection of propofol in the dorsum of the hand (135). The extent of local anesthetic entry has been shown to be directly related to the voltage in an animal model (61). Such a phenomenon, using cocaine for pulpal anesthesia, was described in the late 19th century (115). Gangarosa (49) used iontophoresis with lidocaine and epinephrine when extracting deciduous teeth (see below). Won et al. (152) reported the use of iontophoresis to deliver 4% lidocaine with 1:50,000 epinephrine for soft tissue anesthesia of buccal and lingual mandibular mucosa in a human study with ve volunteers. They reported duration of anesthesia ranging from 25 to 55 minutes. Another method that could be used to increase penetration is phonophoresis. This uses high-frequency radio waves and has been suggested as a possible method of increasing the efcacy of topical applications (98).

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The use of topical anesthetics to reduce the discomfort of intraoral local anesthetic injections
The use of topical anesthetics before injections is common in dentistry. A recent study of over 500 UK general dental practitioners reported that 95% of them used topical anesthesia before injections, 28% of the total sample used this pretreatment before all injections (28). Lidocaine and benzocaine were the most commonly used agents. The benets of topical anesthetics may not be entirely pharmacologicala psychological advantage may accrue. Martin et al. (102) reported that subjects who were informed that they were to receive a topical anesthetic anticipated less injection pain than those not offered such guidance. Another study found a signicant correlation between expected pain experience and actual pain experience (86). Similarly, Pollack (124) studied the effect of suggestion in a sample of 500 dental patients following topical anesthetic application. This worker found that patients who were given a verbal reinforcement of the effects of topical anesthesia reacted less severely to local anesthetic injection compared with those given no such information. A pharmacological effect can be determined in well-designed placebo controlled trials or in dose response studies. A number of investigations have compared topical anesthetics with placebo intraorally and the results are conicting. Some show positive benets from the use of topical anesthesia before needle insertion and others do not. The reasons for discrepancies include variations in the site and duration of application, choice of material (including formulation), and the fact that no gold standard stimulation test has been agreed. There are two aspects of local anesthetic injections that can cause pain. These are needle insertion and deposition of solution. A number of studies have investigated the effects of topical anesthetics on needle insertion in isolation and on the entire injection experience. These studies are described below.

Conventional intraoral topical preparations

Needle penetration studies A double-blind, split-mouth investigation into the effects of the topical application of 22% benzocaine, 2% amethocaine with 18% benzocaine, 5% lidocaine

or placebo for 30 seconds on reducing 25-gauge needle penetration discomfort into palatal mucosa found no signicant difference between any of the active agents and placebo (55). One study (47) compared 20% benzocaine and 60% lidocaine with placebo (but not with each other) during a 20-minute application in the anterior maxillary labial gingiva. The results of that study showed no difference between placebo and 20% benzocaine when a 30-gauge needle was inserted down to bone in this region; however, the 60% lidocaine preparation was superior to placebo in a similar test. Martin et al. (102) investigated the efcacy of topical anesthesia in masking the discomfort of 25-gauge needle penetration in the maxillary buccal sulcus in the premolar region in a modied placebo design; a 3-minute application of 20% benzocaine was compared with placebo. Volunteers received each treatment in a split-mouth investigation; however half of the volunteers were told they would be receiving only placebo and the other half were informed they would be receiving the anesthetic. Participants recorded actual and anticipated pain on a visual analogue scale. The results showed that those volunteers who were expecting to receive placebo anticipated more pain than those who were advised they would have the active agent applied. Actual pain experience did not differ between the active and placebo treatments. These workers concluded that topical anesthetics have little pharmacological effect. Three-minute applications of 5% lidocaine or 20% benzocaine have been shown to be signicantly more effective than placebo in reducing the discomfort of 27-gauge needle penetration in the maxillary buccal fold in the canine region in volunteers (133). In that study there was no difference in efcacy between the active drugs. Another study (153) investigated 27-gauge needle penetration in palatal mucosa in the second molar region following a 30-second application of 5% lidocaine or placebo. The results showed a signicant reduction in discomfort with the active agent. The effectiveness of different quantities of lidocaine contained in adhesive patches in reducing the discomfort of 25-gauge needle penetration intraorally was studied by Hersh et al. (67) in a placebocontrolled study. Active patches contained 10% or 20% lidocaine. The patches were applied to the buccal reected mucosa in both maxilla and mandible in volunteers. Both active patches were superior to placebo in reducing needle penetration in both jaws. A dose response was apparent as the 20% formulation provided signicantly greater anesthesia compared with the 10% patch.

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A double-blind randomized placebo-controlled trial with 40 subjects (20) investigated the efcacies of a 20% lidocaine patch applied for 15 minutes and the 30-second application of a benzocaine gel in reducing 25-gauge needle stick pain in the buccal gingiva in the bicuspid-molar region of either jaw. The needle was inserted to periosteum. When comparing ve-point verbal pain and visual analog scale scores the lidocaine patch was superior to placebo in reducing needle-stick pain in both jaws; benzocaine was signicantly better than placebo in the mandible but not in the maxilla. The lidocaine patch was signicantly more effective than the benzocaine gel at reducing needle-stick discomfort in both jaws. In a further double-blind placebo-controlled studies the same workers (21) increased the application time of the benzocaine gel to 1 minute and compared this with the 15-minute application of the 20% lidocaine patch using a verbal rating score. As in the study above, the lidocaine patch was superior to placebo and benzocaine gels in countering the pain of 25gauge needle insertion to the periosteum; however, the benzocaine did not differ signicantly from placebo in this trial. These workers (21) also compared the discomfort of 25-gauge and 27-gauge needle stick in the maxillary premolarmolar region following the 15-minute application of a patch containing 20% lidocaine or placebo. There was no difference in needle-stick discomfort between gauges; however the active patch was more effective than placebo in reducing discomfort. Zed et al. (155) reported that 5% amethocaine in liposomes was more effective than 20% benzocaine in reducing the discomfort of needle penetration before local anesthetic injections but needle gauge and time of application were not reported. Nakanishi et al. (116) reported that a 4-minute application of 20% benzocaine was signicantly more effective than placebo in reducing the discomfort of 30-gauge needle penetration in the mandibular buccal sulcus in the canine region in a blinded parallel study. A similar study using 27-gauge needles inserted in the pterygotemporal depression to mimic regional block anesthesia showed no difference between placebo and 20% benzocaine after a 4-minute application (116). Injection studies Pollack (124) studied the effects of a 15-second application of a topical anesthetic or placebo before injection in 500 patients and showed no difference in reaction to the local anesthetic delivery between treatments.

Another investigation (76) studied the topical application of 20% benzocaine and placebo for 1 minute for reducing the discomfort of buccal and palatal injections of 2% lidocaine with 1:100,000 epinephrine using 27-gauge needles in volunteers. The results showed that the topical anesthetic reduced injection discomfort on the buccal side but not palatally. Keller (84) investigated a 45-second application of the same topical anesthetics used in the study of Gill & Orr (55) (described above) before the injection of 0.3 ml lidocaine with epinephrine close to the greater palatine foramen with a 25-gauge needle. The results of this study on 60 patients showed no signicant difference in reported pain between treatments with 20% benzocaine, 18% aminobenzoate with 0.1% benzalkonium, and placebo. Kincheloe et al. (86) investigated the effects of a topical local anesthetic agent (material and concentration not reported) and placebo on pain perception on mucosa and injection of 2% mepivacaine with a 27-gauge needle. They reported no difference in injection experience between active agent and placebo. Fukuyama et al. (47) investigated the abilities of 20% benzocaine and 60% lidocaine applied topically for 20 minutes in reducing the discomfort of the injection of 0.9 ml 2% lidocaine with 1:80,000 epinephrine in the maxillary anterior labial gingivae. The benzocaine was no better than placebo; however, the 60% lidocaine formulation decreased visual analogue scale scores for injection compared with placebo. The rather long application time in this study was chosen by the authors because periods shorter than this failed to show any efcacy. They note that this is an unreasonable time clinically. One study (155) compared the effectiveness of the topical application of liposomes incorporating 5% amethocaine with 20% benzocaine gel in reducing both needle penetration and injection discomfort during administration of 4% prilocaine at un-named contralateral sites intraorally. These authors noted that the liposome regimen was more effective in reducing discomfort. Carr & Horton (21) compared the discomfort of the injection of 2% lidocaine with 1:100,000 epinephrine following the 15-minute application of a patch containing 20% lidocaine or placebo in the gingiva in the maxillary premolarmolar region with both 25- and 27-gauge needles. The active patch was more effective than placebo in reducing injection discomfort. All of the studies mentioned above have investigated the use of topical anesthetics before inltration anesthesia. Two studies have investigated the use of topical anesthetics before inferior alveolar nerve

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block injections, which necessitate deeper needle penetration. Meechan et al. (109) found that 20% benzocaine applied for two minutes was no better than no mucosal preparation before inferior alveolar nerve block injections with 2% lidocaine and 1:80,000 epinephrine using a 27-gauge needle in an adult population before mandibular extractions. The data from a retrospective study of 1635 dental patients who received inferior alveolar nerve blocks (27-gauge needle) with or without 20% benzocaine topical anesthetic for one minute (119) suggested that the

topical anesthetic had no effect on needle insertion discomfort. Comparison of positive and negative response studies The results of the needle penetration and injection studies described above are summarized in Tables 3 and 4, which separate them into those showing positive and no difference from placebo. When the Tables are compared some differences are apparent. Negative ndings are more common when the palate

Table 3. Studies showing no difference between effects of topical anesthetic and placebo in reducing needle penetration or local anesthetic injection discomfort
Agents 20% Benzocaine, 5% Lidocaine 20% Benzocaine 20% Benzocaine 20% Benzocaine 20% Benzocaine 20% Benzocaine 20% Benzocaine 20% Benzocaine 20% Benzocaine 20% Benzocaine Duration 30 seconds 30 seconds 45 seconds 1 minute 1 minute 3 minutes 3 minutes 4 minutes 20 minutes 20 minutes Site Palate Maxillary buccal Palate Palate Maxillary and mandibular buccal Maxillary buccal Maxillary buccal Pterygotemporal depression Maxillary buccal Maxillary buccal Test 25-g needle penetration 25-g needle penetration Injection with 25-g needle Injection with 27-g needle 25-g needle penetration 25-g needle penetration 25-g needle penetration 27-g needle penetration 30-g needle penetration Injection with 30-g needle Reference (54) (20) (84) (76) (20) (86) (102) (116) (47) (47)

Table 4. Studies showing positive effects of topical anesthetic over placebo in reducing needle penetration or local anesthetic injection discomfort
Agents 5% Lidocaine 20% Benzocaine 20% Benzocaine 5% Lidocaine 5% Lidocaine 5% Lidocaine, 20% Benzocaine 20% Benzocaine 10% Lidocaine, 20% Lidocaine 20% Lidocaine 20% Lidocaine 60% Lidocaine Duration 30 seconds 30 seconds 1 minute 2 minutes 2 minutes 3 minutes 4 minutes 15 minutes 15 minutes 15 minutes 20 minutes Site Palate Mandibular buccal Maxillary buccal Maxillary buccal Mandibular buccal Maxillary buccal Mandibular buccal Maxillary and mandibular buccal Maxillary and mandibular buccal Maxillary buccal Maxillary buccal Test 27-g needle penetration 25-g needle penetration injection with 27-g needle 27-g needle penetration 27-g needle penetration 27-g needle penetration 30-g needle penetration 25-g needle penetration 25-g needle penetration Injection with 2527-g needle Injection with 30-g needle Reference (153) (20) (76) (150) (73) (133) (116) (67) (20, 21) (21) (47)

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Table 5. Studies showing signicant differences between different topical anesthetic agents in reducing needle penetration or local anesthetic injection discomfort. The lower agent of each pair in the left-hand column was more effective
Agents 20% Benzocaine, 1% Ropivacaine in liposomes 20% Benzocaine, 1% Ropivacaine in liposomes 5% Lidocaine EMLA 20% Benzocaine EMLA 10% Lidocaine, 20% Lidocaine 20% Benzocaine gel, 60% Lidocaine gel 20% Benzocaine gel, 5% Amethocaine in liposomes Duration 2 minutes 2 minutes 5 minutes 10 minutes 15 minutes 20 minutes not reported Site Maxillary buccal Maxillary buccal Periodontal ligament Palate Mandibular buccal Maxillary buccal Not reported Test 30-g needle insertion 30-g needle insertion Intraligamentary injection with 30-g needle 27-g needle insertion 25-g needle insertion Maxillary inltration with 30-g needle Intraoral injection Reference (42) (42) (110) (6) (67) (47) (155)

is the site of application and wider gauge needles seem to be associated with greater failure of topical anesthesia. Also most of the successful applications had at least a 2-minute application. The exceptions are the studies of Yaacob et al. (153), Carr & Horton (20) and part of the investigation of Hutchins et al. (76). The rst of these studies (153) reported a 30second application of lidocaine to be effective in the palate. The design of that investigation was not ideal as the operator was not blinded and the active side was injected rst. It is known that the rst of a pair of injections is likely to be less painful (102) and thus this would have contributed to the effect. Carr & Horton (20) noted that a 30-second application of benzocaine was better than placebo in the mandibular mucosa but did not nd that a similar regimen was effective in the maxillary buccal sulcus; a later study (21), which doubled the application time to 1 minute, failed to produce anesthesia better than placebo in either arch. The study of Hutchins et al. (76) investigated a number of methods of reducing injection discomfort and part of their data suggested that a 1-minute application of 20% benzocaine was better than placebo in disguising injection pain in the buccal sulcus, but not in the palate. These workers injected less anesthetic than was used for the other injection studies that showed a positive response (21, 47) and the authors were unsure of the clinical relevance of their results. It seems therefore that application times of at least 2 minutes are required before needle penetration or injection. Indeed for an effect

on injection discomfort very long application times of lidocaine (1520 minutes) appear to be required. The efcacies of different topical anesthetics are summarized in Table 5 and show that some novel preparations (EMLA, see below; and use of liposomes) may be effective in reducing injection discomfort and can be of use on the palate. It is surprising that the gauge of needle affects the efcacy of topical anesthetics as it has been reported that needles of those gauges used in dentistry (25 30 g) do not differ in the discomfort they produce when inserted into oral mucosa (48).

EMLA
The above studies investigated topical anesthetics designed for intraoral use. A number of investigators have studied EMLA intraorally. EMLA is an acronym for eutectic mixture of local anesthetics and is a 5% mixture of prilocaine and lidocaine. This formulation was developed in the late 1970s and early 1980s (81) and has been used to anesthetize skin before a number of procedures such as venepuncture and minor operations (80, 101). It is one of the most commonly used topical anesthetics in dermatological practice (44). In dentistry it has been used on skin before venepuncture for sedation and has been reported as the sole means of anesthesia before temporomandibular joint arthrocentesis (70). It is not licensed for use intraorally but has shown interesting properties when used in the mouth.

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Needle penetration studies Holst & Evers (73) compared the effects of 2- and 5minute applications of 5% lidocaine and EMLA on the penetration of a 30-g needle into the labial gingiva in the mandibular canine region and the palatal mucosa opposite the upper canine in 10 healthy female volunteers. These workers reported more pain relief following the 5-minute compared with the 2minute application of the active agent. Both anesthetic regimens were more effective than placebo and at 5 minutes EMLA was signicantly better than 5% lidocaine. In a further trial (73) these authors compared the 2-minute application buccally of discs impregnated with EMLA with application of placebo discs to the lower rst premolars. They reported that pain related to penetration of a 27-gauge needle was signicantly reduced under the EMLA disc compared with the placebo. The effect of EMLA on the pain of palatal needle penetration was also investigated in a double-blind placebo-controlled study by Svennson & Petersen (142). These authors used the application of orahesive bandages for 5 minutes over the greater palatine and incisive foramina and measured the pain of 27gauge needle penetration in volunteers using a visual analogue scale. They found that the pain of needle insertion was signicantly reduced by EMLA but not by placebo. This effect was more marked at the greater palatine foramen compared with the incisive foramen. Al-Melh & Andersson (6) also looked at the effect of EMLA in decreasing the discomfort of needle penetration down to bone in the palatal gingiva adjacent to the maxillary canine. They found that EMLA was superior to 20% benzocaine in reducing discomfort over a 10-minute application period. A double-blind split-mouth investigation (150) compared the 2minute application of 5% lidocaine, 15% benzocaine with 1.7% amethocaine, and EMLA on the discomfort produced by insertion of a 27-gauge needle to a depth of 5 mm in the maxillary premolar buccal sulcus. Volunteers reported signicantly less pain with all active agents compared with placebo and the authors concluded that EMLA was the most effective of the topical preparations. Franz-Montan et al. (42) compared 2-minute applications of EMLA with similar applications of 20% benzocaine, 1% plain ropivacaine, and 1% ropivacaine in liposomes in disguising 30-g needle penetration down to the periosteum in the maxillary canine gingiva. EMLA was similar to the other materials on the visual

analogue scale scores reported for penetration but, together with the encapsulated ropivacaine, provided longer-lasting soft tissue anesthesia. Injection studies Meechan & Donaldson (108) investigated the effects of a 5-minute application of 5% lidocaine and EMLA in reducing the discomfort of maxillary inltration injections in children. They found no difference in injection discomfort between treatments. Nayak & Sudha (117) studied the effects of a 3-minute application of EMLA to 2-minute applications of 18% benzocaine or 5% lidocaine before buccal inltration anesthesia of lidocaine with epinephrine with a 26-gauge needle in children in a double-blind, splitmouth investigation. Using visual analogue scores for injection discomfort they reported that EMLA was signicantly better in reducing injection discomfort than the other agents. A third study (125) with 40 children compared a 5-minute application of EMLA with a 2-minute application of 20% benzocaine in reducing the palatal injection when a 27-gauge needle was used. The results showed that there was no difference in visual analogue scores for pain response during injection between treatments. The results of a study (111) that compared the 5-minute application of EMLA with placebo or transcutaneous electrical nerve stimulation (TENS) to palatal mucosa in adult patients about to have maxillary dental extractions showed that EMLA was signicantly more effective than the other treatments in reducing the discomfort of palatal injections of 2% lidocaine with 1:80,000 epinephrine with 27-gauge needles. There has been one randomized double-blind split-mouth study (110) that compared the efcacy of EMLA and 5% lidocaine applied for 5 minutes in the gingival crevice as a means of reducing the discomfort of intraligamentary injections of 2% lidocaine with 1:80,000 epinephrine. The results of that study showed that EMLA was more effective than lidocaine alone in reducing the discomfort of this method of anesthesia When looking at Table 6, which summarizes the results of the studies that have compared EMLA to placebo before intraoral needle penetration or injection it is apparent that this material appears to be effective on the palate. This is useful because this is an area considered difcult to anesthetize with topical anesthetics because of the high degree of keratinization that might make diffusion difcult.

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Table 6. Studies showing positive effects of EMLA over placebo in reducing needle penetration or local anesthetic injection discomfort
Agent EMLA EMLA EMLA EMLA Duration 2 minutes 5 minutes 5 minutes 5 minutes Site Maxillary buccal Palate and mandibular buccal Palate Palate Test 27-g needle penetration 27-g needle penetration 27-g needle penetration Injection with 27-g needle Reference (148) (73) (142) (111)

Use of topical agents to provide anesthesia for intraoral procedures

The use of topical application to obtain anesthesia for intraoral operative procedures is appealing. There are obvious advantages to the patient. Many patients fear dental injections (113). Extensive postoperative numbness may also be troublesome after injection (147). Indeed, patients may accept a less effective form of anesthesia if it means injections can be avoided (103). In addition, such a technique could benet the dental team because it should reduce the incidence of needle-stick injuries. Topical application of anesthetic agents to obtain anesthesia of the dental pulp has been investigated but is not in routine use (see below). It would appear that topical application might be more successful in obtaining anesthesia of the soft tissues intraorally. A number of experimental and clinical studies have looked at the use of topical anesthetics as the sole means for anesthesia of the intraoral soft tissues. Some agents are better than others in this regard.

Clinical Carr & Horton (20) compared the efcacies of a 20% lidocaine bioadhesive patch and 20% benzocaine gel in reducing the discomfort of scaling and root planing in two randomized double-blind placebocontrolled trials, each with 20 patients. The site of application was the buccal attached gingiva in the bicuspid-molar area of each jaw. The patch was applied for 15 minutes and the gel for 30 seconds. The lidocaine patch reduced the discomfort of scaling and root planing when compared with placebo (mean change 22.9 mm on visual analogue scale) whereas the benzocaine gel did not differ from placebo (mean difference 1.3 mm on visual analogue scale). When the different jaws were compared the lidocaine patch was more effective than the benzocaine gel in the maxilla (mean difference of 16.4 mm on visual analogue scale) but not in the mandible (mean difference of 8.2 mm on visual analogue scale). In another study of similar design (only differing in that the time of application of benzocaine was increased to 1 minute) these workers (21) conrmed their previous ndings that the lidocaine patch was superior to placebo in reducing the discomfort of scaling and root planing but that benzocaine did not differ signicantly from placebo in this regard. The use of topical anesthesia as the sole means of pain control for removal of intraoral soft tissue has been reported. One investigation (131) compared the 5-minute topical application of a strip containing 20 mg lidocaine with the injection of plain 2% lidocaine for oral mucosal punch biopsies (approximately 4 mm deep) in an unblinded study with 20 subjects. The results of that study showed that both treatments produced similar anesthetic duration but that biopsies performed under the lm were recorded as being signicantly more painful. The discomfort after the topical application was not associated with the initial punch cut, but with the incision at the base of the biopsy, probably as a result of poor penetration.

Conventional intraoral agents

Experimental The use of a patch containing 50 mg lidocaine for 30 minutes to obtain local anesthesia of the lips and attached gingivae was investigated by Brook et al. (15). Perception to painful stimuli (sharp probing) was eliminated in a mean time of 7.4 minutes after use of the patch. Normal sensation returned in a mean time of 26.4 minutes following patch removal. There was some loss of sensation on the vermilion border and skin surfaces, normal sensation returning to these areas in a mean time of 22.6 minutes following patch removal. A symptomless whitening of the mucosa in the area of application was noted at 24 hours in two volunteers. This disappeared after 48 hours.

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One study (139) compared the 5-minute application of a patch containing 20% lidocaine with the 1-minute application of 20% benzocaine gel before application of rubber dams in children aged 617 years using an unblinded split-mouth design. These workers found no difference in efcacy between treatments but concluded that the patch was not suitable for children because of the lack of adhesion and the length of time of application. In that study, patch adhesion was <30% but was agerelated, especially for girls where the increase in adhesion was 9 percentage points per year of age.

EMLA
Experimental Svensson et al. (141) used argon laser stimulation of the lower labial gingiva to compare the efcacy and duration of effect of lidocaine and EMLA. They measured pain and sensory thresholds following a 2-minute application of 2% lidocaine gel and 2-, 5and 15-minute applications of 1 g EMLA. The latter formulation was signicantly more effective than lidocaine alone in increasing sensory and pain thresholds. The greatest increase in pain threshold was noted immediately after removal of the topical anesthetic for all treatments. Sensory and pain thresholds were elevated for all regimens up to 25 minutes after removal. The duration of EMLA application did not affect the intensity of the anesthetic effect on the gingiva. The authors concluded that a 2-minute application on the gingiva produced analgesia for 10 minutes. Contrary to the results described above, Haasio et al. (60) found no difference in the analgesic effects of EMLA and lidocaine on buccal gingival mucosa on the upper jaw in 10 volunteers. They recorded both sensory and pain thresholds using electrical stimulation. The application and amounts of anesthetic differed between this trial and that described above (141). In this study, 4 g of EMLA was applied over four sites on the buccal gingiva with a toothbrush and the lidocaine formulation was a 10% spray, which was applied to four sites on the upper gingivae (total 200 mg lidocaine). The maximum analgesic effect occurred at a mean time of 13 minutes for EMLA and at 14 minutes for lidocaine. Normal sensation had returned in most cases by 30 minutes for each treatment. Nayak & Sudha (117) looked at the anesthetic onset times of EMLA, 18% benzocaine, and 5% lidocaine in providing anesthesia to blunt probing of the maxil-

lary anterior gingiva in children. They reported that the mean onset times were 75 seconds for benzocaine, 105 seconds for lidocaine, and 138 seconds for EMLA. McMillan et al. (106) compared the effects on the pain-pressure threshold (105) and sensitivity to pin-pricking of EMLA and 5% lidocaine applied topically on the buccal attached gingiva in the maxillary premolar region for 10 minutes. The pain pressure threshold was measured using an algometer with a 4-mm ball-ended tip (106). EMLA was superior to 5% lidocaine in increasing the painpressure threshold and in producing anesthesia to pin-prick. The effects on painpressure threshold suggested that EMLA was superior to lidocaine in penetrating the buccal cortical bone. EMLA produced anesthesia to pin-prick in all 10 volunteers in that trial but lidocaine was successful in only eight. Roghani et al. (130) also looked at the effects of topical anesthetics on the load required on the gingiva to produce discomfort in a double-blind study that compared placebo, 1% dyclonine, 10% cocaine 20% benzocaine, 10% lidocaine, and EMLA on the maxillary anterior gingiva. These workers used a 18 mm ball-ended tip connected to a measuring device and reported that a 3-minute application of EMLA was more effective than the other topical agents and placebo in raising the painpressure threshold. In the study of Franz-Montana et al. (42), the median duration of gingival anesthesia provided after a 2-minute application of EMLA in 30 volunteers was around 14 minutes. The results presented above suggested that EMLA might be useful as a topical anesthetic for minor operative procedures on the gingiva and it has been investigated in this regard in the clinical studies described below. Clinical The effects on the discomfort of scaling of 5-minute applications of EMLA or placebo to the gingival margins in patients with mild chronic periodontitis have been compared in a double-blind, randomized, split-mouth study (143). EMLA reduced the pain and unpleasantness of scaling in both jaws when compared to placebo. The inuence on pain was more marked than the effect on unpleasantness. In another double-blind, split-mouth volunteer study (36) a 5minute application of EMLA allowed a signicantly greater depth of pain-free probe penetration into the gingival crevice compared to similar treatment with 5% lidocaine. The use of a 4-minute application of 4 g EMLA to the gingivae using a toothbrush as a means of pain control for the removal of arch-bars

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used in intermaxillary xation was investigated in a double-blind, placebo-controlled trial in 45 dentate patients (123). Pin-prick sensation was signicantly reduced in the EMLA group 5 minutes after tooth brushing with the topical compared to the placebo, before removal of the arch-bars. Following removal of the arch-bars (mean time 19 minutes after tooth brushing) there was no difference between treatments in response to pin-pricking of the gingiva. Signicantly more patients with EMLA reported no pain compared to those who received placebo during removal of the arch-bars. There is a case report (107) of the use of a 15minute application of EMLA as the only means of pain control for the surgical removal of intraoral soft tissue from the palate in a patient with a needle phobia.

Oraqix
Those studies discussed above, which showed that EMLA was superior to 5% lidocaine, led to the development of a topical preparation of lidocaine and prilocaine dedicated for intraoral use. This material, known as Oraqix, is supplied as a thermosetting agent. Oraqix contains 25 mg g lidocaine and 25 mg g prilocaine. The material is liquid at room temperature but when injected into the gingival crevice it forms an elastic gel (46). Interestingly, although Oraqix was specically formulated for intraoral use, subjects who have received both Oraqix and EMLA in the mouth have reported that the latter was superior with regard to taste and smell (6). Oraqix has been investigated as a means of reducing the discomfort of intraoral injections (6), where it has been shown to be more effective than 20% benzocaine gel in reducing the pain of palatal inltrations in a human volunteer study. The indication for the use of Oraqix however, is for the relief of discomfort during periodontal treatments. It has been evaluated in a number of studies as the sole agent for anesthesia during periodontal treatments (35, 46, 78, 96, 147). When applied to periodontal pockets, onset of action is rapid with an anesthetic effect obvious at 30 seconds (46). An open-label investigation into the efcacy of Oraqix in reducing the discomfort of scaling and root planing in 30 patients showed that pain reduction (as measured by a visual analogue scale) was signicantly greater after a 30-second compared with a 2-minute application of the gel, although there was no difference between a 30-second and a 5-minute application (46). There

was no difference reported in duration of anesthesia to probing between 30-second, 2-minute and 5-minute applications (mean duration was 1820 minutes); however, the authors of that study noted that this does not reect anesthesia for scaling or root planing. A placebo-controlled study with 130 patients (35) looked at the discomfort of periodontal debridement after a 30-second application of Oraqix into periodontal pockets. In that investigation, median pain scores measured by visual analogue scale were low but those recorded after active treatment were signicantly lower than placebo (5 and 13 mm respectively). Verbal rating scores using a ve-point scale did not differ between treatments in that study; 78% reporting no or mild pain with active treatment and 76% with placebo. Another investigation (78) used a similar design to that described above (35) but varied the application time of Oraqix between 30 seconds and 2 minutes. Signicant differences were apparent in visual analogue scale scores between placebo and active treatment and in this study. Differences in the ve-point verbal rating score were also apparent with 90% of patients in the active group and 64% in the placebo group reporting no or mild pain. Rescue anesthesia was required by 11% of the active and 17% of the placebo groups. No data correlating the time of application and efcacy were reported. The data from this study suggested that the effect of Oraqix was more pronounced in subjects with more severe periodontal disease. Following on from that nding, another study (96) looked at the effect of Oraqix in patients who reported moderate to severe pain on periodontal probing (i.e. >30 mm on a visual analogue scale [27]). In this study with 85 patients Oraqix was placed in the periodontal pocket for 3045 seconds. The results showed that visual analogue scale scores and verbal rating scores were less when the active treatment was compared to placebo; 70% of those receiving Oraqix reporting no or mild pain after scaling and root planing, compared with 48% for placebo. None of the 43 patients in the Oraqix group reported severe pain whereas four of 42 patients in the placebo group reported severe or very severe pain. Five per cent of the active and 17% of the placebo patients required rescue anesthesia. Unlike the previous study, the results of this investigation did not show any relationship between the extent of disease and the efcacy of Oraqix. The data from the three double-blind placebo-controlled studies described above (35, 78, 96) were pooled and re-analysed by considering percentage changes between active and placebo treatments (97) and the

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authors concluded that the active treatments reduced discomfort during scaling and root planing by a factor of 50%. One open labeled, cross-over, multi-center study of 170 subjects investigated patients responses to Oraqix and conventional inltration anesthesia for scaling and root planning (147). Evaluations were performed immediately following and 4 hours after treatment. Efcacy of anesthesia, as determined by both operator and patient, was greater following injection compared to application of the gel; however, the majority of patients (70%) preferred anesthesia with Oraqix. This was despite the fact that one in ve patients did not receive adequate pain control after application of the gel. The principal reason for the preference was less numbness after treatment; 63% of subjects were bothered to a signicant degree by the postoperative feeling after the injection compared to 44% after Oraqix. The main reason chosen by those preferring injection (22%) was greater comfort during treatment. In none of these studies (35, 46, 78, 96) were there differences in adverse effects between active and placebo treatments and those reported could have been caused by the operative treatments provided. An interesting nding with Oraqix is the report that onset of anesthesia is rapid and seems to diminish very quickly. There is evidence that a 30-second application is more effective than a 2-minute treatment (46). This is in contrast to the other work described above, which has shown that the efcacy of intraoral topical anesthesia increases with time of application (67). This could be the result of wash away and might vary between methods of application, for example if a patch is used loss of active agent into the mouth (rather than into the tissues) may be reduced. When performing procedures such as scaling it is useful to have anesthesia of the tooth as well as the soft tissues. It is thus valid to ask the question do topical local anesthetics produce pulpal anesthesia? This is addressed below.

attached gingiva in the maxillary premolar region produced signicant elevations in pain threshold compared to base-line in rst premolars and when compared to those teeth adjacent to placebo patches. No teeth in either the test or control group showed total anesthesia. Franz-Montan et al. (42) showed that a 2-minute treatment of 20% benzocaine or 1% ropivacaine (plain and in liposomes) to the maxillary buccal gingiva in the canine region in human volunteers did not alter canine pulp responses during the 20 minutes following application. The application of a drop of 50% lidocaine solution onto exposed human dentin reduced the response to air blasting and probing in an uncontrolled study with six volunteers (7), while an anecdotal report (33) claimed great success when 20% benzocaine was used as a topical application to the dental pulp during endodontic treatment. The application of patches containing 20 mg lidocaine to the buccal and palatal lingual gingiva has been investigated as a means of pain control for dental extractions (144). Both children and adults were included in this study of 49 extractions in 40 patients. The extraction was performed when the gingivae could be detached from the tooth without pain. The mean times to extraction were approximately 19 and 13 minutes for the maxilla and mandible respectively. Successful anesthesia was achieved in 81% of teeth. Gangarosa (49) used iontophoresis for 10 minutes to apply 2% lidocaine with 1:50,000 epinephrine for the extraction of deciduous teeth. The method was successful in 12 out of 13 teeth, which were extracted without discomfort. EMLA The effectiveness of a 5-minute application over the apical areas of maxillary deciduous teeth has been investigated in a double-blind placebo-controlled trial (108). The results showed no difference in response to electrical pulp testing between treatments. The same investigators studied the efcacy of EMLA to eliminate the discomfort of restorative dentistry on deciduous teeth. They found that 80% of the children studied required supplementary local anesthesia to allow treatment to be completed painlessly (108). Another investigation (151) compared the application of EMLA, 10% lidocaine, and placebo on the response of maxillary central incisors to electrical pulp testing. Twelve of the 13 volunteers who received EMLA showed no response to electrical pulp testing between 15 and 30 minutes of application; however, some of the lidocaine-treated and placebo-treated cases also showed failure to respond under maximum

Studies into use of topical anesthetics to provide anesthesia for procedures on teeth
A number of workers have investigated changes in pulpal response to electrical testing after the application of topical anesthetics. Conventional agents Brook et al. (15) reported that the 30-minute application of a patch containing 50 mg lidocaine to the

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stimulation from the pulp tester. Another human volunteer study (42) showed that the 2-minute application of EMLA to the maxillary buccal gingiva in the canine region did not affect canine pulp responses during the 20 minutes after placement. The effectiveness of 1 g topical EMLA as an alternative to inltration anesthesia as pain control for restorative procedures was investigated in an uncontrolled pilot study in 12 patients (149). The authors reported that 75% of subjects obtained adequate analgesia. They concluded that this method provided some, but not complete, anesthesia to allow restorative dentistry to be performed.

Topical anesthetic relief of toothache and post-operative pain

The earliest reference to local anesthetic action of cocoa leaves was an intraoral effect recorded in 1653 when Bernabe Cobo reported that chewing cocoa leaves eased the pain of toothache (18). This may or may not have been a topical effect. Over-the-counter medications containing topical anesthetics such as benzocaine have been available for over 80 years. More recent studies have investigated the use of topically applied anesthetics for the symptomatic treatment of toothache (51, 66, 68, 140). It has been pointed out that signicant soft tissue anesthesia (including periosteum) may inuence the relief of toothache and that penetration through to bone and to the pulpal supply is not essential to produce some relief, as a result of convergence of trigeminal bers at the brainstem (66). Sveen et al. (140) noted that a 7.5% benzocaine gel produced better pain relief than placebo when applied to the gingivae adjacent to painful teeth in a double-blind trial with 49 patients. Pain relief occurred within 34 minutes. The treatment was not entirely successful, with 83% of the active treatments producing relief. A similar study investigated higher concentrations of benzocaine in gels (10% and 20%) and found these to be better than placebo in decreasing the intensity of toothache (51). Hersh et al. (66) also used benzocaine but this time included in an adhesive patch (12 mg benzocaine) as opposed to a gel. They investigated the efcacy of this patch in a double-blind, placebo-controlled trial in 60 patients with toothache. Patches were applied at the mucogingival junction of the affected tooth and remained in place for an hour. These workers reported a large placebo response in this investigation and although the active patch was superior in all their outcome measures (pain intensity and pain

relief scores) the only signicant difference they noted was an increase in the percentage of patients with meaningful pain relief at 30 minutes with the benzocaine patch. The median time to rst noticeable pain relief with the active patch was between 5 and 6 minutes. In a later study, these workers (68) reported a greater number of responders (that is patients who reported a signicant pain reduction) following the application of 20% benzocaine gel compared to placebo for the treatment of toothache. The median onset for meaningful pain relief was 8.3 minutes. Three investigations (8, 52, 57) have looked at the use of topical bupivacaine as a means of reducing post-operative discomfort in children following dental extractions. In one study (57) dental rolls soaked with 7 ml of 0.25% bupivacaine with 1:200,000 epinephrine placed over the extraction sites were more effective than saline-soaked rolls in relieving discomfort following extractions under general anesthesia in children aged between 7 and 15 years. The swabs were placed after the children awoke from the general anesthetic. The other two studies (8, 52) showed that no difference in pain relief was obtained when swabs with 0.25% bupivacaine and epinephrine or placebo (saline or distilled water) were inserted over the extraction sites in children immediately following extractions, while the child was still anesthetized. The mean time of application of the agent was 8 minutes in the former study (8).

Plasma levels following intraoral topical anesthetic application

Anesthetic applied topically is absorbed and will eventually enter the bloodstream. This is important because improper use could lead to toxicity, either as a result of topical application alone or in combination with any injected anesthetic (see above). It has been claimed that toxic reactions are more common after topical application compared to other methods of local anesthetic delivery (3). When considering toxic reactions the amount of drug is important. The concentration of drug in topical preparations is greater than that used for injectable formulations. An animal study (3) demonstrated that entry of local anesthetics into the circulation was quicker after topical administration to the pharynx compared to subcutaneous injection. Topical administration achieved much higher peak levels than slow intravenous infusion of the same dose. The authors of that study concluded that, although the peak plasma level was around a third of that obtained after intravenous

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injection, the prole of entry into the bloodstream following topical administration simulated that after rapid intravenous injection. Certainly toxic reactions, including fatalities, to topically applied local anesthetics have occurred (3, 77). Lidocaine Hersh et al. (67) found that plasma lidocaine levels rose steadily after the use of patches containing either 10 or 20 mg of the local anesthetic during the 15 minutes of patch application and then remained steady over a period of 30 minutes from the 15-minute sample. The average peak plasma levels obtained were 0.016 lg ml for the 10% patch and 0.022 lg ml for the 20% patch. These levels are an order of magnitude less than those achieved after the intraoral injection of 2% lidocaine solutions (19, 56). Brook et al. (15) reported peak lidocaine levels 4560 minutes after a 30-minute application of a patch containing 50 mg lidocaine on the buccal gingivae opposite the premolar teeth in either jaw. The mean peak level was around 0.030 lg ml and the highest concentration recorded was 0.095 lg ml. Haasio et al. (60) reported a mean plasma level 0.35 lg ml for lidocaine 30 minutes after the intraoral delivery of a large dose (200 mg) of lidocaine as a 10% lidocaine spray. The highest concentration noted was 0.66 lg ml at 20 minutes. Leopold et al. (94) investigated lidocaine levels in children after the intraoral application of patches containing 20% lidocaine. A 5-minute application in the maxillary buccal gingiva was used. The maximum level of lidocaine recorded in plasma was 0.128 lg ml (mean 0.082 lg ml). The average time to peak plasma concentration was 9 minutes with a range of 115 minutes. These workers point out that although these levels are well below the toxic concentration they are around four times higher than those reported with the same material in adults (0.022 lg ml see study of Hersh et al. [67] above). EMLA Plasma levels of lidocaine and prilocaine have been investigated after the 4-minute application of 4 g EMLA (100 mg lidocaine and 100 mg prilocaine) with a toothbrush to the gingiva (60, 123). Pere et al. (123) reported that the highest plasma level for lidocaine was 0.26 lg ml at 15 minutes and for prilocaine it was 0.09 lg ml at 30 minutes after the start of the application. The plasma levels of lidocaine were greater than those of prilocaine because of the more

rapid metabolism of the latter. Haasio et al. (60) found that the highest lidocaine concentration was 0.47 lg ml at 5 minutes and the highest prilocaine concentration was 0.21 lg ml at 10 minutes following the application of 4 g EMLA intraorally. These authors noted that absorption was more rapid after EMLA compared to a 10% lidocaine spray, but the only signicant difference was a higher mean plasma concentration of lidocaine at 30 minutes in the 10% lidocaine spray group where the mean plasma lidocaine concentration was 0.35 lg ml compared with 0.14 lg ml in the EMLA group. The highest lidocaine concentration in the EMLA group was 0.47 lg ml at 5 minutes compared to 0.66 lg ml in the lidocaine group at 20 minutes. The plasma concentrations of lidocaine and prilocaine following the 30-minute application of 8 g of EMLA to the buccal mucosa were measured in 12 volunteers by Vickers et al. (149). Peak plasma levels occurred 40 minutes after initial application for both anesthetics; the mean peak level for lidocaine was 0.221 lg ml and for prilocaine was 0.131 lg ml. The maximum concentrations noted in any one subject were 0.418 lg ml (lidocaine) and 0.223 lg ml (prilocaine). Oraqix Plasma levels of lidocaine and prilocaine following application of Oraqix have been reported in two studies. In one study (45), doses of 0.93.5 g Oraqix were applied to periodontal pockets in 10 patients. Blood samples were taken 10, 20, 30, 40, 60, 75, and 90 minutes after application of Oraqix. Peak plasma levels occurred between 20 and 40 minutes after application. The highest concentration of lidocaine reported was 0.266 lg ml (at 40 minutes) with a median of 0.169 lg ml (at 30 minutes). The greatest plasma level of prilocaine was 0.118 lg ml (at 30 minutes) with a median of 0.077 lg ml (at 30 minutes). In another study (65), plasma levels of lidocaine and prilocaine were measured following longer applications of a larger dose of Oraqix. In this study a median of 8.6 g (maximum 8.7 g) of Oraqix was applied over periods up to 3.4 hours and blood samples were taken in a 10-hour period post-application. Peak plasma levels of the anesthetics were achieved 3.7 hours after the start of application for lidocaine and 3.3 hours for prilocaine. The greatest level of lidocaine was 0.55 lg ml and of prilocaine was 0.18 lg ml. Methemoglobin levels were measured in this study; the greatest level noted was 1.73% with a median of 1.23%, occurring 14 hours after application. This represented a rise from the

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Table 7. Results of studies measuring plasma levels of anesthetic agents following topical intraoral and buccal inltration administration
Dose of anesthetic [formulation] 23 mg Lidocaine [10% patch] 46 mg Lidocaine [20% patch] 46 mg Lidocaine [20% patch]* 50 mg Lidocaine [patch] 200 mg Lidocaine [10% spray] 4 g EMLA 4 g EMLA 8 g EMLA Up to 3.5 g Oraqix 8.6 g Oraqix

Average (maximum) peak plasma level (lg ml) 0.016 0.022 0.082 (0.128)* 0.03 (0.095) 0.35 (0.66) Lidocaine 0.21 (0.26), Prilocaine 0.05 (0.09) Lidocaine 0.18 (0.47), Prilocaine 0.1 (0.21) Lidocaine 0.22 (0.42), Prilocaine 0.13 (0.22) Lidocaine 0.169 (0.266), Prilocaine 0.077 (0.118) Lidocaine 0.28 (0.55), Prilocaine 0.11 (0.18) 0.31 0.22

Reference (67) (67) (94*) (15) (60) (123) (60) (149) (45) (65) (56) (56)

36 mg Lidocaine [2% Lidocaine as a buccal inltration] 36 mg Lidocaine [2% Lidocaine with 1:100,000 epinephrine as a buccal inltration]
*A study in children.

pre-application median of 0.77% but was still within normal limits (<2%). Table 7 summarizes the results of the studies that have measured plasma levels of anesthetics following intraoral topical application and also shows the results obtained in one study (56) that investigated plasma levels of anesthetics after buccal inltration anesthesia. It can be seen from Table 7 that, although conventional intraoral topical agents produce levels of anesthetic in plasma that are an order of magnitude below those obtained after injection, large doses of some topical anesthetics achieve plasma levels similar to those obtained after conventional buccal inltration. It is therefore essential when considering maximum doses that both topical and any injected material are considered.

Adverse effects of topical anesthetics

The topical application of anesthetics seems to produce few problems locally. The problems of allergy, especially with ester-type local anesthetics, were mentioned earlier and must always be borne in mind, especially as the ester benzocaine is a popular topical agent. Non-ester agents, such as dyclonine,

have also been reported to produce allergies after topical use in the oro-facial region (126). Nevertheless, reports of damage to mucosa are not common and any adverse effects appear to be reversible (67). An exception is the misuse of the anesthetic agent cocaine. This drug can cause ulceration and gingival necrosis following topical application as a result of vasoconstriction (121, 128). A histological study in hamsters showed that the application of 5% lidocaine for periods up to 24 hours to the oral mucosa revealed no signs of any inammatory response or tissue edema (22) while in humans, the application of 10% or 20% lidocaine patches did not differ from the use of placebo patches with regard to adverse effects on the mucosa (67). There were no adverse local effects reported following a 30-minute application of 8 g EMLA to buccal mucosa in humans (149). Pashley & Parsons (122) described a case of severe pain following application of 5% lidocaine ointment adjacent to teeth with exposed dentine. They suggested that this was the result of an osmotic effect on dentinal tubules caused by the hypertonic topical preparation. It was mentioned above that one of the adverse effects of some local anesthetics is methemoglobinemia and that the drugs most likely to cause this

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problem are benzocaine and prilocaine. There are over 100 case reports of benzocaine-associated methemoglobinemia, mainly associated with the 20% benzocaine spray (148), especially in the pharynx (1, 129). It has been reported that the estimated incidence of methemoglobinemia following topical application before bronchoscopy is 1:7000 (62). It should be pointed out that the doses used on the pharynx are greater than would be applied topically in the mouth, but the fact that methemoglobinemia does occur must be remembered and there are two case reports of methemoglobinemia following topical use of benzocaine in the mouth (39). There has been a case of methemoglobinemia reported following the use of 5 g EMLA in a 12week-old child (76). The methemoglobin level was 28%. In that case the child was also receiving a sulfonamide, which can also produce methemoglobinemia. Normally the application of up to 5 g EMLA to the skin of young children <6 years does not raise methemoglobin levels above safe limits (43).

Conclusions
This paper has looked at the intraoral use of topical anesthesia. The conclusions that can be drawn from the studies reported are that topical anesthetics do have a pharmacological effect when used on oral mucosa, and that some formulations are better than others. When used properly they can be expected to reduce the discomfort of needle penetration before local anesthetic injection; however, the discomfort of anesthetic injection may not be so well disguised with conventional intraoral topical anesthetics and other methods such as slow injection speed should be used. There is evidence that some soft tissue procedures can be performed more comfortably following the use of topical anesthetics; however, pulpal anesthesia is not yet guaranteed by this method. When used sensibly adverse effects are few and not serious. Plasma levels are within safe limits; however, the amount of topical anesthetic used must be considered when supplementing with conventional local anesthesia, particularly in children.

References
1. Abdallah HY, Shah SH. Methemoglobinemia induced by topical benzocaine: a warning for the endoscopist. Endoscopy 2002: 34: 730734.

2. Adriani J. Reactions to local anesthetics. JAMA 1966: 196: 405408. 3. Adriani J, Campbell D. Fatalities following topical application of local anesthetics to mucous membranes. JAMA 1956: 162: 15271530. 4. Adriani J, Zepernick R, Arens J, Authement E. The comparative potency and effectiveness of topical anesthetics in man. Clin Pharmacol Ther 1963: 5: 4962. 5. Aldrete JA, Johnson DA. Evaluation of intracutaneous testing for investigation of allergy to local anesthetic agents. Anesth Analg 1970: 49: 173183. 6. Al-Melh MA, Andersson L. Comparison of topical anesthetics (EMLA Oraqix vs benzocaine) on pain experienced during palatal needle injection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007: 103: e16e20. 7. Amess TR, Matthews B, Barrak F, Matthews RW. Topical anesthesia of dentine in man. J Dent Res 1996: 75: 270 (abstract 2021). 8. Andrezejowski J, Lamb L. The effect of swabs soaked in bupivacaine and epinephrine for pain relief following simple dental extractions in children. Anesthesia 2002: 57: 281283. 9. Arthur GR, Scott DHT, Boyes RN, Scott DB. Pharmacokinetic and clinical pharmacological studies with mepivacaine and prilocaine. Br J Anaesth 1979: 51: 481485. 10. Bangham AD. Membrane models with phospholipids. Prog Biophys Mol Biol 1968: 18: 2995. 11. Bergman S, Kane D, Siegal IA, Ciancio S. In vitro and in situ transfer of local anaesthetics across the oral mucosa. Arch Oral Biol 1969: 14: 3543. 12. Bjerring P, Arendt-Nielsen L. Depth and duration of skin analgesia to needle insertion after topical application of EMLA cream. Br J Anaesth 1990: 64: 173177. 13. Boer F. Drug handling by the lungs. Br J Anaesth 2003: 91: 5060. 14. Boogaerts J, Declercq A, Lafont N, Benameur H, Akodad EM, Dupont JC, Legros FJ. Toxicity of bupivacaine encapsulated into liposomes and injected intravenously: comparison with plain solutions. Anesth Analg 1993: 76: 553555. 15. Brook IM, Tucker GT, Tuckley EC, Boyes RN. A lignocaine patch for dental analgesia safety and early pharmacology. J Control Release 1989: 10: 183188. 16. Brook IM, van Noort R. Controlled delivery of drugs. Br Dent J 1984: 157: 1115. 17. Bucalo BD, Mirikitani EJ, Moy RL. Comparison of skin anesthetic effect of liposomal lidocaine, non-liposomal lidocaine, and EMLA using 30-minute application time. Dermatol Surg 1998: 24: 537541. 18. Calatayud J, Gonzalez A. History of the development and evolution of local anesthesia since the cocoa leaf. Anesthesiology 2003: 98: 15031508. 19. Cannell H, Walters H, Beckett AH, Saunders A. Circulating levels of lignocaine after peri-oral injections. Br Dent J 1975: 138: 8793. 20. Carr MP, Horton JE. Clinical evaluation and comparison of 2 topical anesthetics for pain caused by needle insertion and scaling and root planning. J Periodontol 2001: 72: 479 484. 21. Carr MP, Horton JE. Evaluation of a transoral delivery system for topical anesthesia. J Am Dent Assoc 2001: 132: 17141719.

75

Meechan
22. Carrel R, Friedman L, Binns WH. Laboratory and clinical evaluation of a new topical anesthetic. Anesth Prog 1974: 21: 126131. 23. Carter EL, Copplla CA, Barsanti FA. A randomised doubleblind comparison of two topical anesthesia formulations prior to electrodesiccation of dermatosis papulosa nigra. Dermatol Surg 2006: 32: 16. 24. Caterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure function relationships of voltage-gated sodium channels. Pharmacol Rev 2005: 57: 397409. 25. Catterall WA. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 2000: 26: 1325. 26. Catterall WA. Molecular mechanisms of gating and drug block of sodium channels. Novartis Foundation Symposium 2002: 241: 206218. 27. Collins SL, Moore A, McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimetres? Pain 1997: 72: 9597. 28. Corbett IP, Ramacciato JC, Groppo FC, Meechan JG Topical anaesthetic use amongst UK general dental practitioners. International Federation of Dental Anesthetists, Society Proceedings of the 11th International Dental Congress on Modern Pain Control International Federation of Dental Anesthesiology Societies, 2006; P 93. 29. Crawford OB. Methaemoglobin following the use of prilocaine. Acta Anaesthesiol Scand 1965: 16: 183187. 30. Curley RK, McFarlane AW, King CM. Contact sensitivity to the amide local anesthetics lidocaine, prilocaine and mepivacaine. Arch Dermatol 1986: 122: 924926. 31. De Jong RH, Heavner JE. Diazepam prevents local anesthetic seizures. Anesthesiol 1971: 34: 523531. 32. De Shazo RD, Nelson HS. An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients. J Allergy Clin Immunol 1979: 63: 387394. 33. DeNunzio M. Topical anesthetic as an adjunct to local anesthesia during pulpectomies. J Endodont 1998: 24: 202203. 34. Dingle JT, Gordon JL, Hazleman BL, Knight CG, Page Tomas DP, Shaw IH, Fildes FJT, Oliver JE, Jones G, Turner EH, Lowe JS. Novel treatment for joint inammation. Nature 1978: 271: 372373. 35. Donaldson D, Gelskey SC, Landry RG, Matthews DC, Sandhu HS. A placebo-controlled multi-centred evaluation of an anaesthetic gel (Oraqix) for periodontal therapy. J Clin Periodontol 2003: 30: 171175. 36. Donaldson D, Meechan JG. A comparison of the effects of EMLA cream and topical 5% lidocaine on discomfort during gingival probing. Anesth Prog 1995: 42: 710. 37. Evers H. Present research in local analgesics. Br J Oral Maxillofac Surg 1988: 26: 390394. 38. Finucane BT. Allergies to local anesthetics the real truth. Can J Anesth 2003: 50: 869874. 39. Flyn K. Benzocaine-associated methemoglobinemia in dental patients. Veterans Health Administration Ofce of Patient Care Services Technology Assessment Program 2006: website: http://www.va.gov/VATAP/pubs/nalformattedbenzocainereport4-06.pdf. 40. Foldes FF, Molloy R, McNall PG, Koukal LR. Comparison of intravenously given local anesthetic agents in man. JAMA 1960: 172: 14931498. 41. Fozzard HA, Lee PJ, Lipkind GM. Mechanism of local anesthetic drug action on voltage-gated sodium channels. Curr Pharmaceut Design 2005: 11: 26712686. 42. Franz-Montan M, Silva ALR, Cogo K, Bergamaschi C de C, Volpato MC, Ranali J, de Paula E, Groppo FC. Liposomeencapsulated ropivacaine for topical anesthesia of human oral mucosa. Anesth Analg 2007: 104: 15281531. 43. Frayling IM, Addison GM, Chattergee K, Meakin G. Methaemoglobinaemia in children treated with prilocainelignocaine cream. BMJ 1990: 301: 153154. 44. Friedman PM, Mafong EA, Friedman ES, Geronemus RG. Topical anesthetics update: EMLA and beyond. Dermatol Surg 2001: 27: 10191026. 45. Friskopp J, Huledal G. Plasma levels of lidocaine and prilocaine after application of Oraqix, a new intrapocket anesthetic, in patients with advanced periodontitis. J Clin Periodontol 2001: 28: 425429. 46. Friskopp J, Nilsson M, Isacsson G. The anesthetic onset and duration of a new lidocaine prilocaine gel intrapocket anesthetic (Oraqix) for periodontal scaling root planing. J Clin Periodontol 2001: 28: 453458. 47. Fukuyama H, Suzuki N, Umino M. Comparison of topical anesthesia of 25% benzocaine and 60% lidocaine gel. Oral Surg Oral Med Oral Path Oral Radiol Endodont 2002: 94: 157161. 48. Fuller NP, Menke RA, Meyers WJ. Perception of pain to three different intraoral penetrations of needles. J Am Dent Assoc 1979: 99: 822824. 49. Gangarosa LP. Iontophoresis for surface local anaesthesia. J Am Dent Assoc 1974: 88: 125128. 50. Gangarosa LP. Newer local anesthetics and techniques for administration. J Dent Res 1981: 60: 14711480. 51. Gangarosa LP Sr, Ciarlone AE, Neaverth EJ, Johnston CA, Snowden JD, Thompson WO. Use of verbal descriptors, thermal scores and electrical pulp testing as predictors of tooth pain before and after application of benzocaine gels into cavities of teeth with pulpitis. Anesth Prog 1989: 36: 272275. 52. Gazal G, Bowman R, Worthington HV, Mackie IC. A double-blind randomized controlled trial investigating the effectiveness of topical bupivacaine in reducing distress in children following extractions under general anaesthesia. Int J Paed Dent 2004: 14: 425431. 53. Geszetes A, Mezei M. Topical anesthesia of the skin by liposome-encapsulated tetracaine. Anesth Analg 1988: 67: 10791081. 54. Giddon DB, Quadland M, Rachwall PC, Springer J, Tursky B. Development of a method for comparing topical anesthetics in different application and dosage forms. J Oral Ther Pharm 1968: 4: 270274. 55. Gill CJ, Orr DL. A double blind crossover comparison of topical anesthetics. J Am Dent Assoc 1979: 98: 213214. 56. Goebel WM, Allen G, Randall F. The effect of commercial vasoconstrictor preparations on the circulating venous serum level of mepivacaine and lidocaine. J Oral Med 1980: 35: 9196. 57. Greengrass SR, Andrzejowski J, Ruiz K. Topical bupivacaine for pain control following simple dental extractions. Br Dent J 1998: 184: 354355. 58. Gregg JB, Barnett GL, Ensberg DL. Mucosal slough reaction to topical anesthetic, lidocaine. Arch Otolaryg 1963: 77: 12.

76

Intraoral topical anesthesia

59. Haas DA, Lennon D. A 21-year retrospective study of reports of paresthesia following local anesthetic administration. J Can Dent Assoc 1995: 61: 319320. 60. Haasio J, Jokinen T, Numminen T, Rosenberg PH. Topical anaesthesia of gingival mucosa by 5% eutectic mixture of lignocaine and prilocaine or by 10% lignocaine spray. Br J Oral Maxillofac Surg 1990: 28: 99101. 61. Haga H, Shibaji T, Umino M. Lidocaine transport through living rat skin using alternating current. Med Biol Eng Comput 1999: 43: 622629. 62. Hall DL, Moses MK, Weaver JM, Yanich JP, Voyles JW, Reed DN. Dental anesthesia management of methemoglobinemia-susceptible patients: a case report and review of the literature. Anesth Prog 2004: 51: 2427. 63. Hargreaves KM, Keiser K. Local anesthetic failure in endodontics: mechanisms and management. Endodontic Topics 2002: 1: 2639. 64. Harsanyi BB, Hilchie JC, Mezei M. Liposomes as drug carriers for oral ulcers. J Dent Res 1986: 65: 11331141. 65. Herdevall BM, Klinge B, Persson L, Huledal G, AbdelRehim M. Plasma levels of lidocaine, o-toluidine, and prilocaine after application of 8.5 g Oraqix in patients with generalized periodontitis: effect on blood methemoglobin and tolerability. Acta Odont Scand 2003: 61: 230234. 66. Hersh EV, DeRossi SS, Ciarocca KN, Secreto SA, Ghassemi A. Efcacy and tolerability of an intraoral benzocaine patch in the relief of spontaneous toothache pain. J Clin Dent 2003: 14: 16. 67. Hersh EV, Houpt MI, Cooper SA. Analgesic efcacy and safety of an intraoral lidocaine patch. J Am Dent Assoc 1996: 127: 16261634. 68. Hersh EV, Stoopler ET, Secreto SA, DeRossi SS. A study of benzocaine gel dosing for toothache. J Clin Dent 2005: 16: 103108. 69. Hersh EV, Moore PA. Adverse drug interactions in dentistry. Periodontol 2000 2008: 46: 109142. 70. Hill Fanzca JS. Preoperative application of EMLA cream and the temporomandibular arthrocentesis procedure. Br J Oral Maxillofac Surg 2007: 45: 342343. 71. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 1977: 69: 497515. 72. Hillerup S, Jensen R. Nerve injury caused by mandibular block analgesia. Int J Oral Maxillofac Surg 2006: 35: 437 443. 73. Holst A, Evers H. Experimental studies of new topical anaesthetics on the oral mucosa. Swed Dent J 1985: 9: 185 191. 74. Holti G, Hood FJ. Anaphylactoid reaction to lignocaine. Dent Practit 1965: 15: 294296. 75. Hung OR, Comeau L, Riley MR, Tan S, Whynot S, Mezei M. Comparative topical anaesthesia of EMLA and liposomeencapsulated tetracacine. Can J Anaesth 1997: 44: 707711. 76. Hutchins HS, Young FA, Lackland DL, Fishburne CP. The effectiveness of topical anesthesia and vibration in alleviating the pain of oral injections. Anesth Prog 1997: 44: 87 89. 77. Jakobson B, Nilsson A. Methaemoglobinaemia associated with a prilocainelidocaine cream and trimethoprimsulphamethoxazole. A case report. Acta Anaesthesiol Scand 1985: 29: 453455. 78. Jeffcoat MK, Geurs NC, Magnusson I, MacNeill SR, Mickels N, Roberts F, Robinson P, Salamati A, Yukna R. Intrapocket anesthesia for scaling and root planing: results of a double-blind multicenter trial using lidocaine prilocaine dental gel. J Periodontol 2001: 72: 895900. 79. Johnson ME, Saenz JA, DaSilva AD, Uhl CB, Gores GJ. Effect of local anesthetic on neuronal cytoplasmic calcium and plasma membrane lysis (necrosis) in a cell culture model. Anesthesiology 2002: 97: 14661476. 80. Juhlin L, Evers H. EMLA: a new topical anesthetic. Advan Dermatol 1990: 5: 7591. 81. Juhlin L, Evers H, Broberg F. A lidocaineprilocaine cream for supercial skin surgery and painful lesions. Acta Dermato-Venereol 1980: 60: 544546. 82. Kannaa MD, Whitworth JM, Corbett IP, Meechan JG. Articaine and lidocaine mandibular buccal inltration anesthesia: a prospective randomised double-blind crossover study. J Endodont. 2006: 32: 296298. 83. Kano T, Hashiguchi A, Nakamura M, Morioka T, Mishima M, Nakano M. A comparative study of transdermal 10% lidocaine gel with and without glycyrrhetinic acid monohemiphthalate disodium for pain reduction at venous cannulation. Anesth Analg 1992: 74: 535538. 84. Keller BJ. Comparison of the effectiveness of two topical anesthetics and a placebo in reducing injection pain. Hawaii Dent J 1985: 16: 1011. 85. Kennedy KS, Cave RH. Anapylactic reaction to lidocaine. Arch Otolaryngol Head Neck Surg 1986: 112: 671673. 86. Kincheloe JE, Mealiea WL, Mattison GD, Seib K. Psychophysical measurement on pain perception after administration of a topical anesthetic. Quintessence Int 1991: 22: 311315. 87. Kirkler DM. Allergy to lignocaine. Lancet 1962: i: 159. 88. Kokuba M, Oda K, Kudo M, Machida M, Shinya M. Correlation between the anesthetic potency of local anesthetics and their binding ability to a model membrane. J Anesth 1997: 11: 121125. 89. Kreutz RW, Kinni ME. Life-threatening toxic methemoglobinemia induced by prilocaine. Oral Surg 1983: 56: 480482. 90. Lagan G, McLure HA. Review of local anesthetic agents. Curr Anaesth Crit Care 2004: 15: 247254. 91. Larson CE. Methylparaben An overlooked cause of local anesthetic hypersensitivity. Anesth Prog 1977: 24: 7274. 92. Lederman H, Freedman PD, Kerpel SM, Lumerman H. An unusual skin reaction following local anesthetic injection. Oral Surg 1980: 49: 2833. 93. Lener EV, Bucalo BD, Kist DA, Moy RL. Topical anesthetic agents in dermatologic surgery. A review. Dermatol Surg 1997: 23: 673683. 94. Leopold A, Wilson S, Weaver JS, Moursi AM. Pharmacokinetics of lidocaine delivered from a transmucosal patch in children. Anesth Prog 2002: 49: 8287. 95. Lund PC. Citnaest and methaemoglobin. Acta Anaesthiol Scand 1965: 16: 189196. 96. Magnusson I, Geurs NC, Harris PA, Hefti AF, Mariotti AJ, Mauriello SM, Soler L, Offenbacher S. Intrapocket anesthesia for scaling and root planning in pain sensitive patients. J Periodontol 2003: 74: 597602. 97. Magnusson I, Jeffcoat KK, Donaldson D, Otterbom IL, Henriksson J. Quantication and analysis of pain in non-

77

Meechan
surgical scaling and or root planning. J Am Dent Assoc 2004: 135: 17471754. Malamed SF. Whats new in local anesthesia? Anesth Prog 1992: 39: 125131. Malamed SF. Nerve injury caused by mandibular block analgesia. Int J Oral Maxillofac Surg 2006: 35: 876 877. Malamed SF, Gagnon S, Leblanc D. Efcacy of articaine: a new amide local anesthetic. J Am Dent Assoc 2000: 131: 635642. Manner T, Kanto J, Iisalo E, Lindberg R, Viinamaki O, Scheinin M. Reduction of pain at venous cannulations in children with a eutectic mixture of lidocaine and prilocaine (EMLA cream): comparison with placebo cream and no local premedication. Act Anaesthiol Scand 1987: 31: 735739. Martin MD, Ramsey DS, Whitney C, Fiset L, Weinstein P. Topical anesthesia: differentiating the pharmacological and psychological contributions to efcacy. Anesth Prog 1994: 41: 4047. Matthews DC, Rocchi A, Gafni A. Factors affecting patients and potential patients choices among anaesthetics for periodontal recall visits. J Dent 2001: 29: 173179. McAuley JE. Carl Koller: the man and the drug. Br Dent J 1985: 158: 339342. McMillan AS. Painpressure threshold in human gingivae. J Orofacial Pain 1994: 9: 4450. McMillan AS, Walshaw D, Meechan JG. The efcacy of EMLA and 5% lignocaine gel for anaesthesia of human gingival mucosa. Br J Oral Maxillofac Surg 2000: 38: 58 61. Meechan JG. The use of EMLA for an intraoral soft-tissue biopsy in a needle phobic: a case report. Anesth Prog 2001: 48: 3234. Meechan JG, Donaldson D. The intraoral use of EMLA cream in children: a clinical investigation. J Dent Child 1994: 61: 260262. Meechan JG, Gowans AJ, Welbury RR. The use of patient controlled transcutaneous electronic nerve stimulation (TENS) to decrease the discomfort of regional anaesthesia in dentistry: a randomised controlled clinical trial. J Dent 1998: 26: 417420. Meechan JG, Thomason JM. A comparison of 2 topical anesthetics on the discomfort of intraligamentary injections. Oral Surg Oral Med Oral Pathol 1999: 87: 362365. Meechan JG, Winter RA. A comparison of topical anaesthesia and electronic nerve stimulation for reducing the pain of intraoral injections. Br Dent J 1996: 181: 333335. Mezai M, Gulasekharam V. Liposomes: a selective drug delivery system for the topical route of administration I. Lotion dosage form. Life Sci 1980: 26: 14731477. Milgrom P, Coldwell S, Getz T, Weinstein P, Ramsey D. Four dimensions of fear of dental injections. J Am Dent Assoc 1997: 128: 756762. Mook WH. Skin reactions to apothesin and quinine in susceptible persons. Arch Dermatol 1920: 1: 651655. Morton WJ. Guaiacol-cocain cataphoresis and local anesthesia: a new catophoresis electrode and the Wheeler fractional volt selector. Dent Cosmos 1896: 38: 3853. Nakanishi O, Haas D, Ishikawa T, Kameyama S, Nishi M. Efcacy of mandibular topical anesthesia varies with the site of administration. Anesth Prog 1996: 43: 1419. 117. Nayak R, Sudha P. Evaluation of three topical anaesthetic agents against pain. Indian J Dent Res 2006: 17: 155160. 118. Noble DS, Pierce GF. Allergy to lignocaine. A case history. Lancet 1961: ii: 1436. 119. Nusstein JM, Beck M. Effectiveness of 20% benzocaine as a topical anesthetic for intraoral injections. Anesth Prog 2003: 50: 159163. 120. Oertel R, Berndt A, Kirch W. Saturable in vitro metabolism of articaine by serum esterases. Does it contribute to the persistence of the local anesthetic effect? Reg Anesth 1996: 21: 576581. 121. Parry J, Porter S, Scully C, Flint S, Parry MG. Mucosal lesions due to oral cocaine use. Br Dent J 1996: 180: 462464. 122. Pashley DH, Parsons GS. Pain produced by topical anesthetic ointment. Endodont Dent Traumatol 1987: 3: 8082. 123. Pere P, Iizuka T, Rosenberg PH, Lindqvist C. Topical application of 5% eutectic mixture of lignocaine and prilocaine (EMLA) before removal of arch bars. Br J Oral Maxillofac J 1992: 30: 153156. 124. Pollack S. Pain control by suggestion. J Oral Med 1966: 21: 8995. 125. Primosch RE, Rolland-Asensi G. Comparison of topical EMLA 5% oral adhesive to benzocaine 20% on the pain experienced during palatal anesthetic inltration in children. Ped Dent 2001: 23: 1114. 126. Purcell SM, Dixon SL. Allergic contact dermatitis to dyclonine hydrochloride simulating extensive herpes simplex labialis. J Am Acad Dermatol 1985: 12: 231234. 127. Ravindranathan N. Allergic reaction to lignocaine. A case report. Br Dent J 1975: 138: 101102. 128. Rees TD. Oral effects of drug abuse. Crit Rev Oral Biol Med 1992: 3: 163184. 129. Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature. Ann Pharmacother 1994: 28: 643 649. 130. Roghani S, Duperon DF, Barcohana N. Evaluating the efcacy of commonly used topical anesthetics. Ped Dent 1999: 21: 197200. 131. Roller NW, Ship II. Lidocaine topical lm strip for oral mucosal biopsies. J Oral Med 1975: 30: 5558. 132. Rood JP. A case of lignocaine hypersensitivity. Br Dent J 1973: 135: 411412. 133. Rosivack RG, Koenigsberg SR, Maxwell KC. An analysis of the effectiveness of two topical anaesthetics. Anesth Prog 1990: 37: 290292. 134. Rudner EJ, Clendinning WE, Epstein E. Epidemiology of contact dermatitis in North America: 1972. Arch Dermatol 1973: 108: 537540. 135. Sadler PJ, Thompson HM, Maslowski P, Liddle A, Rowbotham J. Iontophoretically applied lidocaine reduces pain on propofol injection. Br J Anaesth 1999: 82: 432 434. 136. Sakamoto M, Kaho T, Sadanga M, Shimodo O, Morioka T, Mishima M, Nakano N. Dermal patch anaesthesia: comparison of 10% lignocaine gel with absorption promoter and EMLA cream. Anaesthesia 1993: 48: 390392. 137. Schaeffer HE, Krohn DL. Liposomes in topical drug delivery. Invest Ophthalm Vis Sci 1982: 21: 220227. 138. Schmidt J, Metselaar JM, Wauben MHM, Toyka KV, Storm G, Gold R. Drug-targetting by long-circulating liposomal

98. 99.

100.

101.

102.

103.

104. 105. 106.

107.

108.

109.

110.

111.

112.

113.

114. 115.

116.

78

Intraoral topical anesthesia

glucocorticoids increases therapeutic efcacy in a model of multiple sclerosis. Brain 2003: 126: 18951904. Stecker SS, Swift JQ, Hodges JS, Erickson PR. Should a mucoadhesive patch (DentiPatch) be used for gingival anesthesia in children? Anesth Prog 2002: 49: 38. Sveen OB, Yaekel M, Adair SM. Efcacy of using benzocaine for temporary relief of toothache. Oral Surg, Oral Med Oral Pathol 1982: 53: 574576. Svensson P, Bjerring P, Arendt-Neilsen L, Kaaber S. Hypoalgesic effect of EMLA and lidocaine gel applied on human oral mucosa: quantitative evaluation by sensory and pain thresholds to argon laser stimulation. Anesth Prog 1992: 39: 48. Svensson P, Petersen JK. Anesthetic effect of EMLA occluded with orahesive oral bandages on oral mucosa. A placebo-controlled study. Anesth Prog 1992: 39: 7982. Svensson P, Petersen JK, Svensson H. Efcacy of a topical anesthetic on pain and unpleasantness during scaling of gingival pockets. Anesth Prog 1994: 41: 3539. Taware CP, Mazumdar S, Pendharkar M, Adani MH, Devarajan PV. A bioadhesive delivery system as an alternative to inltration anaesthesia. Oral Surg Oral Med Oral PatholOral Radiol Endod 1997: 84: 609615. Torbiner ML, Yagiela JA, Mito RS. Efect of midazolam pretreatment on the intravenous toxicity of lidocaine with and without epinephrine in rats. Anesth Analg 1989: 68: 744749. Ulbricht W. Sodium channel inactivation: molecular determinants and modulation. Physiol Rev 2005: 85: 1271 1301. Van Steenberghe D, Bercy P, de Boever J, Adriaens P, Geers L, Hendrickx E, Adriaenssen C, Rompern E, Malmenas M, Ramsberg J. Patient evaluation of a novel non-injectable anesthetic gel: a multicenter crossover study comparing the gel to inltration anesthesia during scaling and root planning. J Periodontol 2004: 75: 14711478. VHA Pharmacy Benets Management Strategic Healthcare Group and the Medical Advisory Panel and the National Center for Patient Safety. A guidance on the use of topical anesthetics for naso oropharyngeal and laryngotracheal procedures. 2006. website: http://www.pbm.va.gov/ criteria/benzocaine.pdf. Vickers ER, Marzbani N, Gerzina TM, McLean C, PunniaMoorthy A, Mather L. Pharmacokinetics of EMLA cream application to oral mucosa. Anesth Pro 1997: 44: 3237. Vickers ER, Punnia Moorthy A. A clinical evaluation of three topical anaesthetic agents. Aust Dent J 1992: 37: 266 270. Vickers ER, Punnia Moorthy A. Pulpal anesthesia from an application of a eutectic topical anesthetic. Quintessence Int 1993: 24: 547551. Won SH, Ryu HR, Lee SW, Kho HS. Penetration of lidocaine into oral mucosa by iontophoresis and its clinical application. J Dent Res 1995: 74: 576 (abstract 1404). Yaacob HB, Noor GM, Malek SN. The pharmacological effect of xylocaine topical anaesthetic a comparison with placebo. Sing Dent J 1981: 6: 5557. Yagiela JA. Intravascular lidocaine toxicity: inuence of epinephrine and route of administration. Anesth Prog 1985: 32: 5761. Zed CM, Epstein J, Donaldson D. Topical liposome encapsulated tetracaine versus benzocaine: a clinical investigation. J Dent Res 1996: 75: 247.

139.

148.

140.

141.

149.

142.

150.

143.

151.

144.

152.

145.

153.

154.

146.

155.

147.

79