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JJOD 399

Journal of Dentistry
Journal of Dentistry 28 (2000) 314 www.elsevier.com/locate/jdent

Review

Intra-oral topical anaesthetics: a review


J.G. Meechan*
Department of Oral and Maxillofacial Surgery, The Dental School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4BW, UK Received 15 December 1998; received in revised form 1 February 1999; accepted 19 February 1999

Abstract Objective: This review considers the use of topical anaesthetics in the mouth to reduce the discomfort of local anaesthetic injections and intra-oral operative procedures. Data sources: Electronic literature search using Pub Med, manual search of references within papers found by the primary search and manual searching of abstracts from scientic meetings. Study selection: The articles selected for this review investigate or used topical anaesthesia in dental procedures. Conclusions: The use of topical anaesthetics does not guarantee pain-free dental local anaesthesia. Efcacy is dependent upon the duration of application and the gauge of needle used. Evidence is available that the use of topical anaesthesia alone is sufcient to perform some intraoral procedures including periodontal manipulations, operative dentistry and oral surgery. 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Topical anaesthetics; Intra-oral operations; Local anaesthesia

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacology of topical application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Studies into the efcacy of topical anaesthetics prior to needle penetration or local anaesthetic injections . . . . . . . . 3.1. Studies reporting positive results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Studies reporting negative results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. The use of topical anaesthetics to reduce the discomfort of potentially painful intra-oral procedures . . . . . . . . . . . . 4.1. Studies on use in the gingival crevice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Studies on use on gingiva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Study into use of topical as sole anaesthetic for biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Studies into use of topical anaesthetics to provide dentinal/pulpal anaesthesia . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Studies into the use of topical anaesthetics as sole means of anaesthesia for dental extractions . . . . . . . . . . . 4.6. Use of topical agents for post-extraction pain relief . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Plasma levels following topical anaesthetic application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4 7 7 8 9 9 9 10 10 10 11 11 12 12 13

1. Introduction Surface anaesthesia may be achieved by physical methods, such as refrigeration anaesthesia, or by pharmacological means using topically active anaesthetic agents. The ideal local anaesthetic agent should be active
* Tel.: 44-191-2228292; fax: 44-191-2226137. E-mail address: j.g.meechan@ncl.ac.uk (J.G. Meechan)

when applied topically. However not all local anaesthetics used in dental practice achieve this, some such as procaine and mepivacaine cannot achieve a topical effect at clinically acceptable concentrations [1,2]. Effective administration of a local anaesthetic without the need for injection would be a major advance in dental pain control. Benets to patients and operators might include anxiety reduction and a decline in the number of needle-stick injuries.

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The ideal intra-oral topical anaesthetic should have the following properties: be non-allergenic; allow pain-free application; remain at site of application; have an acceptable taste; produce reliable anaesthesia; produce sufcient duration of anaesthesia; produce no local damage; produce no systemic toxicity.

Topical anaesthetics are used in dentistry for the following purposes: 1. to mask the discomfort of local anaesthetic injections; 2. to reduce the pain of operative dental procedures; 3. to relieve the pain of supercial mucosal lesions (such as ulcers); 4. to anaesthetise skin prior to venepuncture for sedation or general anaesthesia. This review considers the use of topical anaesthetics to mask the discomfort of potentially painful oro-dental procedures. The application of topical anaesthetics to treat the symptoms of oral mucosal lesions is not discussed, neither is the use of mechanical equipment such as jet injectors, thermal methods of surface anaesthesia or extra-oral use.

2. Pharmacology of topical application Both amide and ester local anaesthetic agents are active when applied topically. Indeed the only ester-type local anaesthetics available commercially for use in dental practice in the United Kingdom at present are the topical agents benzocaine and amethocaine. Bergman et al [3] investigated the transfer of radioisotope labelled lignocaine and prilocaine across the oral mucosa of the dog. They reported that the rate of transfer was proportional to the concentration of the drug, that increasing the pH increased the rate of transfer, that the addition of a detergent to the solution had a biphasic effect (an early increase in rate of transfer followed by a decrease), and that the different solutions did not differ in their ability to cross the mucosal barrier. Transfer was noted within 2.5 min of application. Adriani et al [1] compared the efcacy of different drugs as topical agents at various sites including the tip of the tongue on human volunteers using electrical stimulation. On tongue they found an effect at 30 s which was not improved by extending the time of application up to 3 min. These workers noted that there was a concentration of drug above which any increase did not result in improved efcacy, up to this dose the latency of onset was decreased and the duration of action increased with increasing dose. They also noted that combining drugs (such as lignocaine and amethocaine) gave no benet, duration of action being

governed by the longer lasting drug. In order of decreasing duration the clinically useful drugs tested were amethocaine, cocaine, dibucaine, dyclonine and lignocaine. These workers also noted that the duration of effect varied with method of delivery, topical anaesthesia lasting less than half the time of an identical dose administered intracutaneously. Similarly, the site of application inuenced duration of topical administration in order of increasing duration the tissues tested were skin (no effect), tip of tongue, lip and palate, and conjunctiva. Like Bergman et al [3] they found effects related to pH of the applied agent. They found that the addition of catecholamine and peptide vasoconstrictors did not inuence the activity of topical anaesthetics. Like Bergman et al [3] they noted an effect of the addition of detergents, these causing a reduction in the latency of onset. Other workers have reported the value of adding absorption enhancing agents in producing effective topical formulations [4]. In total Adriani et al [1] investigated 40 different agents and concluded that those most effective topically were those that were potentially most toxic systemically. The degree of penetration is governed by the duration of application. Bjerring and Arendt-Nielsen [5] investigated depth of analgesia in volunteers (using needle insertion to skin) and noted that this was dependent upon the duration of application of the topical anaesthetic. Local anaesthetics for topical application can be incorporated into a number of different preparations. The type of preparation can affect efcacy. Giddon et al. [6] showed that lower concentrations of lignocaine were needed in lm strips compared to the concentration in sprays to achieve the same level of analgesia. These workers also demonstrated a dose response to lm strip application [6]. The different methods by which topical anaesthetics may be applied intra-orally include: 1. 2. 3. 4. 5. 6. 7. as water soluble salts; dissolved in organic solvents; as oilwater emulsions; as eutectic mixtures; incorporated into patches and controlled release devices; using iontophoresis and phonophoresis; incorporated into liposomes.

It is the uncharged, lipophilic portion of the local anaesthetic (the base) which gains access to nerves, although the charged moiety is required for binding to the receptor site. Water has good penetrative abilities that are useful in topical preparations however the uncharged local anaesthetic molecule is poorly soluble in water. In order to increase the concentration of base in water, oilwater emulsions have been developed. The local anaesthetic is dissolved in the oil and then emulsied in an aqueous vehicle. The maximum concentration of lignocaine that can be obtained in oil droplets is 20% however when lignocaine and prilocaine are combined they produce a eutectic form which can achieve a concentration of 80% of local anaesthetic agent;

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Table 1 Summary of ndings of studies investigating the use of topical anaesthetics to disguise the discomfort of local anaesthetic injections (0 no difference between anaesthetic and placebo; signicant difference between anaesthetic and placebo; signicant difference between different anaesthetic formulations; no signicant difference between different anaesthetic formulations in study without placebo) Comparison 5% tetracaine in liposomes:20% benzocaine 5% lignocaine: EMLA Test method Insertion of needle and injection of 4% prilocaine Intraligamentary injection of 2% lignocaine with adrenaline with 30 gauge needle (double-blind) Insertion of 25 gauge needle (double-blind) 30 gauge needle insertion (double-blind) Site and duration of application Not reported Maxillary rst premolar gingival crevice for 5 min Maxillary and mandibular buccal reected mucosa for 15 min Palatal mucosa upper canine region and buccal mucosa lower second premolar region for 2 and 5 min Reected mucosa upper canine region for 3 min Palatal mucosa for 2 min Subjects Volunteers Volunteers Findings maxilla mandible 2 min 5 mins Reference Zed et al. [21] Meechan and Thomason [31]

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Placebo: 10% lignocaine: 20% lignocaine Placebo: 5% lignocaine: EMLA

Volunteers

Hersh et al. [11]

Volunteers

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Placebo: 20% benzocaine: 5% lignocaine Placebo: 20% benzocaine:

Placebo: 5% lignocaine Placebo: 5% lignocaine Placebo: EMLA Placebo: 5% lignocaine: 15% benzocaine 1.7% amethocaine: EMLA Placebo: EMLA Placebo: EMLA:

Insertion of 27 gauge needle (double-blind) Injection of 2% lignocaine with adrenaline with 30 gauge needle (single-blind) Insertion of 27 gauge needle (single-blind) Injection of local anaesthetic (double-blind) Insertion of 27 gauge needle (double-blind) 5 mm insertion of 27 gauge needle (double-blind) 27 gauge needle insertion (double-blind) Injection of 2% lignocaine with adrenaline using 27 gauge needle (single-blind) Injection of 2% lignocaine with adrenaline with 27 gauge needle (double-blind) Injection of lignocaine with adrenaline Insertion of 25 gauge needle Insertion of 25 gauge needle (double-blind)

Volunteers Volunteers

buccal 0 palatal 0 0

Rosivack et al. [22] Vongsavan and Vongsavan [25]

Palatal mucosa for 30 s Various sites (time not recorded) Nasopalatine and greater palatine formina for 5 min Buccal sulcus upper premolar region for 2 min Buccal to lower rst premolar for 2 min Palatal mucosa for 5 min

Volunteers Child patients Volunteers Volunteers

Yaacob et al. [23] Carrel et al. [26] Svennson and Peterson [28] Vickers and Punnia-Moorthy [29] Holst and Evers [27] Meechan and Winter [30]

Volunteers Patients

Placebo: 20% benzocaine

Buccal and palatal to maxillary premolar for 1 min Maxillary buccal sulcus for 5 min Buccal to maxillary second premolar for 3 min Palate for 30 s

Volunteers

Hutchins et al. [24]

5% lignocaine: EMLA Placebo: 20% benzocaine 22% benzocaine: 2% amethocaine with 18%benzocaine: 5% lignocaine

Child patients Volunteers Volunteers

Meechan and Donaldson [37] Martin et al. [34] Gill and Orr [32]

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Table 1 (continued) Comparison Placebo: 20% benzocaine: 18% amino-benzoate with 0.1% benzalkonium Placebo: Sodium phenolate, menthol, thymol, sodium tetraborate, glycerin, chlorophyll. Placebo: Unnamed topical anaesthetic No treatment 20% benzocaine Test method Injection of lignocaine with adrenaline with 25 gauge needle (single-blind) Injection of local anaesthetic with a 27 gauge needle Site and duration of application Palatal mucosa for 45 s Subjects Patients Findings 0 Reference Keller [33]

Various sites

Patients

Pollack [35]

Injection of 2% mepivacaine with a 27 gauge needle Inferior alveolar nerve block injection of 2% lignocaine with adrenaline with 27 gauge needle (single-blind)

Various sites for 3 min Retromolar area for 2 min

Patients Patients

0 0

Kincheloe et al. [36] Meechan et al. [38]

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this is known as EMLA (eutectic mixture of local anaesthetics) [7]. Controlled release devices [8] are designed to overcome the uncontrolled pulse of drug delivery which occurs after topical application and aim to supply the drug at a predetermined rate over a specic time period. They can also direct delivery so that release only occurs at one surface of the preparation. The intra-oral use of controlled release devices and anaesthetic patches have been investigated by a number of authors. Brook et al. [9] studied the use of a bioadhesive slow-release patch placed opposite either upper or lower premolar teeth. They investigated both soft tissue and pulpal anaesthesia following a 30 min application of the patch which contained 50 mg lignocaine in a double-blind placebo-controlled trial with 9 volunteers (see below). Taware et al. [10] reported on the use of a saliva activated bioadhesive patch containing 20 mg lignocaine. In a pilot study with 3 volunteers they noted that subjective feelings of numbness were apparent in 3 min or less and that the anaesthetic effect peaked at between 15 and 20 min although an effect was apparent for between 45 and 50 min. In a different pilot study with 5 volunteers they reported that the patch provided more profound gingival anaesthesia than a 2% lignocaine topical gel although the onset of anaesthesia was quicker with the gel. Hersh et al. [11] investigated the efcacy and safety of lignocaine patches containing either 10 or 20% active agent (see below). Iontophoresis is a means of delivering local anaesthetics to deeper tissue after topical application [12]. Positively charged drugs such as lignocaine and adrenaline can be encouraged to penetrate the tissue under the inuence of electrical charge. Gangarosa investigated different local anaesthetics for skin iontophoresis and noted that the presence of adrenaline increased efcacy [12]. Cocaine iontophoresis of the dental pulp was reported as long ago as 1896 [13]. Gangarosa [14] described the use of iontophoresis with lignocaine and adrenaline as a means of extracting deciduous teeth (see below). More recently Won et al. [15] investigated the use of iontophoresis as a means of delivering 4% lignocaine with 1:50 000 adrenaline in a human study with 5 volunteers. They tested pain control on buccal and lingual mandibular mucosa with a 25 g load and reported a duration of anaesthesia ranging from 25 to 55 min. Phonophoresis is the use of high frequency radio waves to drive drugs into tissues and has been suggested as a possible method of increasing the efcacy of topical applications [16]. Incorporation of local anaesthetics into liposomes has been used as a means of increasing uptake. Liposomes are articial membranes composed of lipid and aqueous layers similar in composition to biological membranes. The number of layers and the size of the liposome can be controlled depending upon the desired function. A unilammelar structure is ideal for delivery of a hydrophobic drug,

whereas a multilammelar structure with more aqueous phases is better for incorporation of hydrophilic drugs. Liposomes offer the following advantages compared to conventional topical delivery [17]: 1. 2. 3. 4. better tissue penetration; non-allergenic delivery vehicle; act as a depot for controlled release of drug; protection from metabolism therefore a longer lasting effect.

Amethocaine incorporated into liposomes has been shown to provide anaesthesia of skin for up to 4 h following a 1 h application whereas the standard cream preparation was ineffective [18]. Studies reported in the dermatology literature suggest that lignocaine [19] and amethocaine [20] incorporated into liposomes produce as effective anaesthesia of skin as EMLA. Zed et al. [21] reported on the use of liposomes to deliver amethocaine topically intra-orally. 3. Studies into the efcacy of topical anaesthetics prior to needle penetration or local anaesthetic injections The results of studies investigating the efcacy of topical anaesthetics in eliminating the discomfort of needle penetration or local anaesthetic injection are summarised in Table 1. The studies are described below. 3.1. Studies reporting positive results Rosivack et al. [22] compared 5% lignocaine to 20% benzocaine and placebo in reducing the discomfort of 27 gauge needle penetration (with no injection) in the maxillary buccal fold in the canine region in human volunteers. They assessed discomfort using a visual analogue scale (VAS) and found that both active agents were signicantly more effective than placebo but did not differ from one another in reducing needle penetration discomfort. Yaacob et al. [23] also looked at the use of a topical anaesthetic to disguise the discomfort of needle penetration alone. In their study which used a 4-point scale to score pain the stimulus was insertion of a 27 gauge needle into palatal mucosa opposite the second permanent molar tooth in volunteers. They compared a 30 s application of 5% lignocaine to that of placebo and noted a signicant reduction in discomfort with the active agent. This study also compared the pain experience between different ethnic groups and found no difference attributable to race. Hersh et al. [11] applied adhesive patches containing placebo or 10 and 20% lignocaine for 15 min to the buccal reected mucosa in both maxilla and mandible in volunteers. They measured the pain experienced following insertion of a 25 gauge needle using a VAS and found that both active patches were superior to placebo in reducing needle penetration in both jaws. In addition, in the lower arch, the 20% lignocaine patch provided a signicantly greater analgesic effect than the 10% patch.

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Hutchins et al. [24] investigated the topical application of 20% benzocaine and placebo for 1 min in alleviating the discomfort of buccal and palatal injections in volunteers using 27 gauge needles and 2% lignocaine with 1:100,000 adrenaline. They showed that the topical anaesthetic reduced injection discomfort on the buccal side but not palatally. Vongsavan and Vongsavan [25] reported that a 2 min application of 20% benzocaine was more effective than a placebo treatment in reducing the discomfort of palatal injections of lignocaine with adrenaline in 14 human volunteers. Carrel et al. [26] in a double-blind investigation of the use of 5% lignocaine in a commercial presentation and in an experimental gel delivery system compared the efcacy of these preparations to that of placebo in inuencing the reaction of children aged between 3 and 6 years to intra-oral injections. Unfortunately the time of topical anaesthetic contact is not detailed, the injections were given by numerous operators, and the sites of injection are not mentioned. These authors did not subject their data to statistical examination but by analysing the number of children that did not cry during the injection (180 out of 378 for the active treatment; 15 out of 172 for placebo), using the Chi Square test, a signicant positive effect for lignocaine is suggested (x2 78; p 0:001). Holst and Evers [27] investigated the effects of 2 and 5 min applications of 5% lignocaine and EMLA on the labial gingiva in the mandibular canine region and the palatal mucosa opposite the upper canine in 10 healthy female volunteers. They found that there was more pain relief associated with the penetration of a 30 g needle after a 5 than a 2 min application for both treatments; both treatments were more effective than placebo and at 5 min EMLA was significantly better than 5% lignocaine. In a further trial in which discs impregnated with EMLA were applied for 2 min buccally to lower rst premolars these workers found that the pain related to penetration of a 27 gauge needle was signicantly reduced under the EMLA disc compared to the placebo. The effect of EMLA on the pain of palatal needle penetration was investigated in a double-blind placebocontrolled study by Svennson et al. [28]. These workers applied orahesive bandages for 5 min over the greater palatine and incisive foramina and measured the pain of 27 gauge needle penetration in volunteers using a VAS. They concluded that the needle insertion pain was signicantly reduced by EMLA but not by placebo and that this effect was more marked at the greater palatine foramen compared to the incisive foramen. Vickers and Punnia-Moorthy [29] compared the 2 min application of 5% lignocaine, 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 in a double-blind splitmouth investigation. They found that their volunteers

reported signicantly less pain with all active agents compared to placebo and concluded that EMLA was the most effective of the topical preparations. Meechan and Winter [30] compared the efcacy of placebo, transcutaneous electronic nerve stimulation (TENS) and a 5 min application of EMLA on palatal mucosa. They found that EMLA was signicantly more effective than either placebo or TENS in reducing the discomfort of palatal injections of 2% lignocaine with 1:80 000 adrenaline in adult patients having maxillary teeth extracted. Meechan and Thomason [31] compared different topical preparations as treatments to reduce the discomfort of periodontal ligament injections. They found that injection discomfort was less following a 5 min application of EMLA compared to a similar application of 5% lignocaine in a double-blind split-mouth study in volunteers. Zed et al. [21] reported that topical application of liposomes incorporating 5% amethocaine was more effective than 20% benzocaine gel in reducing both needle penetration and injection discomfort during administration of 4% prilocaine at contralateral sites (the exact sites and duration of application are not reported). 3.2. Studies reporting negative results Gill and Orr [32] in a double-blind split-mouth investigation into the effects of the topical application of 22% benzocaine, 2% amethocaine with 18% benzocaine, 5% lignocaine or placebo for 30 s on reducing 25 gauge needle penetration into palatal mucosa found no signicant difference between any of the active agents and placebo. Keller [33] performed a study based on the design of Gill and Orr [32] but in addition to penetrating palatal tissue with a 25 gauge needle this worker injected 0.3 ml of lignocaine with adrenaline close to the greater palatine foramen. The results of this study on 60 patients, which compared a 45 s application of 20% benzocaine, 18% aminobenzoate with 0.1% bezalkonium, and placebo, showed no signicant difference in reported pain between treatments. Martin et al. [34] investigated the pharmacological and psychological effects on 25 gauge needle penetration of topical anaesthetics placed in the maxillary buccal sulcus in the premolar region in a modied placebo design. These investigators compared a 3 min application of 20% benzocaine to placebo in their study, each volunteer 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 active agent. Volunteers recorded actual and anticipated pain on a VAS. These workers reported that those patients who were expecting to receive placebo anticipated more pain than those who were advised they would have the active agent applied. However actual pain experience did not differ between the active and placebo treatments. Interestingly the second injection (irrespective of the treatment

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applied) was signicantly more uncomfortable than the rst injection. These workers conclude that topical anaesthetics have little pharmacological effect. However, they suggest that as those programmed to believe they are receiving an active topical anticipate less pain of injection then a useful psychological benet is obtained. They point out that the practitioner should appreciate this psychological benet and not rely on the pharmacological effect to reduce injection discomfort but use additional psychological approaches. Psychological inuences on the efcacy of topical anaesthesia have been investigated by Pollak [35]. This worker studied the effect of suggestion in a sample of 500 dental patients and found that, in patients receiving a 15 s application of a topical anaesthetic prior to injection, those who were given a verbal reinforcement of the effects of the topical reacted less severely to the injection compared to those given no such information. The results of this study also showed no difference in reaction to the local anaesthetic injection between patients treated with the active topical agent compared to a similar application of a placebo. Kincheloe et al. [36] also looked at pain expectation in their study of the effects of a topical local anaesthetic agent (material and concentration not reported) and placebo on pain perception on mucosa and injection of 2% mepivacaine with a 27 gauge needle. These workers reported no difference in injection experience between active agent and placebo but found a signicant correlation between expected pain experience and actual pain experience. Similarly to Martin et al. [34] these workers reported that there was no difference in pain experience between those patients who were informed they had received a topical anaesthetic and those not given this instruction. Meechan and Donaldson [37] compared the effects of a 5 min application of 5% lignocaine and EMLA in reducing the discomfort of maxillary inltration injections in children. No difference in injection discomfort was noted between treatments. It is important to point out that the results of this study do not refute the use of topical anaesthesia in children as no comparison was made with a placebo, however as there was no difference between treatments it is included in this section as a negative result. All of the studies mentioned above have investigated the use of topical anaesthetics prior to inltration anaesthesia. Meechan et al. [38] found that 20% benzocaine applied for 2 min was no better than no mucosal preparation prior to inferior alveolar nerve block injections with 2% lignocaine and 1:80 000 adrenaline using a 27 gauge needle in an adult population prior to mandibular extractions.

reduce the discomfort of periodontal ligament injections was described above [31]. Other workers have studied the use of anaesthetic agent at this site to reduce the discomfort of periodontal procedures. In a double-blind, randomised, split-mouth study Svensson et al. [39] compared the effects on the discomfort of scaling of applications for at least 5 min of EMLA and placebo to the gingival margins in patients with mild chronic periodontitis. These workers reported that EMLA reduced the pain and unpleasantness of scaling in both upper and lower jaws when compared to placebo; the effect on pain however was more marked than the effect on unpleasantness. The results of a double blind split mouth study [40] using volunteers which compared the depth of pain-free probe penetration into the gingival crevice showed that a 5 min application of EMLA allowed a signicantly greater depth of penetration compared to similar treatment with 5% lignocaine. 4.2. Studies on use on gingiva Brook et al. [9] measured sensory changes in the lips and attached gingivae following application of a patch containing 50 mg lignocaine for 30 min. The active patches abolished perception to painful stimuli (sharp probing) in a mean time of 7.4 min, sensation returned to normal in a mean time of 26.4 min following patch removal. Some loss of sensation was noted on the vermilion border and skin surfaces, normal sensation returning to these areas a mean time of 22.6 min following patch removal. In two volunteers the area of mucosa under the patch showed a white appearance at 24 h which had disappeared at 48 h and was symptomless throughout. Svensson et al. [41] investigated the analgesic efcacy and duration of effect of lignocaine and EMLA on tongue and gingiva labial to the lower incisor teeth using argon laser stimulation. They measured pain and sensory thresholds following a 2 min application of lignocaine and 2, 5, and 15 min applications of EMLA. The greatest increase in pain threshold for all treatments was noted immediately after removal of the topical anaesthetic. The increase in sensory and pain threshold was related to the agent applied; EMLA being signicantly more effective than lignocaine. The duration of EMLA application was positively related to the intensity of the effect on tongue (both sensory and pain perception being more elevated after 15 min compared to 2 min) although such an effect was not apparent on the gingiva. Sensory and pain thresholds were elevated for all treatments up to 25 min after removal. These authors concluded that a 5 min application of EMLA on the tongue gives clinical analgesia for 5 min and that a 2 min application on the gingiva produces analgesia for 10 min. Pere et al. [42] investigated the use of 4 g EMLA applied over 4 min to the gingivae by a toothbrush as a means of pain control for the removal of arch bars used in intermaxillary

4. The use of topical anaesthetics to reduce the discomfort of potentially painful intra-oral procedures 4.1. Studies on use in the gingival crevice The use of local anaesthetics in the gingival crevice to

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xation in a double-blind placebo-controlled trial in 45 dentate patients. They found that pin-prick sensation was signicantly less in the EMLA group 5 min after toothbrushing with the topical compared to the placebo before removal of the arch-bars. However, following removal of the arch bars (mean time 19 min after toothbrushing) there was no difference between treatments in response to pinpricking of the gingiva. They recorded signicantly more patients with EMLA reported no pain (7/14) compared to those who received placebo (2/15). They concluded that EMLA produced signicant analgesia for the removal of arch bars. Haasio et al. [43] compared the analgesic effects of EMLA and 10% lignocaine spray on buccal gingival mucosa on the upper jaw in 10 volunteers. They tested loss of sensation by electrical stimulation and recorded both sensory and pain thresholds. The treatments did not differ in the amount of analgesia they produced. The maximum analgesic effect of EMLA was obtained at a mean time of 13 min and for lignocaine it was 14 min, normal sensation had returned in most cases by 30 min for each treatment. No change in sensory threshold was apparent at any stage with either treatment in this investigation. 4.3. Study into use of topical as sole anaesthetic for biopsy Roller and Ship [44] compared the injection of plain 2% lignocaine to a 5 min application of a strip containing 20 mg lignocaine as anaesthesia for oral mucosal biopsies (either normal or ulcerated tissue) in an unblinded study with 20 subjects. They reported that both techniques produced similar anaesthetic potency and duration and that subjective measures of surgical bleeding were similar. Despite recording similar anaesthetic potency the biopsies performed under the lm were recorded as being signicantly more painful. They noted that pain was not associated with the initial punch cut but was due to incision at the base of the biopsy and concluded that this was due to poor penetration of the topical anaesthetic to the depth of the tissue (the biopsy specimens were approximately 4 mm deep). 4.4. Studies into use of topical anaesthetics to provide dentinal/pulpal anaesthesia Brook et al. [9] looked at changes in response to electrical pulp testing of the teeth adjacent to patches containing 50 mg lignocaine or placebo following a 30 min application. All teeth remained responsive to electrical pulp testing however those adjacent to the active patches showed significant elevations in pain threshold compared to base-line and when compared to those teeth adjacent to placebo patches. Vickers and Punnia-Moorthy [45] investigated the application of EMLA, 10% lignocaine, and placebo on the response to electrical pulp testing of maxillary central incisors. They concluded, although the study was not subjected to statistical analysis, that EMLA was effective in reducing the pulpal response as 12 of the 13 volunteers in whom it

was applied showed no response to electrical pulp testing between 15 and 30 min of application. However some of the lignocaine and placebo treated cases also showed reductions in pulpal response including failure to respond under maximum stimulation from the pulp tester. Vickers et al. [46] performed an uncontrolled pilot study into the effectiveness of 1 g topical EMLA as an alternative to inltration anaesthesia as pain control for restorative procedures on teeth in 12 patients. They reported that 75% of subjects obtained adequate analgesia for drilling and concluded that this method produced sufcient, but not complete, anaesthesia to allow restorative dentistry to be performed. Meechan and Donaldson [37] compared placebo and EMLA applied for 5 min to the maxillary buccal sulcus on the response of deciduous teeth to electrical stimulation in a double-blind study. They found no difference between treatments. They also looked at the ability of EMLA to eliminate the discomfort of restorative dentistry on deciduous teeth and reported that 80% of the children studied required supplementary local anaesthetic injections to complete treatment painlessly. Amess et al. [47] reported on the use of topical lignocaine applied to human dentine. These workers reported that the application of a drop of 50% lignocaine solution onto exposed dentine reduced the response to both air blasting and probing stimuli in a small uncontrolled study with 6 volunteers. De Nunzio [48] reported on the use of 20% benzocaine as a topical application to the dental pulp during endodontic treatment. This author claims great success for the method but this paper is merely a description of a technique and is anecdotal. 4.5. Studies into the use of topical anaesthetics as sole means of anaesthesia for dental extractions Taware et al. [10] used a bioadhesive delivery system to administer lignocaine as the sole means of anaesthesia for dental extractions in both adults and children. They applied patches containing 20 mg lignocaine to the buccal and palatal/lingual gingiva in the apical region of the tooth to be extracted. The patch was maintained in position until the gingiva could be detached from the tooth without pain and then the extraction was performed. The time to extraction differed signicantly between the jaws; the mean time for the maxilla and mandible being approximately 19 and 13 min, respectively. In their uncontrolled trial of 49 extractions in 41 patients they achieved successful anaesthesia in 40 (81%) of teeth. Despite the fact that no vasoconstrictor was used post-operative bleeding was reported as normal. Gangarosa [14] reported on the use of 2% lignocaine with 1:50,000 adrenaline administered by iontophoresis for 10 min for the extraction of deciduous teeth. This worker reported that 12 out of 13 teeth subjected to this form of anaesthesia were extracted without discomfort. The author

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J.G. Meechan / Journal of Dentistry 28 (2000) 314 Table 2 Summary of results of studies measuring plasma levels of anaesthetic agents following intra-oral topical administration Topical agent Amount, duration and location of application 200 mg sprayed on maxillary gingivae 23 mg on premolar buccal reected mucosa for 15 min 46 mg on premolar buccal reected mucosa for 15 min 50 mg buccal gingivae of both jaws for 30 min 8 g buccal mucosa for 30 min Mean peak plasma level: concentration and time 0.35 mg/ml at 20 min 0.016 mg/ml at 15 min 0.022 mg/ml at 15 min 0.03 mg/ml at 45 min Lignocaine 0.22 mg/ml at 40 min Prilocaine 0.13 mg/ml at 40 min Lignocaine 0.21 mg/ml at 30 min Prilocaine 0.05 mg/ml at 30 min Lignocaine 0.18 mg/ml at 20 min Prilocaine 0.10 mg/ml at 10 min Maximum plasma level: concentration and time 0.66 mg/ml at 20 min Not reported Not reported 0.095 mg/ml at 60 min Lignocaine 0.42 mg/ml at 30 min Prilocaine 0.22 mg/ml at 30 min Lignocine 0.26 mg/ml at 15 min Prilocaine 0.09 mg/ml at 30 min Lignocaine 0.47 mg/ml at 5 min Prilocaine 0.21 mg/ml at 10 min Reference

11

10% lignocaine spray 10% lignocaine patch 20% lignocaine patch Lignocaine patch EMLA

Haasio et al. [43] Hersh et al. [11] Hersh et al. [11] Brook et al. [9] Vickers et al. [46]

EMLA

4 g for 4 min to gingivae both jaws 4 g for 4 min to maxillary gingivae

Pere et al. [42]

EMLA

Haasio et al. [43]

describes the use of a mouth electrode ( ve charge) covering the teeth and associated mucosa, the indifferent electrode ( ve charge) being attached at the wrist. 4.6. Use of topical agents for post-extraction pain relief Greengrass et al. [49] investigated the use of topical bupivacaine placed over extraction sockets as a method of pain control following simple exodontia. These workers reported that biting on dental rolls soaked with 7 ml of 0.25% bupivacaine with 1:200,000 adrenaline was more effective than occluding on saline-soaked rolls in relieving discomfort following extractions under general anaesthesia in children aged between 7 and 15 years. 5. Plasma levels following topical anaesthetic application Plasma levels of anaesthetic agents reported following intra-oral topical application are summarised in Table 2. The level of drug entering the circulation after topical application is of interest. Toxic reactions to topically applied local anaesthetics are known to occur [50], indeed fatalities have been reported [51]. It has been claimed that toxic reactions to local anaesthetics are more common after topical than via any other route of administration [51]. It is the amount of drug that is administered that is important with regard to toxicity and topical agents are usually available in concentrations much greater than are found in injected formulations. Adriani and Campbell [51] provided data from a study in dogs which showed that entry into the circulation was quicker after topical administration to the pharynx than following subcutaneous injection, indeed they concluded that the entry prole following topical administration simulated that after rapid intravenous injection (although the peak level was around a third that obtained

after IV injection). Certainly topical administration achieved much higher peak levels than slow intravenous infusion of the same dose. Toxicity to lignocaine occurs at a plasma concentration of around 5 mg/ml [52]. Hersh et al. [11] measured plasma lignocaine levels after the use of patches containing either 10 or 20 mg of the local anaesthetic. They found that plasma lignocaine levels rose steadily during the 15 min of patch application and then remained steady over a period of 30 min from the 15 min sample. Average peak levels were 0.016 mg/ml for the 10% patch and 0.022 mg/ml for the 20% patch; these values are an order of magnitude less than obtained following the intraoral injection of 2% lignocaine solutions [53,54]. Brook et al. [9] measured plasma lignocaine levels in nine volunteers following a 30-min application of a patch containing 50 mg lignocaine on the buccal gingivae opposite the premolar teeth (either upper or lower depending on subject). They reported peak lignocaine levels occurred 45 60 min following patch placement and the highest concentration recorded was 0.095 mg/ml. The mean peak level was around 0.030 mg/ml. Pere et al. [42] investigated plasma levels of lignocaine and prilocaine following the application of 4 g EMLA to the gingiva for 4 min using a toothbrush. The plasma levels of prilocaine were signicantly lower than lignocaine (because of more rapid metabolism). The highest concentration of prilocaine being 0.09 mg/ml at 30 min from the start of the application; for lignocaine the greatest level was 0.26 mg/ml at 15 min. Haasio et al. [43] studied anaesthetic drug plasma levels after application of 4 g of EMLA to upper gingivae with a toothbrush (100 mg lignocaine and 100 mg prilocaine) for 4 min compared to 4 50 mg of 10% lignocaine spray to the upper gingivae. They found that anaesthetic absorption was more rapid after EMLA but the only signicant difference

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was a higher mean plasma concentration of lignocaine at 30 min in the 10% lignocaine spray group where the mean plasma lignocaine concentration was 0.35 mg/ml compared to 0.14 mg/ml in the EMLA group. The highest lignocaine concentration in the EMLA group was 0.47 mg/ml at 5 min compared to 0.66 mg/ml in the lignocaine group at 20 min. The highest prilocaine concentration was 0.21 mg/ml at 10 min. Vickers et al. [46] measured the plasma concentrations of lignocaine and prilocaine following the application of 8 g of EMLA for 30 min to buccal mucosa in 12 volunteers. Peak plasma levels were obtained at 40 min after initial application for both anaesthetics. The mean peak level for lignocaine was 0.221 mg/ml and for prilocaine 0.131 mg/ml. The maximum concentrations recorded in any one patient were 0.418 mg/ml (lignocaine) and 0.223 mg/ml (prilocaine). 6. Adverse effects The application of local anaesthetics seems to produce little adverse effects on mucosa. A histological study of the application of 5% lignocaine to the oral mucosa of hamsters for periods up to 24 h revealed essentially normal epithelium with no signs of any inammatory response or tissue oedema [26]. Hersh et al. [11] investigated adverse effects of patches containing 10 and 20% lignocaine placed intra-orally and found no difference between the active treatments and placebo. Vickers et al. [46] noted no adverse local effects in any subject following a 30-min application of 8 g EMLA to buccal mucosa. Reports of damage to mucosa are rare, any problems appear to be reversible and symptomless [9]. An exception however is the misuse of the anaesthetic agent cocaine. When applied topically on gingiva (a technique sometimes used to assess purity) this drug can cause ulceration and gingival necrosis due to vasoconstriction [55,56]. A possible adverse effect of topical anaesthesia was described in a case report by Pashley and Parsons [57]. These workers describe a case of severe pain following application of 5% lignocaine ointment adjacent to vital teeth with exposed dentine. They postulate that the discomfort was produced by an osmotic effect on dentinal tubules by the hypertonic topical preparation. 7. Conclusions This review has considered a number of possible applications of topical anaesthetics intra-orally in addition to use as a pre-injection treatment. Patients undergoing periodontal procedures [39], restorative treatment on teeth [45,46], extractions [10,14] and biopsies [44] have all been reported to have this treatment performed successfully using only topical anaesthesia. This would appear to indicate great advances in this eld. However the evidence from some of the controlled studies reviewed suggest that these agents

are not reliably effective prior to local anaesthetic injections. Although a number of studies show an analgesic effect [11,2131] others have been quoted which show the topical anaesthetic has no inuence [24,3236]. The reasons for such equivocal results are many. In the studies referred to a number of different stimuli have been applied to assess analgesia prior to local anaesthesia, for example some investigations have looked at needle penetration only [11,22,23,2729], others have used local anaesthetic injections [33,35,36]. In addition, different needle gauges have been utilised and the times of topical anaesthetic application are not consistent. The site of the stimulus varies (palate or buccal sulcus) and nally not all studies randomised the order of treatment (order of stimulus affects perceived discomfort [34]). Other methods used to assess topical anaesthetic activity have included alteration in taste sensation [58]. Therefore the evidence suggests that the ideal intra-oral topical anaesthetic is not presently available. Two features are apparent in those studies where a conventional topical anaesthetic has demonstrated a lack of efcacy prior to inltration local anaesthetic. Either the topical agent was applied for a very short time [24,32,33] (less than or equal to a minute), or a wide bore needle (25 gauge) was used as the stimulus [3234]. Thus, when using accepted formulations such as 20% benzocaine or 5% lignocaine, success is technique-dependent. Efcacy is improved by using application times of at least 2 min and by employing needles of 27 gauge diameter or less. The only study which showed that an application time of less than a minute was successful can be criticised in that the sides of active and placebo treatments were not randomised and this affects pain perception [34]. Few studies have been performed in relation to the efcacy of topical anaesthetics prior to intra-oral injections in children [26,37]. The only placebo-controlled child study recorded [26] used simple subjective measures for efcacy and did not report any statistical analysis, although the data did suggest a positive effect of the topical agent. The only study that has investigated the use of topical anaesthetics prior to deep regional block injections showed no benet was derived by such treatment [38]. The use of topical anaesthesia in the mouth does not appear to produce serious unwanted effects. Concentrations of topical anaesthetic up to 10 times greater than contained in dental local anaesthetic solutions produce plasma levels an order of magnitude below those needed to produce toxicity. However a cautionary note must be made here. All the studies reporting plasma levels after intra-oral use of topical anaesthetics have been performed in adults; plasma levels following intra-oral topical anaesthetic application in children have not been recorded. This is an important point as there is evidence in the medical literature that seemingly low doses of topical anaesthetic applied to the skin of young children can produce toxicity [50]. Some recent advances, such as the introduction of EMLA and the incorporation of anaesthetics into liposomes appear

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to offer exciting possibilities. A number of the studies reported have shown that EMLA is effective intra-orally prior to a number of procedures. Indeed, in all the studies reviewed EMLA is signicantly better than placebo at reducing the pain of intra-oral injections [2730]. The only EMLA study to show no difference between treatments was a comparison with 5% lignocaine as a topical anaesthetic prior to injections in children [37]. Therefore EMLA appears to offer useful properties as an intra-oral topical anaesthetic. However, it must be stressed that this anaesthetic is not currently available in a dedicated intra-oral formulation and the manufacturers do not recommend the use of EMLA on mucosa. The only investigation of the use of liposomes as delivery devices for intra-oral topical anaesthetics showed encouraging results [21]. Further studies into the use of liposomes intra-orally are needed. The most exciting prospects relating to topical anaesthesia concern the use of this method as a sole means of pain control prior to operative dentistry, periodontal treatment and oral surgery. This review has presented evidence that a little progress has been made in reaching these goals. There is still considerable work to be performed before local anaesthetic needles can be excluded form the dental armamentarium. Nevertheless this is a goal worth pursuing and research and development into topical anaesthetics for use in dentistry should be encouraged.

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[36] Kincheloe JE, Mealiea WL, Mattison GD, Seib K. Psychophysical measurement on pain perception after administrastion of a topical anesthetic. Quintessence International 1991;22:311315. [37] Meechan JG, Donaldson D. The intra-oral use of EMLA cream in children: a clinical investigation. Journal of Dentistry for Children 1994;61:260262. [38] 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. Journal of Dentistry 1998;26: 417420. [39] Svensson P, Petersen JK, Svensson H. Efcacy of a topical anesthetic on pain and unpleasantness during scaling of gingival pockets. Anesthesia Progress 1994;41:3539. [40] Donaldson D, Meechan JG. A comparison of the effects of EMLA cream and topical lidocaine on discomfort during gingival probing. Anesthesia Progress 1995;42:710. [41] 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. Anesthesia Progress 1992;39:48. [42] Pere P, Iizuka T, Rosenberg PH, Lindqvist C. Topical application of 5% eutectic mixture of lignocaine and prilocaine (EMLA) before removal of arch bars. British Journal of Oral Maxillofacial Surgery 1992;30:153156. [43] 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. British Journal of Oral Maxillofacial Surgery 1990;28:99101. [44] Roller NW, Ship II. Lidocaine topical lm strip for oral mucosal biopsies. Journal of Oral Medicine 1975;30:5558. [45] Vickers ER, Punnia-Moorthy A. Pulpal anesthesia from an application of a eutectic topical anesthetic. Quintessence International 1993;24:547551. [46] Vickers ER, Marzbani N, Gerzina TM, McLean C, Punnia-Moorthy

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