2.5% EMLA Versus 2% Lignocaine with Adrenaline Injection in Small Oral Mucosal Biopsies: A Parallel Group Randomized Controlled Trial

Abstract

Trial Design

The study was designed as an open label randomized comparative parallel group design with a 1:1 allocation ratio.

Methods

All consecutive patients reporting for small biopsies (incisional or excisional) who gave written informed consent were included in the study between October 2018 and October 2019. They were randomized into two groups, Group A and Group B both receiving intervention in the form of 2.5% EMLA cream and 2% Lignocaine with 1:80,000 Adrenaline injection respectively, to anaesthetise tissue for small mucosal biopsies in the oral cavity.

Results

EMLA was found to be as effective as lignocaine infiltration with a completely painless application and higher satisfaction for overall comfort during procedure. The duration required to achieve anaesthesia was however more. A particular subgroup of pathology was found to be completely resistant to anaesthesia by EMLA.

Conclusion

We recommend the use of EMLA as a sole anaesthetic in small mucosal biopsies and shavings in all patients. We suggest it as a higher and first line recommendation for anaesthesia in needle phobic patients and children.

Introduction

Local anaesthesia is the mainstay of pain control during intraoral operative procedures. Anxiety and fear induced by pain are still associated with dental treatment and are mostly associated with the fear of receiving injections [1]. The pain during this procedure leads to the lack of cooperation by patients, prolonged dental attendance time, unsuccessful/repeated attempts and additional pain [2].

Although the main mode for local anaesthetic drugs application in the mouth is by injection, they can also be applied topically. Topical anaesthesia can reduce the pain of needle insertion as well as allow completion of some intraoral procedures [3]. Lidocaine (LDC), an amine–amide local anaesthetic, and benzocaine have been used as topical anaesthetics although their efficacy in topical anaesthesia is questionable [4, 5].

EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is an emulsion in which the oil phase is an eutectic mixture of lidocaine and prilocaine in a ratio of 1:1 by weight. EMLA, when applied to intact skin under occlusive dressing, provides dermal analgesia [6]. EMLA is known to provide sufficient local anaesthesia in a variety of painful superficial procedures including superficial surgery, laser surgery, epilation, cautery of condylomata, debridement of leg ulcers and venipuncture. In dentistry, EMLA has been used for reducing pain during dental injection, minor gingival surgeries and pocket scaling restorative procedures [7]. Studies on oral mucosal application of EMLA have proved its safety in regard to toxicity level [6].

Considering our personal experience, wherein lot of patients who need to undergo biopsies, default procedure, due to fear of needle injection adding pain to their conditions, we planned this randomized controlled trial to compare the efficacy of topical 2.5% EMLA application in patients requiring small biopsies versus the conventional lignocaine injection.

Aims and Objectives

Aim

To evaluate the role of 2.5% EMLA cream as a sole anaesthetic in small biopsies of oral mucosa.

Primary Objectives

To compare the efficacy of topical 2.5% EMLA application versus 2% lignocaine with adrenaline 1:80,000 infiltration in patients requiring small (maximum 1 cm in size) incisional or excisional biopsies in terms of NRS on application, during needle prick, during biopsy, duration of application to achieve anaesthesia, need of additional anaesthesia, failure, complications and overall satisfaction with comfort during procedure.

Methods

Trial Design

The study was designed as an open-label randomized comparative parallel group design with a 1:1 allocation ratio.

Participants

The study was based in OPD of Department of Dentistry. After ethical approval for the study was taken from the institutional review board, the trial was registered in CTRI. All consecutive patients reporting for small biopsies who gave written informed consent were included in the study between October 2018 and October 2019. The inclusion/exclusion criteria were as follows:

Inclusion Criteria:

1. Aged 18–60 years

2. ASA I or II

3. Small Incisional or excisional biopsies (maximum 1 cm in size)

Exclusion Criteria:

1. Hypersensitivity to amide local anaesthetics

2. ASA III or IV

3. Refusal for consent

4. Large biopsies or bone biopsies

The biopsies were limited to soft tissue mucosal biopsies of any pathology.

Interventions

Group A

After thorough history and obtaining informed consent for the procedure and participation in the study, 2.5-5 g of 2.5% EMLA was applied to the site of biopsy after drying the mucosa, and after a waiting period of 5-10 min, the efficacy of anaesthesia was checked with needle pricks. If anaesthesia was sufficient, procedure was started. If anaesthesia was insufficient, further waiting for 5 min was done. Diagnostic biopsy was completed with BP handle and blade. Sutures were placed, if needed. If the procedure was painful, after documentation of NRS (11-point numerical rating scale), additional EMLA cream was applied once in the EMLA group. The dose given, time to completion of treatment and pain from the treatment (NRS) were documented. Any local irritation, burning or reaction was noted. If the procedure was still painful, the procedure was completed under lignocaine infiltration, and the case was documented as “failed” in EMLA group (see Figs. 1, 2, 3, 4).

Fig. 1.

Case 1 showing EMLA application on midline fibroma

Fig. 2.

Case 1 showing excised fibroma under EMLA

Fig. 3.

Case 2 showing EMLA application on mucocele

Fig. 4.

Case 2 showing dissection to the depth of mucocele

Group B

After thorough history and obtaining informed consent for the procedure and participation in the study, 0.5-5 ml of 2% lignocaine with adrenaline 1:80,000 was infiltrated around the site of biopsy, and after a waiting period of 5 min, the efficacy of anaesthesia was checked with needle pricks. If anaesthesia was sufficient, procedure was started. If anaesthesia was insufficient, further waiting for 5 min was done. Diagnostic biopsy was completed with BP handle and blade. Sutures were placed, if needed. If the procedure was painful, after documentation of NRS, additional infiltration was given once in the lignocaine group. The dose given, time to completion of treatment and pain from the treatment (visual analogue scale) were documented. Any local irritation, burning or reaction was noted. If the procedure was still painful, the case was documented as “failed” in lignocaine group and nerve block was considered for anaesthesia.

Outcome Measures

Primary outcome measures were as follows: NRS (11 points) for pain during EMLA application/lignocaine infiltration, NRS for pain during needle prick (to test for adequate anaesthesia before starting biopsy), NRS for pain during biopsy, overall satisfaction for comfort during procedure on a 5-point Likert scale (after completion of procedure).

Secondary outcome measures were as follows: need of additional anaesthetic, total duration of anaesthetic application required to complete procedure, failure of anaesthetic and complications observed.

No trial outcomes were changed after the trial commencement.

Sample Size Calculation

For sample size calculation, a sampling error of 5% was considered, the power was set to 85% and minimum sample size of 26 was obtained.

Randomization

The randomization was done using the computer randomization software, and the code generated was sealed in a sequentially numbered opaque envelope. Opaque enveloped was sequentially allotted to the patients requiring biopsy. On the day of biopsy, an envelope was opened to reveal the treatment of either topical 2.5% EMLA (Group A) or infiltration 2% lignocaine with adrenaline 1:80,000 (Group B). The randomization, allocation concealment and assigning of participants was done by a person unrelated to the trial and blinded to the patients.

Blinding

The assessor was blinded to the study as unlabelled data values were provided.

Statistical Analysis

The data collected were analysed statistically with a Chi squared/Fishers exact test for nonparametric data, while t test was used for parametric data. Additional analysis was done after excluding the oral cancer cases in both the groups as they seemed refractory and were presumed to be skewing the data.

Results

Participant flow

A total of 71 participants were recruited in this trial and randomly allocated to Group A (EMLA) (n = 35) and Group B (lignocaine) (n = 36) each. All the participants received the intended treatment and were analysed for primary outcomes. After completion of trial, a particular group of patients who underwent biopsies for oral cancer showed extremely high rate of failure compared to the rest of the participants. To prevent skewing of the results as a result of this particular failure group, patients who had biopsies for oral cancer were excluded from both the groups and data re-analysed (Group A n = 6; Group B n = 7 excluded). See the CONSORT flow diagram at Fig. 5.

Fig. 5.

CONSORT flow diagram

Recruitment

Recruitment for the study was done between October 2018 and October 2019, and the follow-up was for a week till the removal of suture. The trial stopped with the finishing of intended recruitment only.

Baseline Data

The baseline demographic and clinical characteristics for each group are represented in the Table 1

Table 1.

Demographic and clinical characteristics

	Group A EMLA	Group B lignocaine
N (sample size)	35	36
AGE range	13–65 years	16–75 years
Average age	34.5 years	39.6 years	p = 0.071982; Not significant
Males	18	24	p = 0.191575; Not significant
Females	17	12
SCC	6	7
Fibroma/polyp/hyperplastic tissue	15	13
Mucocele	13	15
Others	1	1

Numbers analysed

For each group, the initial analysis included all the patients originally allocated to the group (Group A/EMLA n = 35; Group B/lignocaine n = 36). After exclusion of oral cancer cases, each group contained 29 cases each for analysis.

Outcomes, Estimation and Ancillary Analysis

Initial analysis included all the patients. Ancillary analysis was done after exclusion of oral cancer patients from both the groups. The results for both are presented. The results for each primary and secondary outcome are as follows (Table 2).

Table 2.

Results summarized

	Group EMLA	Group lignocaine	p value (significant results in bold)		Group EMLA	Group lignocaine	p value (significant results in bold)
Sample size (n)	35	36		After exclusion-ancillary analysis	29	29
Pain on application	0	3.88 ± 1.86	p < 0.00001		0	3.86 ± 1.95	p < 0.00001
Pain on needle prick	0.46 ± 1.24	0.44 ± 0.50	p = 0.955005		0.27 ± 1.13	0.37 ± 0.49	p = 0.326674
Pain during biopsy	1.66 ± 2.64	0.36 ± 0.49	p = 0.00257		0.83 ± 1.93	0.34 ± 0.48	p = 0.098186
Duration of application of anaesthesia	12 min ± 2.76 min	7.28 min ± 1.96 min	p < 0.00001		11.55 min ± 2.70 min	7.07 min ± 1.94 min	p < 0.00001
Need of additional anaesthesia	No = 22 Yes = 13	No = 33 Yes = 3	Fischer’s test value = 0.0046; p < 0.05		No = 21 Yes = 8	No = 27 Yes = 2	Fischer’s test value = 0.0787; p > 0.05
Failure	No = 27 Yes = 8	No = 36 Yes = 0	Fischer’s test value = 0.0022; p < 0.05		No = 26 Yes = 3	No = 29 Yes = 0	Fischer’s test value = 0.2368; p > 0.05
Complications	No = 35 Yes = 0	No = 34 Yes = 2	Fischer’s test value = 0.493; p > 0.05		No = 29 Yes = 0	No = 27 Yes = 2	Fischer’s test value = 0.4912; p > 0.05
Overall satisfaction with comfort during procedure#	S = 26 US = 9	S = 11 US = 25	p = 0.000226		S = 26 US = 3	S = 9 US = 20	p < 0.00001

^#S satisfied, US unsatisfied

Pain on Application

Mean pain on application for Group A (EMLA) was 0, while for Group B it was 3.88 (SD 1.86), and the result was statistically significant at p < 0.05. After exclusion analysis, it was 0 (Group A) versus 3.86 (SD 1.95) (Group B) and statistically significant at p < 0.05. The EMLA group had statistically significant absence of pain on application in comparison with lignocaine group.

Pain on Needle Prick

Mean pain on needle prick for Group A (EMLA) was 0.46 (SD 1.24), while for Group B it was 0.44 (SD 0.50), and the result was statistically not significant at p < 0.05. After exclusion analysis, it was 0.27 (SD 1.13) (Group A) versus 0.37 (SD 0.49) (Group B) and statistically not significant at p < 0.05.

Both EMLA and lignocaine groups had similar intensity of pain on needle prick.

Pain During Biopsy

Mean pain during biopsy for Group A (EMLA) was 1.66 (SD 2.64), while for Group B it was 0.36 (SD 0.49), and the result was statistically significant at p < 0.05. After exclusion analysis, it was 0.83 (SD 1.93) (Group A) versus 0.34 (SD 0.48) (Group B) and statistically not significant at p < 0.05.

The pain felt during biopsy was more in EMLA group compared to lignocaine group, but was similar to that in lignocaine group once the cancer cases were excluded.

Duration of Application Required for Anaesthesia

Mean duration required to achieve anaesthesia for Group A (EMLA) was 12 min (SD 2.76), while for Group B it was 7.28 min (SD 1.96), and the result was statistically significant at p < 0.05. After exclusion analysis, it was 11.55 min (SD 2.70) (Group A) versus 7.07 min (SD 1.94) (Group B) and statistically significant at p < 0.05.

The duration of application required to achieve anaesthesia was shorter for the lignocaine group.

Need of Additional Anaesthesia

The need for additional anaesthesia was 22 “No” and 13 “Yes” in Group A versus 33 “No” and 3 “Yes” in Group B, and the result was statistically significant at p < 0.05 using Fischer’s exact test. After exclusion analysis, it was 21 “No” and 8 “Yes” in Group A versus 27 “No” and 2 “Yes” in Group B, and the result was statistically not significant at p < 0.05.

The need for additional anaesthesia during biopsy was more in EMLA group compared to lignocaine group, but was similar to that in lignocaine group once the cancer cases were excluded.

Failure

Failure to achieve anaesthesia with the drug being used was 27 “No” and 8 “Yes” in Group A versus 36 “No” and 0 “Yes” in Group B, and the result was statistically significant at p < 0.05 using Fischer’s exact test. After exclusion analysis, it was 26 “No” and 3 “Yes” in Group A versus 29 “No” and 0 “Yes” in Group B, and the result was statistically not significant at p < 0.05.

The failure to achieve anaesthesia during biopsy was more in EMLA group compared to lignocaine group, but was similar to that in lignocaine group once the cancer cases were excluded.

Complications

Complication or side effects with the drug being used was 35 “No” and 0 “Yes” in Group A versus 34 “No” and 2 “Yes” in Group B, and the result was statistically significant at p < 0.05 using Fischer’s exact test. After exclusion analysis, it was 29 “No” and 0 “Yes” in Group A versus 27 “No” and 2 “Yes” in Group B, and the result was statistically not significant at p < 0.05.

No complications were encountered in EMLA group although there were 2 episodes of syncope in the lignocaine group, but the difference was statistically not significant.

Satisfaction for Comfort During Procedure

For statistical analysis, the 5-point Likert scale was simplified with very unsatisfied, unsatisfied and neutral clubbed under “UNSATISFIED”, whereas satisfied and very satisfied were clubbed under “SATISFIED”.

For comfort during procedure, 26 rated “satisfied” and 9 rated “unsatisfied” in Group A versus 11 rated “satisfied” and 25 rated “unsatisfied” in Group B, and the result was statistically significant at p < 0.05 using Chi squared test. After exclusion analysis, 26 rated “satisfied” and 3 rated “unsatisfied” in Group A versus 9 rated “satisfied” and 20 rated “unsatisfied” in Group B, and the result was statistically significant at p < 0.05.

Overall, satisfaction levels with comfort during procedure were statistically more with EMLA group in comparison with lignocaine group.

Harms

No harm or side effect was noted with EMLA or lignocaine in terms of drug effects. Vasovagal syncope was encountered in 2 patients in Group B, the aetiology of which is multifactorial.

Discussion

Limitations

The limitation of this trial is the relatively small sample size. However, to the best of our knowledge, no similar trial has been done in the literature, and hence, the trial holds its relevance. But to generalize the findings on a larger scale, large multicentre trials are recommended.

Another aspect of value is the inability to blind the clinician and patients as both the drugs have a completely different mode of application. EMLA is a new modality to be used for biopsy, and therefore, the need to obtain a detailed consent precludes blinding in these patients.

Generalizability and Interpretation

Most studies available in the literature study the role of EMLA as a topical anaesthetic to relieve the pain of needle prick [8–10] rather than an independent anaesthetic for the complete procedure. EMLA has been used for small procedures in gynaecology [11] and urology [12], but sparsely in dentistry.

The manufacturers of EMLA do not suggest its use in oral cavity, but there has been a wide off-label use considering it has been found effective in oral cavity in numerous studies [13]. The safety and toxicity studies have been done mostly on penile or genital mucosa and it has been demonstrated to be safe in use [14].

Since the original application of EMLA was not intended in the oral cavity, the cream lacks the adhesiveness and viscosity for an oral application. Many studies have found this to be a problem limiting the potential effectiveness of EMLA [15]. Some authors have suggested the use of cellulose disks [9] to retain the cream at intended location or custom made a mixture with Orabase-B Plain [15]. Our experience concurs with the same as we experienced a little difficulty with the application of EMLA. Due to its low viscosity, it tends to flow away, and hence, till a specialized adhesive formula is introduced by the manufacturers we suggest a few tips for application. One needs to make sure that the mucosa is dry before application, a thick layer must be applied and a low-volume suction is used to evacuate any pooling of saliva. Some literature also suggests the use of customized splints [16] to retain the drug in position, but we did not require the same.

Our findings from the trial are suggestive of the fact that EMLA can be as effective as lignocaine in small biopsies with much lesser pain on application. Merely the absence of a needle prick makes a patient much more comfortable which is depicted in our results of higher overall satisfaction in comfort during procedure in the EMLA group.

The application times in most our cases required 10 min for EMLA which concurs with studies that longer application times than 10 min yield a similar effectiveness and no more [7].

The limitation of the application was identified mainly in two areas. One was that after the trial we found that most failures of EMLA application happened in the oral cancer cases where the effectiveness of anaesthesia approached almost zero. Most such cases required lignocaine infiltration to complete the biopsy. This could not be attributed to the depth of the lesion as many other mucoceles were deep enough, but responded with optimum anaesthesia to EMLA. We hypothesize that the reason that EMLA was ineffective in oral squamous cell carcinoma cases could be multifactorial. One of the factors could be the presence of peritumoural inflammation and vascularity. Inflammation/vascularity is known to increase the clearance of topical anaesthetics resulting in a faster wearing off as well [17]. Topical EMLA acts by mucosal absorption and tendency to deposit near the nerve endings. Alteration of mucosal surface in the ulcerated surface of carcinomas could preclude this deposition near the nerve endings and a faster absorption by the submucosal tissue. The fibrin clot forming on the surface of overtly ulcerated tissues could also would provide a partial barrier [18]. Another aspect is that studies have identified by immunohistochemical staining that FABP-4 (fatty acid-binding proteins) expression in the SCC tumour tissue was much higher than that in the non-tumour area of the same specimen [19]. Fatty acids contribute to the epidermal permeability barrier [20] and this could be contributory to mucosal permeability alteration in SCC cases and hence failure.

Another limitation was that EMLA lacks the surgical field preparation properties that lignocaine with a vasoconstrictor like adrenaline offers, and hence, one must limit it to small biopsies and lesions that are not expected to bleed much.

An important aspect of this study was that the absence of a needle during the procedure in EMLA cases made the patients very receptive to treatment especially in children and women. We found a much less refusal tendency in patients who were undergoing biopsy under EMLA. This is a major indication for the use of EMLA wherein small mucosal biopsies or shavings can be completed in needle phobic or anxious patients. No incidence of syncope was encountered in these patients.

Conclusion

EMLA was found to be as effective as lignocaine infiltration with a completely painless application and higher satisfaction for overall comfort during procedure. The duration required to achieve anaesthesia was, however, more. We recommend the use of EMLA as a sole anaesthetic in small mucosal biopsies and shavings in all patients. We suggest it as a higher and first-line recommendation for anaesthesia in needle phobic patients and children. We suggest that EMLA as a sole anaesthetic may not be used in cases of oral cancer biopsies and lesions that tend to bleed heavily requiring vasoconstriction for a good surgical field. It may, however, be used as an adjunct to minimize pain of needle prick in such cases.

Funding

None.

Availability of Data and Material

Will be provided on request.

Compliance with Ethical Standards

Conflict of interest

None declared.

Consent to Participate

Taken from all participants.

Consent for Publication

Taken from all participants.

Code Availability

Not applicable.

Ethics Approval

Approved by Institutional Ethical Committee.