A New Protocol to Evaluate the Effect of Topical Anesthesia

Abstract

This double-blind, placebo-controlled, randomized cross-over clinical experimental study tested the reliability, validity, and sensitivity to change of punctuate pain thresholds and self-reported pain on needle penetration. Female subjects without orofacial pain were tested in 2 sessions at 1- to 2-week intervals. The test site was the mucobuccal fold adjacent to the first upper right premolar. Active lidocaine hydrochloride 2% (Dynexan) or placebo gel was applied for 5 minutes, and sensory testing was performed before and after application. The standardized quantitative sensory test protocol included mechanical pain threshold (MPT), pressure pain threshold (PPT), mechanical pain sensitivity (MPS), and needle penetration sensitivity (NPS) assessments. Twenty-nine subjects, mean (SD) age 29.0 (10.2) years, completed the study. Test-retest reliability intraclass correlation coefficient at 10-minute intervals between examinations was MPT 0.69, PPT 0.79, MPS 0.72, and NPS 0.86. A high correlation was found between NPS and MPS (r = 0.84; P < .001), whereas NPS and PPT were not significantly correlated. The study found good to excellent test-retest reliability for all measures. None of the sensory measures detected changes in sensitivity following lidocaine 2% or placebo gel. Electronic von Frey assessments of MPT/MPS on oral mucosa have good validity.

Topical local anesthetics (TLAs) are commonly used in dental practice to reduce acute and chronic pain and facilitate dental procedures. TLAs reduce or eliminate acute pain and are used (a) in dental procedures such as needle penetration,^1,2 scaling and root planing,³ mucosal punch biopsies,⁴ and application of orthodontic appliances⁵ and rubber dam clamps⁶; (b) for postsurgical pain⁷; and (c) in recurrent and chronic pain conditions associated with ulcers and atypical odontalgia.⁸

A pharmacologic effect can be observed in well-designed placebo-controlled trials and in dose-response studies. When TLAs were compared with intraoral placebos before needle insertion, studies reported conflicting results in effect, measured as reduced or eliminated pain. Variations in choice of site, duration of application, type and concentration of drug, study design, and measures for evaluating treatment effect are some of the possible explanations for the differences observed in these studies.¹

The most common assessment of changes in pain during needle penetration of the mucosa is a self-report measure such as the visual analog scale (VAS) or a verbal pain rating scale. The disadvantage with these scales is that interindividual differences in subject response are large, which means that significant differences in pain reduction between groups receiving TLA or placebo are difficult to detect, especially when the sample size is small.

How topical anesthesia influences not only self-reported pain but also the somatosensory afferent nervous system has been the focus of few studies and is little understood.⁹ An understanding of the underlying pathophysiologic mechanisms of pain generation requires knowledge of the nature of the somatosensory changes. The German Research Network on Neuropathic Pain recently addressed this issue in their presentation of a comprehensive quantitative sensory test (QST) protocol, which includes assessment of Aδ-, Aβ-, and C-fiber function as well as temporal pain summation (wind-up). This protocol was recently found to exhibit acceptable interexaminer and intraexaminer reliabilities of most QST measures in the orofacial region.¹⁰ Standard deviations in subject response are also believed to be smaller, allowing differences to be detected in a smaller sample.

One drawback to QST, however, is that it is time consuming; one site requires approximately 30 minutes to assess. A newly developed device—the electronic von Frey (EvF, Somedic AB, Hörby, Sweden)—is able to capture Aδ- and C-fiber function; the instrument is also faster and easier to use inside the mouth than QST and has been reported to be useful in assessing intraoral pain.¹¹ Before the EvF device can be generally recommended for intraoral measurements, the reliability, validity, and sensitivity to change must be investigated.

To advance the field and better understand the pain-relieving effect and the underlying mechanisms of topical anesthesia, a well-designed structured protocol is necessary, ideally comprising both self-report measures and quantitative somatosensory tests. The aims of this study were, therefore, to determine the reliability, validity, and sensitivity to change of punctuate pain thresholds and of self-reported pain on needle penetration, and to measure the effect of topically administered lidocaine gel compared with placebo gel on pain thresholds and self-reported pain intensity.

The hypotheses were that (a) mechanical (punctuate) pain threshold (MPT) has acceptable validity as a substitute for needle penetration of oral mucosa, (b) the test-retest reliability for MPT is higher than for self-report of pain during needle penetration, (c) topical anesthesia significantly decreases the MPT but not needle pain sensitivity (NPS), and (d) a significant difference occurs between topical anesthesia and placebo in the MPT but not in NPS because a threshold assessment based on the average of 3 measurements would be more precise than 1 single self-reported pain rating.

MATERIALS AND METHODS

Participants

Thirty healthy female participants were recruited by posting advertisements and flyers at Malmö University.

The inclusion criteria were (a) female sex, (b) good health, and (c) age 18–75 years. Exclusion criteria were (a) dental treatment scheduled for the time of the study, (b) intake of medication during the time of the study (analgesics, hypnotics, or antidepressants), (c) pain in the mouth or face, (d) known hypersensitivity to lidocaine, (e) neurologic diseases, (f) acute severe systemic disease or poor general health, (g) inflammatory oral and mucosal disease, (h) pregnancy, and (i) widespread pain.

To ascertain that all criteria for study participation were fulfilled, the subjects completed a self-report form assessing medical history, present medication, and grade of anxiety in the dental treatment situation.

The Regional Ethics Review Board at Lund University (2010/582) and the Swedish Medical Product Agency (151/34283) approved the study protocol. All participants signed informed consent forms. The study was conducted according to the Declaration of Helsinki. Subjects received compensation of Swedish krona 750 (approximately $100 USD) for their participation.

Study Design

The study was a prospective, double-blind, placebo-controlled randomized cross-over clinical experimental study. Thirty volunteers were examined individually on 2 occasions. Each session required approximately 45 minutes. Testing occurred at the mucogingival fold adjacent to the mesial surface of the first upper right premolar. During testing, the examiner was blinded to treatment (TLA/placebo). In randomized order, subjects were assigned lidocaine gel or a placebo gel. A standardized QST protocol was followed, which comprised these measures: MPT, pressure pain threshold (PPT), mechanical pain sensitivity (MPS), and NPS. All measurements were made 4 times (before application and 10, 20, and 30 minutes following application of gel). After 1–2 weeks, all participants were examined again (test-retest reliability). Figure 1 illustrates a flowchart for the study. TLA was lidocaine 2% in gel (Dynexan Mundgel, Kreussler Pharma GmbH, Wiesbaden, Germany). Prior to the application of the study medication, the area to be treated was dried with a swab. A pea-sized amount of gel (corresponding to approximately 0.2 g gel or 4 mg lidocaine) was uniformly applied in a thin layer on the gingival mucosa approximately 1 cm below the gingival margin of tooth no. 14 and gently massaged for 1 minute into the target area. A cotton swab was then placed on the area for 5 minutes to ensure that the medication remained in place. The placebo gel, similar in appearance to Dynexan, was administered in an identical manner. The pharmacologic substances were stored in identical tubes (Kreussler Pharma GmbH). Both Dynexan and the placebo were imported to Sweden for this study. Subjects were asked to report any side effects related to the experimental procedures described in this clinical research protocol.

Figure 1.

Flowchart of experimental design. Gel I and II are lidocaine 2% and placebo gel, and subjects were randomized to testing order (cross-over). Gel application time was 5 minutes. MPT indicates mechanical pain threshold; PPT, pressure pain threshold; MPS, mechanical pain sensitivity—self-report of pain and discomfort during pinprick stimulus; and NPS, needle penetration sensitivity—self-report of pain and discomfort during needle penetration of oral mucosa.

Sensory Measures

The standardized quantitative somatosensory examination protocol included determination of the following measures.

Mechanical Pain Threshold (MPT)

Pinprick or punctuate pain is considered to assess sensory Aδ-fiber function. The MPT was measured with an EvF device (SENSEBox, Somedic AB). The contact surface of the probe was flat with a diameter of 0.2 mm. Applied forces ranged from 0 g to 200 g. To prevent slippage of the probe, the examination site was dried with gauze before testing. Care was also taken that the instrument did not accidentally touch other intraoral tissues (such as lip or tooth). The probe was applied perpendicularly to the examination site. During the test, pinprick force was increased at a rate of 25 g/s. At the first sensation of pain, the subject pressed a button to interrupt stimulation. The subject was also asked to rate the painful stimulus as sharp or dull. MPT was defined as the mean of 3 measurements.

Pressure Pain Threshold (PPT)

To test the function of deep pain, thought to be mediated through C- or Aδ-fibers, the PPT was measured with an electronic pressure algometer (Somedic Algometer, Somedic AB). The probe surface area was 0.18 cm² (diameter 4.8 mm). During the test, pressure was increased at a rate of 50 kPa/s. At the first painful sensation, the subject pressed a button to interrupt stimulation. The subject was also asked to rate the painful stimulus as sharp or dull. PPT was determined as the mean of 3 measurements.

Mechanical Pain Sensitivity (MPS)

Pain and discomfort during punctuate stimulation were assessed with an EvF device in the form of self-report. A fixed force of 75 g was applied with a contact time of approximately 2 seconds. The subject rated (a) pain intensity on a 0–100-point VAS with the endpoints 0 indicating “no pain” and 10 indicating “most intense pain imaginable” and (b) discomfort on a 0–100-point VAS with the endpoints 0 indicating “no discomfort” and 100 indicating “most intense discomfort imaginable.” The subject was also asked to rate the stimulus as either sharp or dull. The test was conducted once, and the subject was blinded to whether MPS or NPS was performed.

Needle Penetration Sensitivity (NPS)

Pain and discomfort during needle penetration were assessed with an EvF device in the form of self-report. A 25-gauge injection needle applied to the EvF device penetrated the gingiva. The subject rated (a) pain intensity on a 0–100-point VAS with the endpoints 0 indicating “no pain” and 100 indicating “most intense pain imaginable,” and (b) discomfort on a 0–100-point VAS with the endpoints 0 indicating “no discomfort” and 100 indicating “most intense discomfort imaginable.” The subject was also asked to rate the stimulus as sharp or dull. The test was conducted once, and the subject was blinded to whether MPS or NPS was performed.

Reliability, Validity, and Sensitivity to Change

Test-retest reliability over 10 minutes was calculated for all measures. Intravariability was analyzed for each measure and reliability using kappa and intraclass correlation coefficient (ICC) statistics. Face validity was analyzed by comparing subject responses to the different stimuli, in other words the ratings of each stimulus type (MPT, PPT, MPS, and NPS) as sharp or blunt. The correlation between the outcomes determined convergent and discriminant validity—convergent validity was analyzed by comparing sharp/dull reports between NPS and MPS, whereas discriminant validity was analyzed by comparing NPS and PPT. Sensitivity to change was determined by comparison of data before application and 10 and 20 minutes after application of topical lidocaine 2% and placebo.

Statistical Methods

The study was explorative, which makes it difficult to calculate with certainty the number of individuals needed to demonstrate acceptable reliability for threshold measurements. The primary endpoint was the punctuate pain threshold, measured by applying an increasing force on the gingiva (MPT). Our calculation assumed an alpha of .05 and beta of .20. An intraindividual variability of 30% has been reported in numerous sensory investigations of the face. To observe a 25% difference between intraoral and extraoral sites, 23 individuals would be needed to achieve statistical significance in MPT. Previous studies on MPT and PPT reliability have shown that 21 subjects are needed to demonstrate acceptable reliability.¹⁰

For comparisons within individuals, Student's paired t test was used for numerical variables and McNemar test for categorical variables. Comparisons between independent groups were analyzed using a χ² test or Fisher exact test for categorical variables. The ICC calculated the test-retest reliability for all variables. An ICC < 0.4 was considered poor agreement,; 0.4–0.59 fair, 0.6–0.75 good, and > 0.75 excellent.¹² Validity was determined by analyzing the correlation between NPS–MPS and NPS–PPT using Pearson correlation coefficient (r). A significance level of 5% was used in all tests. IBM SPSS Statistics v. 20 (IBM, Armonk NY) was used in all calculations.

RESULTS

Twenty-nine female subjects, mean (SD) age 29.0 (10.2) years (range 19–60), completed the study. The study was conducted at Malmö University between September 11, 2011 and January 18, 2012.

No significant differences between lidocaine and placebo gels occurred for MPT, PPT, MPS (pain/discomfort), or NPS (pain/discomfort) at any time point. Figure 2 illustrates mean values and SD of the MPT after lidocaine and placebo application at the 0, 10-, 20-, and 30-minute assessments. No significant differences between the substances occurred at any time point.

Figure 2.

Mean values and standard deviations of the mechanical pain threshold (MPT; g) for lidocaine and placebo at the 0, and 10-, 20-, and 30-minute assessments (n = 29).

Figure 3 illustrates mean values and SD of the PPT after lidocaine and placebo application at the 0, 10-, 20-, and 30-minute assessments. No significant differences between the substances occurred at any assessments.

Figure 3.

Mean values and standard deviations of the pressure pain threshold (PPT; kPa) for lidocaine and placebo at the 0, and 10-, 20-, and 30-minute assessments (n = 29).

Figure 4 illustrates mean values and SD of MPS pain and discomfort after lidocaine and placebo. No significant differences between the substances occurred at any assessments.

Figure 4.

Mean values and standard deviations of mechanical pain sensitivity (MPS; visual analog scale) for lidocaine and placebo at the 0, and 10-, 20-, and 30-minute assessments; (a) pain intensity and (b) discomfort (n = 29).

Figure 5 illustrates mean values and SD of NPS pain and discomfort after lidocaine and placebo. No significant differences between the substances occurred at any assessments.

Figure 5.

Mean values and standard deviations of needle penetration sensitivity (NPS; visual analog scale) for lidocaine and placebo at the 0, and 10-, 20-, and 30-minute assessments; (a) pain intensity and (b) discomfort (n = 29).

Table 1 shows the sensitivity of measures to detect differences between compounds and the estimated sample size of individuals needed to find a significant difference between compounds. Calculations were based on data from registration at 20 minutes. The assumed relevant difference was estimated to 30% of the placebo effect at 20 minutes after gel application.

Table 1.

The Sensitivity of Measures to Detect Differences Between Compounds. Estimated Sample Size (No. of Individuals/Group) Needed to Detect a 30% Difference for Each Outcome Measure at 80% and 90% Power, Respectively

The test-retest reliability ICC values were MPT 0.69, PPT 0.79, MPS 0.72, and NPS 0.86.

Table 2 shows the proportions (%) of sharp/dull reports before application and after 5 minutes of application of the compounds for each of the measures (time points 10 minutes and 20 minutes). A high percentage of agreement in reports of perceived (sharp/dull) stimuli was found for MPT, MPS, and NPS, whereas PPT differed. A significantly high positive correlation was found between NPS and MPS (r = 0.84; P < .001), whereas no significant correlation was found between NPS and PPT (r = −0.22; P = .25).

Table 2.

Proportions (%) of Sharp/Dull Ratings for Each of the Measures Before (Time Point 10 Minutes) and After (Time Point 20 Minutes) Application of the Compounds

None of the subjects who completed the study reported any adverse events. One subject dropped out after the first session and was not included in the statistical analysis. The reason for not participating in the second session was pain and discomfort during the first session.

DISCUSSION

The main finding in the study is that good to excellent test-retest reliability (over 10 minutes) was found for all measures—thresholds as well as self-report measures. None of the measures were sensitive enough to detect differences in anesthetic effect between lidocaine 2% and placebo gel. Measuring MPT/MPS with an EvF device has good validity as a substitute for needle penetration of oral mucosa.

In studies on the anesthetic effect of topical compounds, common drawbacks in many studies are problems with design such as small sample size, randomization, blinding, and unreliable or non–patient-oriented measures. To minimize mistakes in study design, several leading scientific journals have made a united effort to set up guidelines for randomized controlled trials in the Consolidated Standards of Reporting Trials (CONSORT) statement.¹³ The 25-item CONSORT checklist can help avoid pitfalls. This study was conducted as a prospective randomized, double-blind, placebo-controlled cross-over study. To ensure high study quality, CONSORT and Good Medical Practice guidelines were followed.^13,14 Since this pilot study was designed to investigate a new device, the EvF, the sample size was limited to 30 individuals, based upon calculations of threshold measurements from similar somatosensory devices measuring MPT.

Several studies have found that self-reported pain intensity and measurement of pain thresholds differ between genders.¹⁵ Female participants often report higher pain intensity and exhibit lower pain thresholds (such as for pinprick and pressure pain) than male participants.^16,17 Therefore, to reduce variability in this pilot study, we focused on female participants.

We hypothesized that a significant difference between before and after lidocaine application would be found for MPT but not for NPS, and that a significant difference between lidocaine and placebo would be found for MPT and not for NPS. These hypotheses were not confirmed. This study found no significance difference in pain thresholds or self-reported pain (or discomfort) intensity between lidocaine and placebo in any of the sensory measures used. This finding is in line with several other randomized controlled trials, reporting that the effect of topical anesthesia did not differ significantly from placebo.¹

In contrast, other studies have found indications of a difference in effect between topical anesthesia and placebo.¹⁸ There are several possible explanations. One might be the difference in procedure: our study evaluated pain on needle penetration after topical application to the oral mucosa in healthy individuals, whereas another study evaluated pain on probing of the periodontal pocket in advanced periodontitis after placing the topical compound in the periodontal pocket. A second possibility is difference in the anesthetic effect of the tested compounds or in their concentration. Our study compared only 2% lidocaine with placebo, so we have no data to either support or refute this possibility, but a review article comparing studies using different topical compounds for needle penetration reported conflicting results.¹ A third possibility is the relatively low number of included participants, which limits the power to detect statistically significant differences between groups. It is important to note the difference between a statistically significant and a clinically significant (or relevant) difference, the latter being a difference in effect that is perceived as meaningful or clearly beneficial to the patient. A review analyzing 10 randomized controlled trials found that a 30% reduction in pain intensity corresponded to a clinically relevant difference in pain for the patient.¹⁹ Based upon a 30% reduction in self-reported pain and pain threshold in this material, our study indicated that a sample size of 104–126 individuals would be needed to detect differences between the 2 compounds, depending on which measure was used.

Pain is a personal experience and encompasses both pain intensity and discomfort. Pain intensity is the sensory-discriminative experience of pain, whereas discomfort is related to the emotional experience of pain.²⁰ In our study, no significant difference was found in discomfort rating between the compounds in any of the measures. Pain emotions and psychologic factors interact, which was highlighted in one study, which reported that whether injections were preceded by an active or a placebo agent did not alter subjects' experience. But, subjects who believed they would receive the active agent anticipated significantly less pain than subjects who thought they would receive a placebo.²¹ Comfort and trust between patients and dentists are important aspects in the dental situation.

This study attempted to develop a protocol including both self-report and clinical measures to gain a better understanding of the pain relieving effect of the TLA compounds. It is essential that measures being used in clinical trials mirror endpoints that not only are important for the patient, such as self-reported pain and discomfort, but also reflect the biologic mechanisms related to pain. This study included 2 pain threshold measures. MPT is able to capture mainly Aδ-fiber function, and PPT mainly C-fiber function. A good convergent validity was found in the study for MPS versus NPS, indicating that the subject experienced the same sharp stimulus independent of whether EvF was used or needle penetration of the oral mucosa occurred. Significant difference was found in the reports of dull/sharp experience between PPT and NPS, indicating good discriminant validity. This finding supports the notion that the measures activate different afferent fibers and provides information on the mechanism of the drug being investigated. Self-reported pain can be assessed with verbal scales, behavioral scales, numerical scales, or the VAS.²² This study used VAS pain intensity and VAS discomfort, which are common measures in the pain research field.²³ In our study, self-reported pain and discomfort, regardless of whether NPS or MPS was used, showed similar reliability and validity, but with the advantage that MPS does not penetrate the mucosa, which NPS does.

Topical anesthesia has been reported to have a pain-relieving effect, and in clinical practice, topical anesthesia is applied a few minutes before needle penetration of the oral mucosa. For this reason, test-retest reliability was conducted at 10-minute intervals in this study. Good to excellent reliability was found for all measures: MPT, PPT, MPS, and NPS. Whereas PPT reliability was similar compared to another study assessing intraoral reliability, MPT reliability on gingiva was slightly lower in our study.¹⁰ A possible explanation is that slightly different intraoral test sites and different equipment were used. The present study used a newly developed device, the EvF, to assess MPT. This instrument provides an increasing force, whereas the other study used a set of 7 custom-made pinprick stimulators of constant force in a staircase method of limits. The EvF has the advantage of being more time efficient and easier to apply intraorally than weighted pinprick needles. In the present study, the investigated site was in the mucogingival fold (because that is where infiltration injections are usually placed), which is more densely innervated compared with the attached gingiva. This may explain the lower threshold values and the larger variability in the present study.

The dropout of one subject did not influence the outcome. No adverse events occurred, but adverse events have been reported with the use of topical lidocaine in other studies.¹ It should be emphasized that among the participants, perceived pain was largely independent of whether a needle penetrated the mucosa or the EvF was used; average pain intensity was 27 on a 0–100 scale. Most subjects thus experienced mild pain from these stimuli (VAS 0–30), but in some cases subjects reported severe pain (VAS 60–100).

In conclusion, the study found good to excellent test-retest reliability for all sensory measures. Measuring MPT/MPS using an EvF device has good validity as a substitute for needle penetration of oral mucosa. None of the applied measures were sensitive enough to detect differences in anesthetic effect between topical lidocaine 2% and placebo gel. The proposed protocol has the advantage of providing information about self-reported pain and discomfort as well as biologic changes in the somatosensory system in the evaluation of a topical compound.