Liposomal anesthetic gel for pain control during periodontal therapy in adults: a placebo-controlled RCT

Abstract Periodontal therapy usually requires local anesthesia. If effective, a non-invasive, liposomal anesthetic gel could increase the levels of acceptance of patients in relation to periodontal therapy. Objective: This study investigated the efficacy of liposomal anesthetic gel for pain control during periodontal therapy. Methodology: Forty volunteers with moderate to severe chronic periodontitis were recruited, of which at least three sextants required periodontal therapy. At least one of the selected teeth had one site with a probing depth of ≥4 mm. The volunteers received the following three gels: a placebo, lidocaine/prilocaine (Oraqix®), or a liposomal lidocaine/prilocaine, which were applied to different sextants. Pain frequency was registered during treatment and the volunteers received a digital counter to register any painful or uncomfortable experiences. At the end of each session, the volunteers indicated their pain intensity using rating scales (NRS-101 and VRS-4). The volunteers had their hemodynamic parameters measured by a non-invasive digital monitor. Results: Pain frequency/intensity did not show statistical difference between intervention groups. The tested gels did not interfere with the hemodynamic indices. Dental anxiety, suppuration and probing depth could influence pain during periodontal therapy. Conclusion: Our results suggest limited indications for the use of non-invasive anesthesia when used for scaling and root planing. Intra-pocket anesthetic gel could be a good option for anxious patients, or those who have a fear of needles.


Introduction
Severe periodontitis is the sixth most prevalent condition worldwide, affecting 11% of the global population (743 million people aged 15-99 worldwide).
It has remained static on a global scale during the last two decades. The age-standardized incidence of the disease did not change from 1990-2010 (696 and 701 cases per 100,000 person-years, respectively). These prevalence and incidence rates were similar for males and females, and increased with age, with a steep increase among individuals aged from 30 to 40 years old, remaining stable thereafter. 1 Periodontal therapy usually involves supra and/ or subgingival scaling and root planing (SRP), 2 which can be performed using periodontal curettes or sonic and ultrasonic instruments. The prevalence of pain and discomfort during SRP is variable, but studies report around 15% to 33% of patients describing it as a significantly painful experience. 3,4 Reasons for this include tissue trauma caused by instrumentation, dentin hypersensitivity, 2 and the unpleasant noise and sensation produced by periodontal curettes and sonic or ultrasonic instruments when they come into contact with the tooth structure. 5,6 The usual technique to control pain and discomfort during SRP is applying local anesthetic injections (nerve block or infiltration anesthesia). [7][8][9] However, patients often report a fear of needles, and complain about pain and discomfort caused by their insertion and prolonged numbness in the surrounding soft tissues. 7,8,10,11 These factors can lead patients to delay, or even avoid, periodontal therapy. 7,12 New anesthetic formulations have been developed to improve treatment conditions and ameliorate the patients' level of acceptance of dental procedures. 11,13 Oraqix ® (25 mg/g lidocaine and 25 mg/g prilocaine) was developed with the addition of a thermosetting agent. 9,14,15 The onset of anesthesia has been shown to range from 30 seconds to 2 minutes after its application, and some studies have demonstrated that it is the best non-invasive anesthesia option for SRP thus far. 8,11,14,16 Another alternative is the combination of local anesthetics with liposomal formulations, which can increase the duration of anesthesia, decrease central nervous and cardiac toxicity, and decrease circulating plasma levels. [17][18][19] Studies have shown significant skin and oral mucosa anesthesia using liposome-encapsulated anesthetics; 20-22 but until now, there has been no evaluation of their efficacy in the periodontal pocket, especially during SRP.
The aim of this study was to compare the effects of a liposomal, lidocaine/prilocaine, thermosetting anesthetic gel for pain control during scaling and root planing (anti-infective periodontal therapy) compared to Oraqix ® (positive control) gel, and a placebo gel (negative control). Our primary outcome was the frequency/intensity of pain, obtained by using a digital counter to register any painful experience; a numerical rating scale (NRS-101) and a verbal rating scale (VRS-4) were used. The secondary outcomes were hemodynamic parameters (systolic blood pressure, diastolic blood pressure, heart rate and oxygen saturation). The null hypothesis was that there would be no difference between intervention groups (placebo and anesthetic gels) in relation to pain control during scaling and root planing.

Study population
A flowchart of the overall study design is shown in Figure 1

Inclusion and exclusion criteria
The volunteers had to be aged 18 or older; they needed anti-infective periodontal therapy and had to have at least three sextants with a minimum of two vital teeth requiring scaling and root planing. They also needed to have sought dental care at the University Dental Clinic. At least two sites per sextant with a probing depth of 4 mm or more and clinical signs of periodontal disease (presence of supra/subgingival calculus and/or dental biofilm, as well as bleeding/ suppuration on probing) were required for them to be included in this study.
The exclusion criteria were: individuals undergoing periodontal maintenance; any allergic reaction to amide anesthetic; consumption of any analgesic or anti-inflammatory drugs in the 12 hours prior to treatment; individuals with a history of alcoholism; smokers; pregnant or lactating women; individuals

Evaluation of clinical parameters
The data regarding probing depth, width of keratinized mucosa, bleeding on probing (presence or absence), dental plaque (presence or absence) and suppuration (presence or absence) were obtained at baseline. Measurements were performed using a standardized UNC periodontal probe (Hu-Friedy ® , Rio de Janeiro, RJ, Brazil). The volunteers were also asked to complete Corah's Dental Anxiety Scale (DAS) before the first treatment session.
The large multilamellar liposomes were obtained by the thin film hydration method. Subsequently, The placebo gel had the same composition as the liposomal gel, but without the anesthetic bases, and served as negative control. All the selected volunteers received the gels on different teeth, from different sextants, using a cross-over design and with oneweek intervals between each appointment to avoid cross-over contamination (spill-over effect). 23 The anesthetic agents were stored in identical syringes and were identified only by letters. The anesthesia was administered by a blinded operator (SCSP) according to a randomization process, who also performed the periodontal therapy procedures. The sextants were isolated with cotton rolls and the anesthetic gel was placed inside the periodontal pocket for about one minute before SRP. A second examiner (GSM) was responsible for collecting the data of each volunteer.
The volunteers could ask for rescue anesthesia (3% prilocaine with 0.03 IU/mL felypressin injection, Citanest ® , Dentsply, Catanduva, SP, Brazil) if they were still feeling pain after two applications of gel.

Pain evaluation
Pain frequency was obtained during the SRP procedures; the volunteers received a digital counter to register any painful or uncomfortable experience. At the end of each session, the volunteers were asked to indicate pain intensity using the numerical rating scale (NRS-101), and discomfort using a four-point verbal rating scale (VRS-4) (1=none; 2=mild; 3=moderate; 4=severe). If rescue anesthesia was required, the pain and discomfort scores were obtained before it was Liposomal anesthetic gel for pain control during periodontal therapy in adults: a placebo-controlled RCT J Appl Oral Sci. 2020;28:e20190025 5/12 administered. The volunteers were also asked to rate how unpleasant the taste of the anesthetic agent was ("acceptable"; "slightly unpleasant"; "very unpleasant" and "I would not like to receive it again").

Assessment of hemodynamic parameters
During the treatments, the volunteers had their hemodynamic parameters (systolic blood pressure, diastolic blood pressure, heart rate and oxygen saturation) measured by a non-invasive digital The clinical parameters, such as distribution of sextants, probing depth (≤3 mm, 4-5 mm or 6 mm) and keratinized mucosa (≤2 mm or >2 mm), were compared using the chi-square test (χ 2 ). The mean number of teeth, dental plaque, bleeding on probing, suppuration, probing depth and width of keratinized mucosa were analyzed by the Kruskal-Wallis test (nonnormal distribution).
A univariate regression analysis, with random intercept, was performed to explore the relationship between the primary outcome of interest (pain frequency/intensity) and the various risk factors 24 , comprising the following levels: site level (dental plaque, bleeding on probing, suppuration probing depth and width of keratinized mucosa), sextant level (position and number of teeth) and subject level (age, gender, periodontal diagnosis and dental anxiety).
The hemodynamic parameters (systolic and diastolic blood pressure, heart rate and oxygen saturation) were analyzed at baseline, during and after treatment by repeated measures ANOVA and the paired t-test.

Results
Of the forty randomized volunteers, thirty-eight managed to conclude the study and two did not return for the second appointment. Figure 1 shows the study flowchart. The sample comprised 23 (60%) females and 15 (40%) males, aged from 26 to 73 years old (mean age: 43.6±11.2 years old) and diagnosed with localized periodontitis (45%) or generalized periodontitis (55%).      (26) 10 (26) Very unpleasant 0 (0) 2 (5) 0 (0) I would not like to receive it again 0 (0) 0 (0) 0 (0) *ANOVA; ‡Kruskal-Wallis; †2 . ns not statistically significant (p≥0.05); s statistically significant (p<0.05) Table 4-Data obtained in trans-and postoperative scaling and root planing in the three intervention groups Liposomal anesthetic gel for pain control during periodontal therapy in adults: a placebo-controlled RCT J Appl Oral Sci. 2020;28:e20190025 9/12 Table 3 presents a comparison of the mean (±SD) hemodynamic parameters (secondary outcomes) of the different groups. Systolic blood pressure (Sys. BP), diastolic blood pressure (Dia. BP) and heart rate (HR) were assessed at distinct moments of the appointments, i.e., at baseline, during the procedure, and after the procedure; oxygen saturation (SpO 2 ) was checked at baseline and after treatment. The results suggest that this type of intra-pocket anesthetic gel for periodontal SRP did not interfere with the hemodynamic indices.
The results showed that the volume of gel applied, the number of applications, the need for additional (rescue) anesthesia, the time required to perform SRP during each session, the difficulties during periodontal treatment, and the discomfort caused by periodontal therapy were similar between the groups, as were the volunteers' perceptions of the gel's flavor, with no statistically significant differences between intervention groups (Table 4).

Discussion
The results of this study did not show statistically significant differences between intervention groups regarding pain and discomfort; therefore, the null hypothesis was accepted. Nevertheless, a recent systematic review concluded that topical anesthesia is superior to a placebo during probing and SRP because it reduces the risk and intensity of pain, as well as the need for rescue anesthesia. 25 However, there are many differences between studies regarding intra-pocket anesthesia, such as study design; 8,16 composition of the anesthetic gel; 10,11,26 use of occluded anesthesia; 26 numerically small point estimate differences between treatments; 27 and type of intervention. 14 Most of these studies did not consider variables such as the influence of acoustic or sound stimuli on the patients' perception of pain, anxiety and fear; 5,6 the possible discomfort caused by swallowing the gel during the procedures; 10,28,29 as well as short application time (30 seconds to 2 minutes), 8,11,14,16  This study is the first to evaluate hemodynamic parameters (systolic blood pressure, diastolic blood pressure, heart rate and oxygen saturation) and anxiety during SRP using non-invasive anesthesia.
No statistically significant differences were found between groups, suggesting that lidocaine/prilocaine intra-pocket anesthetic gels do not interfere with these parameters. Anxiety and fear can have a pain-increasing effect, creating an intentional bias towards the painful stimuli or pain-related sensation.
Anxiety-induced somatic changes may occur from the activation of the hypothalamus-pituitary-adrenal J Appl Oral Sci. 2020;28:e20190025 10/12 axis, the main result being increased secretion of cortisol. Endogenous or exogenous epinephrine may cause or contribute to hemodynamic and cardiac changes. 32 Dental anxiety may have an impact on the effect of local anesthesia, blood pressure, and oxygen saturation; it is significantly associated with increased heart rate. 2,33 Lidocaine-prilocaine cream may cause methemoglobinemia and change arterial blood saturation and pulse oximetry. 34 On the other hand, the lidocaine-prilocaine concentration observed after the intra-pocket application of Oraqix ® was below the threshold levels for toxic effect. 15 Our study found a significant association between dental anxiety and pain, indicating that the use of non-invasive anesthesia might be a good option for anxious patients who have had previous negative experiences with conventional anesthesia. 35 Some authors have reported that the use of splitmouth and cross-over designs significantly increased efficiency in statistical testing; 14,23 however, others have argued that a parallel group study design would be more appropriate for this type of research in order to avoid the possibility of a carry-over or spillover effects caused by the volunteers' perception of pain. 8,23 Even though a parallel group design might contribute to subject blinding, 8 it could be influenced by factors such as age, gender, ethnicity, previous pain experience and education. 14 Our results showed that around 18% to 39% of the volunteers reported severe pain, suggesting that SRP can be a painful procedure for some patients. However, such findings can be widely divergent because they are influenced by factors such as age, type of periodontal therapy, and gender. [2][3][4] In similar studies, some patients submitted to SRP using a placebo or anesthetic gel asked for rescue anesthesia, implying that this type of gel has limited applications. 8,11,16,36 In our study, pain and discomfort were assessed during/after SRP using pain frequency and two painrating scales: a numerical rating scale (NRS-101) and a four-point verbal rating scale . Pain frequency provides similar results in comparison to the pain scale. 3,4 The NRS-101 and VRS-4 scales are widely applied due to their validity, reliability and sensitivity; 37,38 nevertheless, they have some limitations linked to the patients' age and education level, as well as to their difficulty expressing pain using numbers. 39 In other similar studies using non-invasive periodontal anesthesia, the most common rating scales used were VRS and the visual analogue scale (VAS). [7][8][9]11,13,16,26,35 Although the latter is considered more sensitive, it has also been claimed that it is not as easy to understand as the NRS-101 and VRS-4 scales, which could lead to higher failure rates. 37 It is important to note that there is no ideal scale for measuring pain and the results need to be carefully interpreted by researchers. 39

Conclusion
In conclusion, we did not find differences between intervention groups in relation to pain frequency/ intensity (primary outcome). The use of intra-pocket anesthetic gel for periodontal SRP did not interfere with the hemodynamic parameters (secondary outcome).
Our results suggest limited indications for the use of non-invasive periodontal anesthesia: firstly, because periodontal procedures usually cause low or moderate pain, and secondly, because patients sometimes prefer not to receive local anesthesia. Nevertheless, some patients may experience severe pain during non-surgical periodontal therapy, and conventional local anesthesia is often necessary. The use of an intra-pocket anesthetic gel could be a good option for maintenance patients, anxious patients, or those who have a fear of needles. This is the first study to evaluate liposomal, thermosetting anesthetic gel during SRP. Consequently, further studies should be performed to verify its application in dental practice.