Efficiency of Flurbiprofen 2.5% in Comparison to 98% Aloe Vera Gel as an Adjunctive Therapy to Scaling and Root Planning in the Initial Treatment of Stage III Chronic Periodontitis in Smoking Patients
Phase: PHASE4
Conditions: Periodontitis Chronic Generalized Severe
Sponsor: Beirut Arab University

 
 
 
 
Clinical efficacy of flurbiprofen 2.5% in comparison to 98% Aloe Vera gel as 
adjunctive therapy in the initial treatment of stage III chronic periodontitis in 
smoking patients. 
                                        (Randomized Controlled Clinical Study) 
  
 
 
 
 
 
 
 
 
 
 
 
 
                                                                             
 
 
                          
 
 
 
 
 
 
      August 11, 2023 

Title page 
Clinical efficacy of flurbiprofen 2.5% in comparison to 98% Aloe Vera gel as adjunctive therapy in 
the initial treatment of stage III chronic periodontitis in smoking patients (Randomized Controlled 
Clinical Study) 
Authors: 
Ali M. Issa1 , Nour A. Alaaeddine2 , Hadi B. Zahr3 , Nayer M. Aboelsaad4, May K. Saab5 
Author's contribution:  
A.I. 1, N.A. 2 and H.Z. 3 formulated the study design and drafted the protocol. M.S. 5  formulated the drugs 
A.I. 1 and N.A. 2 H.Z 3 performed the experiments. A.I. 1, N.A. 2 and H.Z. 3 collected the data. N.A. 4 analyzed 
and interpreted the results then revised the entire manuscript. All authors read and approved the final 
manuscript.  
Author for correspondence: 
Prof. Nayer Aboelsaad 
Phone: +961 1 300 110 ext. (2549) 
Mobile: +961 79109899 
E-mail: n.mohamedaboelsaad@bau.edu.lb 
Word count: 3817 
Total number of references: 39 
Running title: Flurbiprofen Vs. Aloe Vera in Treatment of Periodontitis 
 
1 B.D.S., Department of Periodontology, Faculty of Dentistry, Beirut Arab University, Lebanon.  
2 B.D.S., Department of Periodontology, Faculty of Dentistry, Beirut Arab University, Lebanon. 
3 B.D.S., Department of Periodontology, Faculty of Dentistry, Beirut Arab University, Lebanon. 
4 PhD, Department of Periodontology, Faculty of Dentistry, Beirut Arab University, Lebanon. 
5 PhD, Degree in Pharmaceutical Sciences, Faculty of Pharmacy, Beirut Arab University, Lebanon. 

 
Clinical efficacy of flurbiprofen 2.5% in comparison to 98% Aloe 
Vera gel as adjunctive therapy in the initial treatment of stage III 
chronic periodontitis in smoking patients. 
Background: In recent years, various methodologies have been introduced 
to enhance the outcomes of scaling and root planing (SRP), with the intent 
of potentially eliminating the necessity for periodontal surgical interventions 
under specific circumstances. Noteworthy among these novel approaches 
are the utilization of non-steroidal anti-inflammatory drugs (NSAIDs) and 
herbal remedies like Aloe Vera. This present study endeavors to clinically 
assess the impact of flurbiprofen gel in contrast to Aloe Vera gel, as 
supplementary agents to SRP, in the elimination of periodontal pocket 
depths among individuals afflicted by stage III chronic periodontitis, 
particularly focusing on the subset of smoking patients. Materials and 
Methods: In this study, 60 patients with stage III/grade C periodontitis were 
enrolled. They were divided into three groups using the split mouth method: 
Group one (G1), which received Flurbiprofen and placebo, Group two (G2), 
which received Aloe Vera and placebo, and Group three (G3), which received 
Flurbiprofen and Aloe Vera. At the baseline, the fourth, eighth-, twelfth 
weeks and six months following treatment, the plaque index (PI), gingival 
index (GI), bleeding on probing (BOP), clinical attachment level (CAL), and 
probing depth (PD) were all measured. Statistical Analysis: Statistical 
analysis was done using SAS 9.4 Software (SAS Institute Inc., Cary, NC, USA). 
Means and standard deviations (SD) were calculated for all continuous 
variables (periodontal parameters: CAL, PD, BOP, GI, PI) at the baseline, 
fourth week, eighth week, and twelfth week and 6 months. 
Keywords: periodontitis, flurbiprofen, aloe vera, root planing. 
                               

Introduction: 
Inflammation and periodontal tissue destruction is a consequence of periodontal pockets 
originating from chronic periodontitis. [1] The latter is an infectious disease resulting from the 
interaction between the invasion of biofilm microorganisms and periodontal immune response 
in a vulnerable host. [2]  
During periodontal attachment loss, PGE2 production levels primarily by macrophages and 
fibroblasts are increased in the tissues and gingival crevicular fluid (GCF). [3,4] PGE2 promotes 
the release of MMPs, in addition to osteoclastic bone resorption, and it play a significant role in 
the alveolar bone loss observed in periodontitis. [5] 
Smoking has been identified as a major risk factor in the development and progression of periodontal 
disease. Epidemiological studies have presented a significantly higher risk for periodontal disease in 
smokers compared to non-smokers, and the increased risk is proportional to the duration and rate of 
smoking (Eke et al., 2016).[6] 
The first main goal during the treatment of periodontal disease is eliminating microbial source 
and causative factors, thus preventing further progression of the disease and maintaining 
periodontal tissue health. [7] Surgical and non-surgical modalities are available for the treatment 
of periodontal diseases. [7] The non-surgical option consisting of mechanical debridement of the 
tooth surface with scaling and root planning (SRP), [8] improves pocket depth (PD) and increases 
clinical attachment level (CAL) to some extent, [9]  
However, mechanical debridement alone may not be enough in patients with deep periodontal 
PD or having areas of furcation involvements. [10] Some pathogens like Actinobacillus 
actinomycetemcomitans, Porphyromonas gingivalis, Prevotella Intermedia, Bacteroides forsytus, 
peptostreptococci micros may not be eliminated as a result of the limited access in deep 
subgingival areas, thus increasing the risk of treatment failure. [10] 
Research have shown the significance of PGE2 in the development of periodontal diseases, 
[11]and since prostaglandins are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs), 
[12] researchers have explored the possible use of NSAIDs as possible host–response modulators 
in the treatment of periodontal disease.[13] However, achieving noticeable periodontal 
improvements requires daily administration of NSAIDs for extended periods which may lead to 
undesirable side effects gastrointestinal (GI), renal, cardiovascular (CV), cerebrovascular, and 
central nervous system (CNS) adverse effects [14] 
 

It is advised to consider using local drug delivery (LDD) as an adjunct to conventional periodontal 
therapy to reach the best clinical outcomes. LDD is an effective method of delivering drugs. 
Higher drug concentrations at the targeted area can be reached using LDD with a lower drug dose 
than the usual systemic delivery and thus fewer side effects. [15] 
 
A topic that seems of particular interest is the development local NSAID formulations (e.g., gels, 
toothpaste, and rinses) with daily usage. These products may lead to an improvement in the 
reduction of detrimental systemic effects of non-selective NSAIDS in the long-term host 
modulation of periodontitis-susceptible patients. [16] Moreover, studies demonstrated that 
prostaglandin production inhibitors, like NSAIDs, can affect bone loss in periodontal disease. [17] 
The available data suggests that when flurbiprofen, an NSAID, is delivered locally through gel 
media during SRP, it enhances the benefits of the latter treatment and expedites the resolution 
of inflammation [18].  
Numerous adjunctive therapies to SRP have been explored in the field of periodontics. Among 
these, laser treatment [19], topical and systemic antibiotics like azithromycin [20] and 
clarithromycin [21], as well as chemicals such as hyaluronic acid [22] and various antiseptic and 
anti-inflammatory agents with immunomodulatory properties [19,23], have been documented 
to offer potential advantages.[24]  
Herbal products have gained preference over conventional drugs due to their considerable 
natural efficacy, enhanced safety profile, and cost-effectiveness. Conversely, modern 
pharmaceuticals are associated with various adverse effects. Prolonged use of these drugs has, 
at times, led to antibiotic resistance, prompting a gradual integration of herbal medicines as 
dietary supplements to address prevalent human health and oral issues.[25]  
Numerous natural/herbal medications, including green tea and salvadora persica, have been the 
subject of investigation as potential adjuncts to SRP for the management of periodontal diseases, 
offering the advantage of reduced side effects [26,27]. 
Among these herbal options, Aloe Vera, a cactus-like plant belonging to the Liliaceae family, 
stands out with its rich composition of approximately 360 species, containing 75 active 
ingredients such as vitamins, enzymes, minerals, lignins, sugars, saponins, amino acids, and 
salicylic acids [28]. In vitro and animal model studies have demonstrated medicinal effects of Aloe 
Vera, encompassing anti-inflammatory, anti-arthritic, and anti-bacterial properties [28-29]. 
Moreover, the treatment effects of Aloe Vera on systemic disease such as cancers, regulation of 
blood glucose levels, wound and infection healing have been investigated in some studies. [28-

30] Aloe Vera also inhibits the cyclooxygenase pathway, dropping the production of 
prostaglandins, thus decreasing the inflammation. [31] 
Some studies stated the use of aloe Vera in dentistry in numerous areas like disinfecting dental 
unit water network, [32] gutta-percha sterilization, [33] antiseptic effect on candida albicans, [34] 
Aphthous stomatitis management, [35] as an ingredient in toothpastes [36-37] and 
mouthwashes.[28] Up to date, limited studies have been reported in relation to the effect of 
topical application of aloe Vera in the periodontal pocket for periodontal disease management. 
[38] 
 
 
 
The null hypothesis is that flurbiprofen has no statistically significant effect in comparison to Aloe 
Vera gel as an adjunctive to SRP in the reduction of periodontal pockets in smoking patients with 
chronic periodontitis stage III. 
 Aim of this study: 
This study aims to evaluate clinically the effect of flurbiprofen gel in comparison to Aloe Vera gel 
as adjunctive to SRP in the reduction of periodontal pockets in patients with chronic periodontitis 
stage III in smoking patients. 
 
Materials and methods: 
Participants: 
This study was conducted at the Department of Oral Surgical Sciences, Division of 
Periodontology, Faculty of dentistry, Beirut Arab University (BAU)-Lebanon after approval of 
Institutional Review Board (IRB) with trial NO 2022-H-0100-D-R-0487.Patients were first briefed 
about the study and written consent was obtained. The study was performed in compliance with 
the principles of the Declaration of Helsinki. 
The estimated sample size will be calculated according to http://epitools.ausvet.com.au/, by 
taking the means of clinical attachment level at 3 months in both groups from a previous similar 
study conducted by (39) where mean for test site = 5.75±0.35 and mean for control site is = 
6.4±0.3, where the variance will be calculated to be 0.35 , assuming a confidence level of 95% 
and a study power of 80%. The calculated sample size will be 14 patients per group (28 operating 
sites).  However, as some dropouts may be expected, a minimum of 20 patients per group were 
recruited 

Inclusion criteria: 60 patients were selected who had clinical periodontal loss and radiographic 
bone loss of stage III/grade C with no history of systemic disease. They had at least 2 periodontal 
sites with a pocket depth of six mm or greater, radiographic evidence of bone loss extending to 
the middle third of the root, and clinical attachment loss of five mm or more.  Eligible subjects 
were categorized as current smokers if they consistently smoked more than 10 cigarettes per day 
for a minimum of 5 years. Additionally, individuals with no record of undergoing any periodontal 
treatment within the six months preceding the study were considered for inclusion. These 
stringent criteria aimed to ensure a relevant and homogeneous patient cohort for the research 
investigation. 
Exclusion criteria: Patients with systemic illnesses such as diabetes mellitus or conditions that 
could potentially impair wound healing were excluded from participation. Additionally, 
individuals who were pregnant or lactating were not considered for inclusion in the study. 
Subjects who had been prescribed systemic antibiotics or non-steroidal anti-inflammatory drugs 
(NSAIDs) within the three months preceding the study were also excluded. Furthermore, 
individuals with confirmed or suspected hypersensitivity to Flurbiprofen or aloe Vera, the focus 
of the investigation, were not included in the study population. These stringent exclusion criteria 
aimed to control for potential confounding factors and establish a well-defined and relevant 
patient group for the research analysis. 
Clinical protocol 
 Initial therapy was performed on all patients and consisted of full mouth scaling and root planing 
on 2-4 sessions, by hand and ultrasonic instrumentation, with oral hygiene instructions 
reinforcement and proper brushing technique (modified Bass technique) instructions. Note that 
patients received the same toothbrushes, toothpaste, and interdental brushes. Oral hygiene was 
reinforced at every visit. 
The selected patients were allocated into three groups (each containing 20) with the help of a 
computerized randomizer (Randomizer.org), and using a split mouth design, sites were randomly 
allocated for each patient into either test or control group using a coin flip method: 
- 
Group one (G1): comprised of 20 patients who received treatment involving the 
application of flurbiprofen gel as an adjunct to scaling and root planing. Specifically, on 
the test site of each patient, one milliliter of 2.5% flurbiprofen gel was applied, while on 
the contralateral side, scaling and root planing were performed as the control 
intervention. 
- 
Group two (G2): comprised of 20 patients who received treatment involving the 
application of aloe Vera gel as an adjunct to scaling and root planing. Specifically, on the 

test site of each patient, one milliliter of 98% aloe Vera was applied, while on the 
contralateral side, scaling and root planing were performed as the control intervention. 
- 
Group three (G3): The intervention involved applying flurbiprofen gel on one site, while 
the contralateral side received an application of 98% aloe vera. 
 
Clinical measurements: 
The clinical periodontal parameters were recorded by one blinded examiner from the mesio-
buccal, mid-buccal, disto-buccal, disto-lingual, mid-lingual, and mesio-lingual surfaces of each 
tooth using a colour coded periodontal probe (PQWBR - Hu Friedy Mfg. Inc. Chicago, IL, USA):  
and checked by another blinded examiner. Examiners were calibrated to ensure intra-examiner 
as well as inter-examiner agreement when measuring PD and CAL values. Fifteen patients were 
examined twice before the trial, 24 hours apart. Calibration was considered accepted if both 
measurements at the baseline and after 24 hours were similar to one mm at the 90% level.  
 In this clinical study, various clinical measurements were undertaken to assess the oral health 
status of the participants. These measurements included the clinical attachment level (CAL), 
probing depth (PD), plaque index (PI), gingival index (GI), and bleeding on probing (BOP). 
Initially, the PI and GI were measured at four sites per tooth, with gingival bleeding being 
recorded within 15 seconds. To prevent misinterpretation of gingival bleeding as BOP, patients 
were asked to rinse with water after this assessment. Subsequently, all teeth were probed at six 
different locations per tooth. CAL was determined as the distance from the cemento-enamel 
junction (CEJ) to the pocket depth, while the PD was measured as the distance from the gingival 
margin to the base of the pocket. BOP was recorded 15 seconds after probing. It is important to 
note that these clinical parameters were recorded at the baseline (1st visit) before the treatment 
and were repeated at the fourth week (2nd visit), eighth week (3rd visit), twelfth week (fourth 
visit), and at 6 months (5th visit). During this observation period, participants received 
reinforcement of plaque control and additional instructions to maintain optimal oral hygiene  
 
 
 
 
 
 

Preparation of gels: 
Aloe Vera: 
Aloe vera gel used in this study was %98 aloe vera® gel concentration (Avivir; Denmark) and 2% 
normal saline. Commercial preparation method of %98 concentration of aloe vera gel was 
washing the ripe aloe Vera leaves thoroughly under water and cutting off their skin. Each leaf 
was cut into several pieces and seeping gel from the pieces were collected in a sterile container 
and stored at 4°C until the time of application. [38] 
Flurbiprofen: 
Gel was made of 20% poloxamer and 10% ethanol as an Optimum formulation with sustained 
release up to 48 hours and a reasonable sol gel transition phase. 
 
Statistical analysis: 
Statistical analysis was done using SAS 9.4 Software (SAS Institute Inc., Cary, NC, USA). Means 
and standard deviations (SD) were calculated for all continuous variables (periodontal 
parameters: CAL, PD, BOP, GI, PI) at the baseline, fourth week, eighth week, and twelfth week 
and 6 months. Repeated linear mixed-effects models (PROC MIXED in SAS) were used to examine 
the changes in all periodontal parameters over the five-time points within each group and 
between groups. An unstructured covariance matrix was used, residual plots were visually 
reviewed to check model fit, and extreme outliers were eliminated using the restricted likelihood 
distance. A Tukey-Kramer 8 correction was applied to all pairwise comparisons. One-way ANOVA 
was used to examine group differences in PD reduction and CAL. A p-value of 0.05 was considered 
statistically significant. 
 
 
 
 
 
 
 
 

 
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