Clinical trial NCT04373421
Conditions: Impacted Third Molar Tooth
Sponsor: Yuzuncu Yıl University
Start date: 2018-08-15; Completion date: 2020-06-01
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Surgical removal of impacted third molars is one of the most frequent procedures carried out in the oral and maxillofacial surgery clinics. There are a varying range of postoperative complications including pain, edema and swelling. Antibiotics, analgesics and mouthwashes are usually prescribed for the treatment of these complications. Patients undergoing impacted third molar surgery are frequently prescribed chlorhexidine mouthwashes with/without benzydamine hydrochloride. However, to preclude the adverse effects of these chemical agents, there has been a search for plant-derived alternatives with anti-inflammatory, antibacterial and analgesic properties as part of the oral care routine following surgical removal of impacted third molars. However, there is no study investigating the comparison of different essential oils in the literature. Thus, this multicenter study was aimed to evaluate the effects of St. John's wort oil and virgin olive oil on the postoperative complications and compared with chlorhexidine gluconate plus benzydamine hydrochloride mouthwash after the removal of impacted wisdom teeth.This study was aimed to evaluate the effects of St. John's wort oil, virgin olive oil, and chlorhexidine gluconate plus benzydamine hydrochloride on the postoperative complications after the removal of impacted wisdom teeth.

Detailed description:

Arms: arm 1: Chlorhexidine is one of the most commonly used medications after tooth extraction. It exhibits a wide spectrum of antiseptic, bactericidal and bacteriostatic effects. The most common side effect of chlorhexidine is oral discoloration, taste changes and allergic responses. Furthermore, it has been reported that chlorhexidine has cytotoxic effect on gingival fibroblasts, epithelial cells, neutrophils and red blood cells; also shows incremental trend in genotoxicity as the duration of usage is increased. Benzydamine hydrochloride is a nonsteroidal anti-inflammatory drug that elicits anti-inflammatory, analgesic, anesthetic and antimicrobial effects. It is often used in addition to the topical application of chlorhexidine.. However, side effects such as urticaria, erythema, pruritus, photosensitivity, bronchospasm and renal problems can be observed associated with the use of benzydamine. arm 2: St. John's Wort (Hypericum perforatum) is a European medicinal plant with a history of more than 2000 years which possessing a variety of important constituents including phloroglucinols (hyperforin and adhyperforin), naphthodianthrones (hypericin and pseudohypericin), xanthones, essential oil, biflavones (biapigenin and amentoflavone), flavonol derivatives and phenolic compounds. The important components of St. John's Wort such as hypericin and hyperforin exert anti-inflammatory, antimicrobial, anticancer effects as well as stimulating tissue growth and differentiation. Hypericin exhibits anti-inflammatory effects by inhibiting the production of interleukin-12; whereas hyperforin reveals this effect by inhibiting the mechanisms of cyclooxygenase 1, 5-lipoxygenase and prostaglandin E2. St. John's Wort oil is extracted by maceration of the hypericum herb in carrier oil, such as virgin olive oil. arm 3: The olive oil, a product extracted from the fruit of Olea europaea, exerts also antioxidant and anti-inflammatory effects due to its important contents including oleic acids, phenolic acids, secoiridoids and flavonoids. The oral application of olive oil has been shown to have protective anti-inflammatory effects and accelerated epithelial healing.
Interventions: intervention 1: Chlorhexidine Gluconate 0.12 % Mouthwash + benzydamine hydrochloride intervention 2: St. John's wort oil intervention 3: Virgin olive oil
Intervention descriptions: intervention 1: After anesthesia, the horizontal incision was made with no. 15 scalpel blade and a full thickness mucoperiosteal flap was raised. In all surgical procedures, bone removal and/or tooth sectioning were performed under abundant irrigation. Following the extraction, granulation tissues were removed, and post extraction cavity was irrigated with sterile 0.9% saline solution. After the bleeding was controlled, the mucoperiosteal flap was repositioned by 3.0 silk sutures. The patients were postoperatively prescribed paracetamol (Parol® 500 mg, Atabay Chemical Industry, Istanbul, Turkey) to use when required with a maximum of 4 doses per day. Patients were instructed to maintain a soft diet, and refrain from mouth washing, brushing and flossing during the first 24 hour. They were also instructed to rinse their mouth with 15 ml of mouthwash for 30 seconds, 3 times a day, and continue until the 7th postoperative day. intervention 2: After anesthesia, the horizontal incision was made with no. 15 scalpel blade and a full thickness mucoperiosteal flap was raised. In all surgical procedures, bone removal and/or tooth sectioning were performed under abundant irrigation. Following the extraction, granulation tissues were removed, and post extraction cavity was irrigated with sterile 0.9% saline solution. After the bleeding was controlled, the mucoperiosteal flap was repositioned by 3.0 silk sutures. The patients were postoperatively prescribed paracetamol (Parol® 500 mg, Atabay Chemical Industry, Istanbul, Turkey) to use when required with a maximum of 4 doses per day. Patients were instructed to maintain a soft diet, and refrain from mouth washing, brushing and flossing during the first 24 hour. They were also instructed to rinse their mouth with 15 ml of mouthwash for 30 seconds, 3 times a day, and continue until the 7th postoperative day. intervention 3: After anesthesia, the horizontal incision was made with no. 15 scalpel blade and a full thickness mucoperiosteal flap was raised. In all surgical procedures, bone removal and/or tooth sectioning were performed under abundant irrigation. Following the extraction, granulation tissues were removed, and post extraction cavity was irrigated with sterile 0.9% saline solution. After the bleeding was controlled, the mucoperiosteal flap was repositioned by 3.0 silk sutures. The patients were postoperatively prescribed paracetamol (Parol® 500 mg, Atabay Chemical Industry, Istanbul, Turkey) to use when required with a maximum of 4 doses per day. Patients were instructed to maintain a soft diet, and refrain from mouth washing, brushing and flossing during the first 24 hour. They were also instructed to rinse their mouth with 15 ml of mouthwash for 30 seconds, 3 times a day, and continue until the 7th postoperative day.

Protocol documents:
Prot_SAP_000.pdf: 
01 August 2018 
Effect of St. John’s wort oil and olive oil on the postoperative 
complications after third molar surgery: randomized, double-blind 
clinical trial 
NCT Number: NCT04373421 
Study Protocol, and Statistical Analysis Plan 
Study Protocol 
This randomized double-blind clinical trial will be conducted in Ankara Yıldırım 
Beyazıt University Oral and Maxillofacial Surgery Clinic and Van Yüzüncü Yıl University. 
Ethical approval of the study was obtained from Van Yüzüncü Yıl University Faculty of 
Medicine Clinical Research Ethics Committee in accordance with the Declaration of Helsinki 
(Decision Date and Number: 01.08.2018-08). Signed informed consent will be obtained from 
all patients. 
90 healthy individuals who need third molar surgery will be included in this study. 
Inclusion criteria: Between 18-40 years of age, having asymptomatic unilateral mandibular 
impacted third molars (mesioangular) with similar angular positions according to the Winter 
classification and a similar degree of impaction according to Pell and Gregory's classification 
(class II, level B). Patients with a history of smoking, drug use, and pericoronitis associated 
with the lower third molar will be excluded. Pregnant and lactating women, patients with 
periodontal problems in the adjacent second molars (ie, increased periodontal depth, gingival 
recession), or patients without adjacent second molars on the operative side will also be 
excluded. 
The predictive variable will be the type of mouthwash used in the study (St. John's 
wort oil and olive oil) and the control (chlorhexidine gluconate + benzydamine hydrochloride) 
groups. The outcome variable will be patient-reported pain and difficulty in jaw function, 
trismus, facial swelling, the number of analgesics used in the first postoperative week, and 
postoperative periodontal status. 
All patients included will be randomly divided into 3 groups. St. John's wort oil will 
be given; Extra virgin olive oil will be given to the patients in the second group, and the 
mouthwash containing chlorhexidine gluconate and benzydamine hydrochloride will be given 
to the patients in the third group. Randomization will be performed by permutation method in 
MedCalc 11.5.1 software (MedCalc Software Inc, Ostend, Belgium). Three types of 
mouthwash will be given to the clinicians without notifying the surgical procedure or 


postoperative controls, which are individually placed in boxes by the assistant personnel 
categorized as group 1, group 2 and group 3. 
All procedures will be performed by the same surgeons in each center, using a 
standard protocol in each medical center. Local anesthesia will be administered using 0.01 mg 
/ ml epinephrine and 2 ml articaine hydrochloride 40 mg / ml (Maxicaine Fort, VEM Drug, 
Istanbul, Turkey). Horizontal incision no. 15 scalpel blades and full thickness mucoperiosteal 
flaps will be removed. In all surgical procedures, bone removal and / or tooth cutting will be 
performed under copious irrigation. Following extraction, the granulation tissues will be 
removed and the post-extraction cavity washed with sterile 0.9% saline solution. After the 
bleeding is controlled, the mucoperiosteal flap will be repositioned with a 3.0 silk suture. 
Paracetamol (Parol® 500 mg, Atabay Kimya Sanayi, Istanbul, Turkey) was prescribed to the 
patients to use when necessary, with a maximum of 4 doses per day after surgery. Patients 
will be instructed to maintain a gentle diet for the first 24 hours and to avoid mouthwashing, 
brushing, and flossing. In addition, they will be asked to rinse their mouths with 15 ml of 
mouthwash 3 times a day for 30 seconds and continue until the 7th day after surgery. 
The maximum mouth opening (MMO) will be measured in millimeters with a caliper 
from the incisal edge of the right upper and lower incisors. To evaluate the trismus, the 
percentage difference in MMO at the postoperative period (B), subtract the preoperative 
measurement (A) from the postoperative measurement, and then divide the preoperative 
measurement (A) and multiply by 100 (percentage difference = [B - A] / B × 100) . Facial 
swelling will be assessed using a thread and a millimeter ruler and five additional 
measurements will be made: distance I (from mandible to labial commissure); distance II 
(from angle of mandible to nose border) distance III (from the angle of the mandible to the 
outer corner of the eye); distance IV (from angle of mandible to tragus) and distance V (from 
mandible to soft pogonion). To evaluate the changes in the above distances in the 
postoperative period, the percentage of facial swelling will be calculated by subtracting the 
preoperative measurement from the postoperative measurement and then dividing it by the 
preoperative measurement and multiplying by 100. 
A 7-day planned pain diary will be given to patients to evaluate postoperative pain and 
jaw function. To record the level of pain, patients will be instructed to grades on 100 mm 
visual analog scales (VAS) where 0 indicates no pain and 100 indicates the worst pain 
imaginable. To assess the difficulty in jaw function, patients will be asked to rate it at 100 mm 
VAS, where 0 indicates no limitation and 100 indicates severe limitation. They will also be 
asked to note how many painkillers they take per day. Patients will be evaluated for facial 


swelling and trismus on postoperative 1st, 3rd and 7th days. In addition, complications such 
as alveolitis and infection will be recorded observationally. 
All clinical periodontal assessments were to be measured by a blind examiner and 
mesio-buccal, mid-buccal, disto-buccal and disto-lingual were selected around adjacent 
second molar measurements for four regions. The plaque index defined by Silness and Loe 
will be used to evaluate patients' dental plaque status. Plaque thickness on the third gum of the 
teeth will be evaluated. The scores for each unit will then be summed up and divided by the 
total number of areas evaluated to arrive at the plaque index. The gingival bleeding index, 
introduced by Ainamo and Bay, will be used in the assessment of patients' gingivitis. The 
second molar will be probed gently with a periodontal probe (Williams probe, Hu-Friedy, 
Chicago, IL, USA) and then if bleeding occurs within 10 seconds, the bleeding sites will be 
noted as "positive". The number of positive bleeding zones will be divided by the total 
number of zones present and multiplied by 100 to express the gingival bleeding index as a 
percentage. Both the plaque index and the gingival bleeding index will be recorded 
preoperatively and on the 7th and 14th days and 1 month after surgery. The probing pocket 
depth will be measured by inserting a periodontal probe into the gingival groove until 
resistance is felt, and the measurements will be recorded to the nearest millimeter. Probing 
depths will be evaluated for the second molar tooth before surgery and 1 month after surgery. 
If there is gingival recession in the second molars, the distance between the cement-enamel 
junction and the free gingival border will be measured at the last follow-up visit. 
Statistical Analysis Plan 
Based on previous trial studies, a power analysis was performed using the Power 
Analysis of Sample Size (PASS) software program, showing that the Standard deviation (σ) 
for pain ranged from 4.87 to 5.07. For this reason, the standard deviation was accepted as 5. 
The effect size was accepted as (d) 2 by the researcher for the 95% confidence coefficient and 
approximately 80% power value, and the Z value was used as 1.96 for 0.05. type I error rate. 
Using the sample size calculation equation, the sample size was found to be 24 (n = Z2σ2 / 
d2). Descriptive statistics (frequency, mean and standard deviation) were determined for each 
variable. Kruskal-Wallis H test will be used for comparisons between groups, and Wilcoxon 
signed rank test will be used for in-group comparisons. All analyzes will be performed using 
SPSS Version 21.0 (SPSS, Inc., Chicago, IL). A value of p <0.05 will be considered 
statistically significant for all analyzes.