- Email: [email protected]
A Double-Blind Randomized Study Evaluating the Effect of Intra-Alveolar Chlorhexidine Gel on Alveolar Osteitis After Removal of Mandibular Third Molars
Accepted Manuscript A double-blind randomized study evaluating the effect of intra- alveolar chlorhexidine gel on alveolar osteitis after removal of mandibular third molars Nelly Freudenthal, DDS Mika Sternudd, DDS Leif Jansson, DDS, PhD Karin Wannfors, DDS, PhD PII:
S0278-2391(14)01407-4
DOI:
10.1016/j.joms.2014.08.035
Reference:
YJOMS 56484
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 15 May 2014 Revised Date:
22 August 2014
Accepted Date: 27 August 2014
Please cite this article as: Freudenthal N, Sternudd M, Jansson L, Wannfors K, A double-blind randomized study evaluating the effect of intra- alveolar chlorhexidine gel on alveolar osteitis after removal of mandibular third molars, Journal of Oral and Maxillofacial Surgery (2014), doi: 10.1016/ j.joms.2014.08.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
A double-blind randomized study evaluating the effect of intra- alveolar chlorhexidine gel on alveolar osteitis after removal of mandibular third molars
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Nelly Freudenthal, DDS,a Mika Sternudd, DDS, b Leif Jansson, DDS, PhD, cd Karin Wannfors , DDS, PhD e a
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DDS, Eastman Institute Maxillofacial surgery, Public Dental Service, Stockholm County Council, Sweden. b DDS, Public Dental Service, Visby, Gotland County, Sweden. c DDS, PhD,Head of Department of Periodontology, Public Dental Service at Kista and Skanstull, Stockholm County Council, Sweden. d Adjunct lecturer at Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden. e DDS, Phd, Former head of Oral and Maxillofacial clinic, Sodersjukhuset, Stockholm, Sweden.
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Corresponding author: Nelly Freudenthal Eastman Institute Maxillofacial surgery Dalagatan 11 11324 Stockholm Tel Business: 0812316570 E-mail: [email protected]
ACCEPTED MANUSCRIPT Purpose: The main purpose of the present investigation was to determine if intra-alveolar chlorhexidine gel (CHX) is an effective preventative treatment for alveolar osteitis (AO), as has been strongly suggested by previous investigators. Another goal was to evaluate if there is a correlation between the use of analgesics during the postoperative week and the
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development of AO, a correlation that could be a supplement to the commonly used diagnostic criteria for AO.
Material and Methods: A double-blind, randomized study was performed to assess if intra-
SC
alveolar administration of CHX reduces AO. To achieve this, the extraction and the postoperative course of 100 impacted mandibular 3rd molar teeth were studied. Ninety-seven
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percent of the teeth operated on had a diagnosed pathology. The extraction alveoli were treated either with CHX or placebo. The intake of analgesics was recorded for seven day after the operation.
Results: Statistically significant differences in AO between the control and experimental
degree of significance.
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groups were not found. The intake of analgesics reflected the occurrence of AO with a high
Conclusion: The present study did not verify that application of CHX gel improves healing
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after removal of impacted 3rd molars. The patients` postoperative analgesic intake reflected
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the development of AO.
ACCEPTED MANUSCRIPT In 10-40 % of cases where lower third molars are removed, alveolar osteitis (AO) occurs as a postoperative complication.1,2 AO is the most common complication following removal of impacted third molars; it is a painful condition usually developed three to four days after tooth extraction. AO is an inflammatory condition of the extraction socket. The etiology is not fully
RI PT
understood, but an infectious component is suspected. An increased local fibrinolysis, as a result of plasminogen pathway activation leading to disintegration of the clot, has been suggested as one explanation for the pathogenesis of AO.2 Factors such as surgical trauma,
SC
difficulty of surgery, smoking and bacterial infection have been suggested as contributing factors.2 As a prevention for AO, preoperative rinsing with 0.2 % chlorhexidine (CHX)
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solution has been used3,4 and encouraging reports have been presented using CHX rinsing of extraction sockets.5,6 Two reports states good results from the postoperative application of CHX gel directly into the socket.7,8 Thus, the aim of the present study was to determine if CHX –gel is an effective treatment against AO and to verify previous results showing the
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advantages with this procedure. A second goal of the study was to determine if postoperative intake of analgesics is correlated to the development of AO, and thus could be used as a
EP
complementary diagnostic criteria for AO.
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Materials and Methods Study design
This study was designed as a controlled, double-blind study carried out at the Oral and Maxillofacial Surgery Clinic at the South Hospital in Stockholm, Sweden. Ethical approval (2010/830-32) was obtained by the Regional Ethical review board. A high scientific level was secured by using a randomization process. The monitoring procedures were performed by a monitor at Karolinska trial Alliance, M62. The code list (active gel or placebo) was developed in advance through a randomizing process. The code list was locked and was not unlocked
ACCEPTED MANUSCRIPT until the study was completed. Neither the surgical team nor the patient knew whether active gel or placebo was given to the patient. The active gel used, was legally approved by the Swedish Medical Products Agency in front of the study, as it was not a registered pharmaceutical. The placebo gel was already
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registered as a pharmaceutical product.
In order to reach statistical power, 100 mandibular third molars were included in the study. Two third molars were extracted in five patients and one third molar in 90 patients.
SC
Thus, in total 95 patients were included aged between 19 and 65. All teeth had a diagnosed pathology, such as pericoronitis, suspected cyst formation or resorption of adjacent teeth. The
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study was performed during the time period February 2011 to March 2012. All patients were invited to participate in the study if they denied suffering from immuno-depressive conditions, were not pregnant, or were judged being unable to follow the study due to severe illness or functional disability. In addition, patients with bisphosphonate, corticosteroid intake
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or were on antibiotic treatment were excluded as well as subjects, who declared being allergic to CHX, paracetamol or codeine. All invited patients carefully read the study instructions and agreed to participate. The included teeth were randomly divided into two study treatment
EP
groups, and were subsequently given numbers. The following background variables were registered during the study:
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● Age
● Gender ●
Smoking habits
●
Daily medication intake
The following variables were recorded in connection to surgery: •
Surgeon
●
Anatomical variations of the 3rd molar
ACCEPTED MANUSCRIPT ●
Reason for surgery ( Preoperative diagnosis)
●
Surgery time (minutes)
The Criteria for the AO diagnosis was postoperative pain, which increases in severity with
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time, accompanied by a partially or totally disintegrated blood cloth within the alveolar socket with or without halitosis.8 The main variable evaluated was the AO diagnosis, yes or no, for each tooth in relation to the use or not the use, of the active gel. The intake of analgesic tablets
SC
(type and frequency) day 1-7 after surgery was registered by the patients.
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Surgery
The patients were operated by three senior house officers working at the Oral and Maxillofacial Surgery Clinic. Neither the surgeons nor their assistant nurses were involved in the randomization procedure. All patients were given AlvedonR (paracetamol) 1g ahead of the
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surgical procedure. They were also offered oral sedation with DormicumR, 1mg/mL (midazolam) and those accepting this were thus given 10-15 mL. All patients were operated on under local anesthesia using lidocaine 20mg/mL+ epinephrine 12,5 microg/mL (Xylocain-
EP
AdrenalinR). The surgical procedure followed a standard protocol as follows: A buccal mucoperiosteal flap was raised and all bone covering the crown of the tooth was removed
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using a round burr. Saline was used for cooling. The crown was separated from the root, the root was divided and all parts were removed together with remaining coronary sac tissue. The socket was rinsed with saline. Thirty seconds after removal 10 mL Cervitec gel (IvoclarR), containing 0,2% CHX and 0,2% NaF was placed into the alveolus in the experimental group. In the control group, placebo gel (APL dentalgel) containing 0,2% NaF was applied. The wound was tightly closed by the use of Vicryl RapidR .
ACCEPTED MANUSCRIPT Postoperatively the patients were prescribed AlvedonR (paracetamol 1g) and Citodon R (paracetamol + 500 mg/codeine 5mg). They were informed to start only using AlvedonR and to add CitodonR when needed. All analgesic medication during 7 days was recorded by the patients. The patients` second visit was set 1 week after surgery. The following measurements
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were registered by one of the surgeons not taking part in the actual surgical procedure: 1: the occurrence of post extraction AO, yes or no; 2: the patients` intake of analgesics day 1-7.
SC
The registration was saved together with the patients` individual study protocol.
Statistics
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The descriptive statistics and statistical analyses were performed using a statistical package (IBM SPSS Statistics 19.0). Differences between treatment group and placebo group were analyzed by using unpaired t-tests and chi-square tests. Stepwise logistic regression analysis, using the incidence of AO as the dependent variable, was adopted in order to investigate the
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influence of potential back ground factors and risk indicators on the occurrence of AO. The results are shown as mean and standard deviations. Results were considered statistically significant at p<0.05. A power calculation showed that 100 patients were required to obtain a
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power of 80% and significance level of 5% if the hypothesis was a difference of 20% between
Results
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treatment groups according to AO frequency (5 and 25%, respectively).
Five teeth had to be excluded from the study due to medical complications during surgery or the immediate postoperative period. In two cases the surgery could not be completed due to the patients` anxiety. In one case it was discovered immediate after surgery that the patient had started corticoid medication. In another two cases the surgery was complicated by a postoperative purulent infection disabling a correct AO diagnosis. The total number of teeth
ACCEPTED MANUSCRIPT do be analyzed was therefore 95. The mean age of the patients was 33 yrs (S.D. 10.3) and 47% were males. Ten percent declared that they were smokers. Thirty-two percent of the patients took some kind of daily medicine. However, none of them had been under antibiotic treatment 14 days before the actual surgery. There were no statistically significant differences
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between the treatment groups according to individual background variables (Table 1). The preoperative diagnoses or conditions for the mandibular third molars are presented in Table 2. The most frequent diagnosis was pericoronitis (59%). In three cases, the teeth were extirpated
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prophylactically.
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The total incidence of AO was found to be 21%. The incidence rate of AO was 19% in the placebo gel group (control group) and 23% in the chlorhexidine gel group (experimental group) (Table 3). This difference was not statistically significant. The incidences of AO did not differ significantly between the three surgeons and the frequencies were 17, 18 and 25%,
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respectively.
AO was diagnosed after surgical removal for one out of two retained third mandibular molars (Table 4). Both retained teeth had the preoperative diagnosis widened follicular sac.
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For partially erupted molars in a mesial or horizontal position, the AO incidence was found to be 24% after surgical removal, while the incidence was lower (17%) for partial erupted teeth
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in a distal or a vertical position. However, these differences were not statically different. The incidence of AO was 25% (14 cases out of 56 cases) for teeth with the preoperative diagnosis pericoronitis (Table 2). No significant correlation was found between preoperative diagnosis and incidence of AO. The mean surgery time was 23.5 (S.D. 1.04) minutes and the surgery time was not statistically correlated to the incidence of AO (Table 4). Among the smokers (10%), the AO incidence was found to be 30% and for non-smokers the incidence was 20%. This difference was not statistically significant. In the multiple logistic regression analysis
ACCEPTED MANUSCRIPT with the incidence of AO as the dependent variable, none of the independent variables was significantly associated to the incidence of AO. The mean total number of consumed analgesic tablets (CitodonR, AlvedonR and other analgesic tablets) the first week after surgery is illustrated in Figure 1. The relative frequency
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of individuals who used CitodonR was reduced from 47% the first day to 12% after seven days. The corresponding percentages for consumption of AlvedonR were 67 and 49%, respectively. The mean number of total analgesic tablet intake in seven days was 17.3 (S.D.
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10.7) for patients without AO after surgery and 26.6 (S.D. 13.8) for those with AO. This difference was statistically significant (p=0.002). None of the background variables or
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anatomical variables was significantly correlated to the number of consumed analgesic tablets. There were no statistically significant differences according to total intake of CitodonR tablets between the non-AO group (mean 5.2 (S.D. 6.5) and the AO group (mean 8.0 (S.D. 11.0). However, the patient group with AO consumed 15.0 (S.D. 8.1) tablets of AlveodonR
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and this volume differed significantly (p=0.03) from the non-AO group (mean 10.8 (S.D. 7.5). The mean number of consumed CitodonR tablets was reduced between the first and fourth day after surgery for patients in the non-AO group (Figure 2a), while the daily intake of CitodonR
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was increased between day 1 and day 4 in AO group (Figure 2b).
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Discussion
The design of the present study fulfills the requirements testing pharmaceuticals. The present study design is similar to that of Torres-Lagares et al. 2006,8 but with some important differences. The teeth included in Torre`s study (as well as in the Babar et al. study7) were consecutively referred. The indication for removal varied from retention or obstruction for eruption to a status of pathology. However, in our study all teeth had a diagnosed pathology. Minor differences in the mean age of patients were also apparent such that our patients were
ACCEPTED MANUSCRIPT slightly older. There were nearly as many women as men in our study while there were more women in the Torres-Lagares et al. study. 8One of, or a combination of these circumstances might have been of importance for the differences in the outcome between the studies. It is known that the risk for AO is higher in elderly patients and that women are more
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susceptible to inflammatory reactions than men.10-12 While it is difficult to draw any conclusions from these circumstances, the fact that all teeth in the present study showed signs of pathology and the Torres-Lagares et al. study8 seemed to include all patients referred for
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removal of 3rd molars, might have influenced the results.
Smoking habits have been judged to be of importance for the development of AO.14 Our
et al. study.8
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study included 10 % smokers, while 25% of the patients were smoking in the Torres-Lagares This fact might also have influenced the results. In our placebo group 19%
developed AO versus 30% in the Torres –Lagares placebo group. These findings might reflect an effect of smoking and the development of AO.13,14 Moreover, Torres-Lagares et al.8
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proved only 11 % AO in his experimental group which may suggest that the effect of CHX is more effective in smoking patients. As a conclusion, our result differs from that of TorresLagares since we could not recognize any difference in AO frequency between our
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experimental group and our placebo group.
Babar et al.7 also showed a positive effects of CHX treatment. However, that study
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evaluated the effect of CHX as early as the 3rd postoperative day. This is undesirable since according to Blum´s definition,9 AO cannot be reliably diagnosed until a week after surgery. Our second hypothesis was that patients developing AO would consume more analgesics during the postoperative week than those without AO. More specifically, they would increase the intake after 3-5 days. Our study showed that the mean number of analgesic increased for patients with AO. The intake of CitodonR increased between day 1-4 for the AO group and
ACCEPTED MANUSCRIPT decreased between day 1-4 for the non-AO group. The intake of analgesics reflected the development of AO and could thus be used as a complementary diagnostic criteria. In conclusion, the treatment with a CHX gel did not significantly reduce the incidence of AO after surgical removal of impacted third molars. The degree of impact was the only
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anatomical variable that was best correlated to the incidence of AO, but was not statistically significant. Finally, the intake of analgesics reflected the occurrence of AO with a high degree of significance. Smoking habits were not recognized as a risk factor, but this could be due to
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the low incidence of smokers in this study.
ACCEPTED MANUSCRIPT REFERENCES
1. Eshgpour M, Nejat AH: Dry socket following surgical removal of impacted third
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molar in an Iranian population: Incidence and risk factors. Niger J Clin Pract 16:496, 2013
2. Kolokythas A, Olech E, Miloro M: Alveolar osteitis: a comprehensive review of
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concepts and controversies. Int J Dent 249073, 2010
3. Caso A, Hung LK, Beirne OR: Prevention of alveolar osteitis with chlorhexidine: A
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meta-analytic review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 99:155, 2005
4. Daly B, Sharif MO, Newton T, et al: Local interventions for the management of alveolar osteitis (dry socket). Cochrane Database Syst Rev 12:CD006968, 2012
Assoc 23:71, 1995
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5. Garibaldi JA, Greenlaw J, Choi J, et al: Treatment of post-operative pain. J Calif Dent
6. Shepherd J: Rinsing with chlorhexidine may reduce incidence of dry socket after third
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molar surgery. Evid Based Dent 6:36 doi:10.1038/sj.ebd.6400333, 2005 7. Babar A, Ibrahim MW, Baig NJ, et al: Efficacy of intra-alveolar chlorhexidine gel in
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reducing frequency of alveolar osteitis in mandibular third molar surgery. J Coll Physicians Surg Pak 22:91, 2012 8. Torres-Lagares D, Gutierrez-Perez JL, Infante-Cossio P, et al: Randomized, doubleblind study on effectiveness of intra-alveolar chlorhexidine gel in reducing the incidence of alveolar osteitis in mandibular third molar surgery. Int J Oral Maxillofac Surg. 35:348, 2006 9. Blum IR: Contemporary views on dry socket (alveolar osteitis): a clinical appraisal of
ACCEPTED MANUSCRIPT standardization, aetiopathogenesis and management: a critical review. Int J Oral Maxillofac Surg 31:309, 2002 10. Benediktsdóttir IS, Wenzel A, Petersen JK, et al: Mandibular third molar removal: Risk indicators for extended operation time, postoperative pain, and complications.
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Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 97:438, 2004
11. Malkawi Z, Al-Omiri MK, Khraisat A: Risk indicators of postoperative complications following surgical extraction of lower third molars. Med Princ Pract 20:321, 2011
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12. Blondeau F, Daniel NG: Extraction of impacted mandibular third molars: postoperative complications and their risk factors. J Can Dent Assoc 73:325, 2007
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13. Halabí D, Escobar J, Muñoz C, et al: Logistic regression analysis of risk factors for the development of alveolar osteitis. J Oral Maxillofac Surg. 70:1040, 2012 14. Congiusta MA, Veitz-Keenan A: Study confirms certain risk factors for development of alveolar osteitis. Evid Based Dent 14:86 doi:10.1038/sj.ebd.6400954, 2013
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15. Freudlsperger C, Deiss T, Bodem J, et al: Influence of Lower Third Molar Anatomic Position on Postoperative Inflammatory Complications. J Oral Maxillofac Surg.
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70:1280, 2012
ACCEPTED MANUSCRIPT Table 1. BACKGROUND AT INDIVIDUAL LEVEL FOR TREATENT GROUPS Placebo gel Chlorhexidine gel
p
34 (20-65)
33 (19-62)
NS
Males/females (%)
44/56
51/49
NS
Smokers (%)
12
8
NS
Daily medication intake (%)
27
37
NS
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Age (mean (range))
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Variable
Table 2. PREOPERATIVE DIAGNOSES OR CONDITIONS FOR THE THIRD
Preoperative diagnosis/condition
N
Pericoronitis
56
Caries
12
Deepened periodontal pocket on
11
the distal site on adjacent 2nd
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mandibular molar
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MANDIBULAR MOLARS AND INCIDENCIES OF ALVEOLITIS
Alveolitis (N) 14 1 3
Widened dental follicular sack
8
2
No pathology
3
0
2
0
1
0
1
0
1
0
Crown fracture Food impaction
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Apical periodontitis
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Resorption on the distal surface on adjacent 2nd mandibular molar
ACCEPTED MANUSCRIPT Table 3. FREQUENCY DISTRIBUTIONS OF INCIDENCE OF ALVEOLITIS FOR
Treatment
No alveolitis Alveolitis Total
Placebo gel
38
9
47
Chlorhexidine gel 37
11
48
Total
20
95
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75
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THE TREATMENT GROUPS
Table 4. FREQUENCY DISTRIBUTIONS OF ANATOMICAL VARIABLES AND
SURGERY Variable Totally impacted molar
Distal or vertical position
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Surgery time (minutes, mean + S.D.)
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No alveolitis
Alveolitis
p
1
1
NS
37
12
NS
38
8
NS
23 + 10
25 + 11
NS
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Mesial or horizontal position
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SURGICAL TIME ACCORDING TO THE INCIDENCE OF ALVEOLITIS AFTER
ACCEPTED MANUSCRIPT Legends FIGURE 1. The distribution of mean number of the total analgesic tablet intake during seven days after surgery for patients without and with alveolitis.
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FIGURE 2A. The distribution of mean number of citodon, alveodon and other analgesic tablets intake during seven days after surgery for patients without alveolitis.
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FIGURE 2B. The distribution of mean number of citodon, alveodon and other analgesic
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EP
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tablets intake during seven days after surgery for patients with alveolitis.
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EP
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SC
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
S0278-2391(14)01407-4
DOI:
10.1016/j.joms.2014.08.035
Reference:
YJOMS 56484
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 15 May 2014 Revised Date:
22 August 2014
Accepted Date: 27 August 2014
Please cite this article as: Freudenthal N, Sternudd M, Jansson L, Wannfors K, A double-blind randomized study evaluating the effect of intra- alveolar chlorhexidine gel on alveolar osteitis after removal of mandibular third molars, Journal of Oral and Maxillofacial Surgery (2014), doi: 10.1016/ j.joms.2014.08.035. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
A double-blind randomized study evaluating the effect of intra- alveolar chlorhexidine gel on alveolar osteitis after removal of mandibular third molars
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Nelly Freudenthal, DDS,a Mika Sternudd, DDS, b Leif Jansson, DDS, PhD, cd Karin Wannfors , DDS, PhD e a
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DDS, Eastman Institute Maxillofacial surgery, Public Dental Service, Stockholm County Council, Sweden. b DDS, Public Dental Service, Visby, Gotland County, Sweden. c DDS, PhD,Head of Department of Periodontology, Public Dental Service at Kista and Skanstull, Stockholm County Council, Sweden. d Adjunct lecturer at Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden. e DDS, Phd, Former head of Oral and Maxillofacial clinic, Sodersjukhuset, Stockholm, Sweden.
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Corresponding author: Nelly Freudenthal Eastman Institute Maxillofacial surgery Dalagatan 11 11324 Stockholm Tel Business: 0812316570 E-mail: [email protected]
ACCEPTED MANUSCRIPT Purpose: The main purpose of the present investigation was to determine if intra-alveolar chlorhexidine gel (CHX) is an effective preventative treatment for alveolar osteitis (AO), as has been strongly suggested by previous investigators. Another goal was to evaluate if there is a correlation between the use of analgesics during the postoperative week and the
RI PT
development of AO, a correlation that could be a supplement to the commonly used diagnostic criteria for AO.
Material and Methods: A double-blind, randomized study was performed to assess if intra-
SC
alveolar administration of CHX reduces AO. To achieve this, the extraction and the postoperative course of 100 impacted mandibular 3rd molar teeth were studied. Ninety-seven
M AN U
percent of the teeth operated on had a diagnosed pathology. The extraction alveoli were treated either with CHX or placebo. The intake of analgesics was recorded for seven day after the operation.
Results: Statistically significant differences in AO between the control and experimental
degree of significance.
TE D
groups were not found. The intake of analgesics reflected the occurrence of AO with a high
Conclusion: The present study did not verify that application of CHX gel improves healing
EP
after removal of impacted 3rd molars. The patients` postoperative analgesic intake reflected
AC C
the development of AO.
ACCEPTED MANUSCRIPT In 10-40 % of cases where lower third molars are removed, alveolar osteitis (AO) occurs as a postoperative complication.1,2 AO is the most common complication following removal of impacted third molars; it is a painful condition usually developed three to four days after tooth extraction. AO is an inflammatory condition of the extraction socket. The etiology is not fully
RI PT
understood, but an infectious component is suspected. An increased local fibrinolysis, as a result of plasminogen pathway activation leading to disintegration of the clot, has been suggested as one explanation for the pathogenesis of AO.2 Factors such as surgical trauma,
SC
difficulty of surgery, smoking and bacterial infection have been suggested as contributing factors.2 As a prevention for AO, preoperative rinsing with 0.2 % chlorhexidine (CHX)
M AN U
solution has been used3,4 and encouraging reports have been presented using CHX rinsing of extraction sockets.5,6 Two reports states good results from the postoperative application of CHX gel directly into the socket.7,8 Thus, the aim of the present study was to determine if CHX –gel is an effective treatment against AO and to verify previous results showing the
TE D
advantages with this procedure. A second goal of the study was to determine if postoperative intake of analgesics is correlated to the development of AO, and thus could be used as a
EP
complementary diagnostic criteria for AO.
AC C
Materials and Methods Study design
This study was designed as a controlled, double-blind study carried out at the Oral and Maxillofacial Surgery Clinic at the South Hospital in Stockholm, Sweden. Ethical approval (2010/830-32) was obtained by the Regional Ethical review board. A high scientific level was secured by using a randomization process. The monitoring procedures were performed by a monitor at Karolinska trial Alliance, M62. The code list (active gel or placebo) was developed in advance through a randomizing process. The code list was locked and was not unlocked
ACCEPTED MANUSCRIPT until the study was completed. Neither the surgical team nor the patient knew whether active gel or placebo was given to the patient. The active gel used, was legally approved by the Swedish Medical Products Agency in front of the study, as it was not a registered pharmaceutical. The placebo gel was already
RI PT
registered as a pharmaceutical product.
In order to reach statistical power, 100 mandibular third molars were included in the study. Two third molars were extracted in five patients and one third molar in 90 patients.
SC
Thus, in total 95 patients were included aged between 19 and 65. All teeth had a diagnosed pathology, such as pericoronitis, suspected cyst formation or resorption of adjacent teeth. The
M AN U
study was performed during the time period February 2011 to March 2012. All patients were invited to participate in the study if they denied suffering from immuno-depressive conditions, were not pregnant, or were judged being unable to follow the study due to severe illness or functional disability. In addition, patients with bisphosphonate, corticosteroid intake
TE D
or were on antibiotic treatment were excluded as well as subjects, who declared being allergic to CHX, paracetamol or codeine. All invited patients carefully read the study instructions and agreed to participate. The included teeth were randomly divided into two study treatment
EP
groups, and were subsequently given numbers. The following background variables were registered during the study:
AC C
● Age
● Gender ●
Smoking habits
●
Daily medication intake
The following variables were recorded in connection to surgery: •
Surgeon
●
Anatomical variations of the 3rd molar
ACCEPTED MANUSCRIPT ●
Reason for surgery ( Preoperative diagnosis)
●
Surgery time (minutes)
The Criteria for the AO diagnosis was postoperative pain, which increases in severity with
RI PT
time, accompanied by a partially or totally disintegrated blood cloth within the alveolar socket with or without halitosis.8 The main variable evaluated was the AO diagnosis, yes or no, for each tooth in relation to the use or not the use, of the active gel. The intake of analgesic tablets
SC
(type and frequency) day 1-7 after surgery was registered by the patients.
M AN U
Surgery
The patients were operated by three senior house officers working at the Oral and Maxillofacial Surgery Clinic. Neither the surgeons nor their assistant nurses were involved in the randomization procedure. All patients were given AlvedonR (paracetamol) 1g ahead of the
TE D
surgical procedure. They were also offered oral sedation with DormicumR, 1mg/mL (midazolam) and those accepting this were thus given 10-15 mL. All patients were operated on under local anesthesia using lidocaine 20mg/mL+ epinephrine 12,5 microg/mL (Xylocain-
EP
AdrenalinR). The surgical procedure followed a standard protocol as follows: A buccal mucoperiosteal flap was raised and all bone covering the crown of the tooth was removed
AC C
using a round burr. Saline was used for cooling. The crown was separated from the root, the root was divided and all parts were removed together with remaining coronary sac tissue. The socket was rinsed with saline. Thirty seconds after removal 10 mL Cervitec gel (IvoclarR), containing 0,2% CHX and 0,2% NaF was placed into the alveolus in the experimental group. In the control group, placebo gel (APL dentalgel) containing 0,2% NaF was applied. The wound was tightly closed by the use of Vicryl RapidR .
ACCEPTED MANUSCRIPT Postoperatively the patients were prescribed AlvedonR (paracetamol 1g) and Citodon R (paracetamol + 500 mg/codeine 5mg). They were informed to start only using AlvedonR and to add CitodonR when needed. All analgesic medication during 7 days was recorded by the patients. The patients` second visit was set 1 week after surgery. The following measurements
RI PT
were registered by one of the surgeons not taking part in the actual surgical procedure: 1: the occurrence of post extraction AO, yes or no; 2: the patients` intake of analgesics day 1-7.
SC
The registration was saved together with the patients` individual study protocol.
Statistics
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The descriptive statistics and statistical analyses were performed using a statistical package (IBM SPSS Statistics 19.0). Differences between treatment group and placebo group were analyzed by using unpaired t-tests and chi-square tests. Stepwise logistic regression analysis, using the incidence of AO as the dependent variable, was adopted in order to investigate the
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influence of potential back ground factors and risk indicators on the occurrence of AO. The results are shown as mean and standard deviations. Results were considered statistically significant at p<0.05. A power calculation showed that 100 patients were required to obtain a
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power of 80% and significance level of 5% if the hypothesis was a difference of 20% between
Results
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treatment groups according to AO frequency (5 and 25%, respectively).
Five teeth had to be excluded from the study due to medical complications during surgery or the immediate postoperative period. In two cases the surgery could not be completed due to the patients` anxiety. In one case it was discovered immediate after surgery that the patient had started corticoid medication. In another two cases the surgery was complicated by a postoperative purulent infection disabling a correct AO diagnosis. The total number of teeth
ACCEPTED MANUSCRIPT do be analyzed was therefore 95. The mean age of the patients was 33 yrs (S.D. 10.3) and 47% were males. Ten percent declared that they were smokers. Thirty-two percent of the patients took some kind of daily medicine. However, none of them had been under antibiotic treatment 14 days before the actual surgery. There were no statistically significant differences
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between the treatment groups according to individual background variables (Table 1). The preoperative diagnoses or conditions for the mandibular third molars are presented in Table 2. The most frequent diagnosis was pericoronitis (59%). In three cases, the teeth were extirpated
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prophylactically.
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The total incidence of AO was found to be 21%. The incidence rate of AO was 19% in the placebo gel group (control group) and 23% in the chlorhexidine gel group (experimental group) (Table 3). This difference was not statistically significant. The incidences of AO did not differ significantly between the three surgeons and the frequencies were 17, 18 and 25%,
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respectively.
AO was diagnosed after surgical removal for one out of two retained third mandibular molars (Table 4). Both retained teeth had the preoperative diagnosis widened follicular sac.
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For partially erupted molars in a mesial or horizontal position, the AO incidence was found to be 24% after surgical removal, while the incidence was lower (17%) for partial erupted teeth
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in a distal or a vertical position. However, these differences were not statically different. The incidence of AO was 25% (14 cases out of 56 cases) for teeth with the preoperative diagnosis pericoronitis (Table 2). No significant correlation was found between preoperative diagnosis and incidence of AO. The mean surgery time was 23.5 (S.D. 1.04) minutes and the surgery time was not statistically correlated to the incidence of AO (Table 4). Among the smokers (10%), the AO incidence was found to be 30% and for non-smokers the incidence was 20%. This difference was not statistically significant. In the multiple logistic regression analysis
ACCEPTED MANUSCRIPT with the incidence of AO as the dependent variable, none of the independent variables was significantly associated to the incidence of AO. The mean total number of consumed analgesic tablets (CitodonR, AlvedonR and other analgesic tablets) the first week after surgery is illustrated in Figure 1. The relative frequency
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of individuals who used CitodonR was reduced from 47% the first day to 12% after seven days. The corresponding percentages for consumption of AlvedonR were 67 and 49%, respectively. The mean number of total analgesic tablet intake in seven days was 17.3 (S.D.
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10.7) for patients without AO after surgery and 26.6 (S.D. 13.8) for those with AO. This difference was statistically significant (p=0.002). None of the background variables or
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anatomical variables was significantly correlated to the number of consumed analgesic tablets. There were no statistically significant differences according to total intake of CitodonR tablets between the non-AO group (mean 5.2 (S.D. 6.5) and the AO group (mean 8.0 (S.D. 11.0). However, the patient group with AO consumed 15.0 (S.D. 8.1) tablets of AlveodonR
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and this volume differed significantly (p=0.03) from the non-AO group (mean 10.8 (S.D. 7.5). The mean number of consumed CitodonR tablets was reduced between the first and fourth day after surgery for patients in the non-AO group (Figure 2a), while the daily intake of CitodonR
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was increased between day 1 and day 4 in AO group (Figure 2b).
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Discussion
The design of the present study fulfills the requirements testing pharmaceuticals. The present study design is similar to that of Torres-Lagares et al. 2006,8 but with some important differences. The teeth included in Torre`s study (as well as in the Babar et al. study7) were consecutively referred. The indication for removal varied from retention or obstruction for eruption to a status of pathology. However, in our study all teeth had a diagnosed pathology. Minor differences in the mean age of patients were also apparent such that our patients were
ACCEPTED MANUSCRIPT slightly older. There were nearly as many women as men in our study while there were more women in the Torres-Lagares et al. study. 8One of, or a combination of these circumstances might have been of importance for the differences in the outcome between the studies. It is known that the risk for AO is higher in elderly patients and that women are more
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susceptible to inflammatory reactions than men.10-12 While it is difficult to draw any conclusions from these circumstances, the fact that all teeth in the present study showed signs of pathology and the Torres-Lagares et al. study8 seemed to include all patients referred for
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removal of 3rd molars, might have influenced the results.
Smoking habits have been judged to be of importance for the development of AO.14 Our
et al. study.8
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study included 10 % smokers, while 25% of the patients were smoking in the Torres-Lagares This fact might also have influenced the results. In our placebo group 19%
developed AO versus 30% in the Torres –Lagares placebo group. These findings might reflect an effect of smoking and the development of AO.13,14 Moreover, Torres-Lagares et al.8
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proved only 11 % AO in his experimental group which may suggest that the effect of CHX is more effective in smoking patients. As a conclusion, our result differs from that of TorresLagares since we could not recognize any difference in AO frequency between our
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experimental group and our placebo group.
Babar et al.7 also showed a positive effects of CHX treatment. However, that study
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evaluated the effect of CHX as early as the 3rd postoperative day. This is undesirable since according to Blum´s definition,9 AO cannot be reliably diagnosed until a week after surgery. Our second hypothesis was that patients developing AO would consume more analgesics during the postoperative week than those without AO. More specifically, they would increase the intake after 3-5 days. Our study showed that the mean number of analgesic increased for patients with AO. The intake of CitodonR increased between day 1-4 for the AO group and
ACCEPTED MANUSCRIPT decreased between day 1-4 for the non-AO group. The intake of analgesics reflected the development of AO and could thus be used as a complementary diagnostic criteria. In conclusion, the treatment with a CHX gel did not significantly reduce the incidence of AO after surgical removal of impacted third molars. The degree of impact was the only
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anatomical variable that was best correlated to the incidence of AO, but was not statistically significant. Finally, the intake of analgesics reflected the occurrence of AO with a high degree of significance. Smoking habits were not recognized as a risk factor, but this could be due to
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the low incidence of smokers in this study.
ACCEPTED MANUSCRIPT REFERENCES
1. Eshgpour M, Nejat AH: Dry socket following surgical removal of impacted third
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molar in an Iranian population: Incidence and risk factors. Niger J Clin Pract 16:496, 2013
2. Kolokythas A, Olech E, Miloro M: Alveolar osteitis: a comprehensive review of
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concepts and controversies. Int J Dent 249073, 2010
3. Caso A, Hung LK, Beirne OR: Prevention of alveolar osteitis with chlorhexidine: A
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meta-analytic review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 99:155, 2005
4. Daly B, Sharif MO, Newton T, et al: Local interventions for the management of alveolar osteitis (dry socket). Cochrane Database Syst Rev 12:CD006968, 2012
Assoc 23:71, 1995
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5. Garibaldi JA, Greenlaw J, Choi J, et al: Treatment of post-operative pain. J Calif Dent
6. Shepherd J: Rinsing with chlorhexidine may reduce incidence of dry socket after third
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molar surgery. Evid Based Dent 6:36 doi:10.1038/sj.ebd.6400333, 2005 7. Babar A, Ibrahim MW, Baig NJ, et al: Efficacy of intra-alveolar chlorhexidine gel in
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reducing frequency of alveolar osteitis in mandibular third molar surgery. J Coll Physicians Surg Pak 22:91, 2012 8. Torres-Lagares D, Gutierrez-Perez JL, Infante-Cossio P, et al: Randomized, doubleblind study on effectiveness of intra-alveolar chlorhexidine gel in reducing the incidence of alveolar osteitis in mandibular third molar surgery. Int J Oral Maxillofac Surg. 35:348, 2006 9. Blum IR: Contemporary views on dry socket (alveolar osteitis): a clinical appraisal of
ACCEPTED MANUSCRIPT standardization, aetiopathogenesis and management: a critical review. Int J Oral Maxillofac Surg 31:309, 2002 10. Benediktsdóttir IS, Wenzel A, Petersen JK, et al: Mandibular third molar removal: Risk indicators for extended operation time, postoperative pain, and complications.
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Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 97:438, 2004
11. Malkawi Z, Al-Omiri MK, Khraisat A: Risk indicators of postoperative complications following surgical extraction of lower third molars. Med Princ Pract 20:321, 2011
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12. Blondeau F, Daniel NG: Extraction of impacted mandibular third molars: postoperative complications and their risk factors. J Can Dent Assoc 73:325, 2007
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13. Halabí D, Escobar J, Muñoz C, et al: Logistic regression analysis of risk factors for the development of alveolar osteitis. J Oral Maxillofac Surg. 70:1040, 2012 14. Congiusta MA, Veitz-Keenan A: Study confirms certain risk factors for development of alveolar osteitis. Evid Based Dent 14:86 doi:10.1038/sj.ebd.6400954, 2013
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15. Freudlsperger C, Deiss T, Bodem J, et al: Influence of Lower Third Molar Anatomic Position on Postoperative Inflammatory Complications. J Oral Maxillofac Surg.
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70:1280, 2012
ACCEPTED MANUSCRIPT Table 1. BACKGROUND AT INDIVIDUAL LEVEL FOR TREATENT GROUPS Placebo gel Chlorhexidine gel
p
34 (20-65)
33 (19-62)
NS
Males/females (%)
44/56
51/49
NS
Smokers (%)
12
8
NS
Daily medication intake (%)
27
37
NS
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Age (mean (range))
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Variable
Table 2. PREOPERATIVE DIAGNOSES OR CONDITIONS FOR THE THIRD
Preoperative diagnosis/condition
N
Pericoronitis
56
Caries
12
Deepened periodontal pocket on
11
the distal site on adjacent 2nd
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mandibular molar
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MANDIBULAR MOLARS AND INCIDENCIES OF ALVEOLITIS
Alveolitis (N) 14 1 3
Widened dental follicular sack
8
2
No pathology
3
0
2
0
1
0
1
0
1
0
Crown fracture Food impaction
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Apical periodontitis
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Resorption on the distal surface on adjacent 2nd mandibular molar
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Treatment
No alveolitis Alveolitis Total
Placebo gel
38
9
47
Chlorhexidine gel 37
11
48
Total
20
95
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75
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THE TREATMENT GROUPS
Table 4. FREQUENCY DISTRIBUTIONS OF ANATOMICAL VARIABLES AND
SURGERY Variable Totally impacted molar
Distal or vertical position
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Surgery time (minutes, mean + S.D.)
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No alveolitis
Alveolitis
p
1
1
NS
37
12
NS
38
8
NS
23 + 10
25 + 11
NS
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Mesial or horizontal position
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SURGICAL TIME ACCORDING TO THE INCIDENCE OF ALVEOLITIS AFTER
ACCEPTED MANUSCRIPT Legends FIGURE 1. The distribution of mean number of the total analgesic tablet intake during seven days after surgery for patients without and with alveolitis.
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FIGURE 2A. The distribution of mean number of citodon, alveodon and other analgesic tablets intake during seven days after surgery for patients without alveolitis.
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FIGURE 2B. The distribution of mean number of citodon, alveodon and other analgesic
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tablets intake during seven days after surgery for patients with alveolitis.
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