Shepherd34 performed a review study of 32 publications from 12 countries and concluded that, done preoperatively and at seven days postoperatively, rinsing the mouth with 0.12% CHX had a significant preventive effect on AO incidence. Sridhar et al.35 worked on 50 patients and reported similar results using 0.2% CHX solution twice daily at one day before and for seven days after surgical extraction.

Metin et al.36, in a prospective randomized clinical trial of 99 subjects, showed that a one-week-long postoperative mouth rinse with 0.2% CHX solution regimen was adequate and that there was no need to use CHX for a week before extraction. Caso et al.37, through their review of seven randomized prospective clinical trials, concluded that mouth rinsing with CHX solution post-extraction for several days reduced the incidence of AO. Delilbasi et al.38, in their study, worked on 177 subjects and showed that the effectiveness of 0.2% CHX solution was enhanced when used in combination with amoxicillin and clavulanic acid.(Table 1, Fig. 1)

Torres-Lagares et al.39, in a pilot study of 30 patients, concluded that 0.2% CHX gel was a good prophylactic agent and that it can be applied only once in the intra-alveolar site after impacted third molar removal to reduce edema and AO incidence. Hita-Iglesias et al.40 compared the effectiveness of 0.2% CHX gel versus 0.12% CHX solution in the prevention of AO in 73 patients. They concluded that bioadhesive 0.2% CHX gel has more advantages and capabilities than does the CHX solution in reducing the incidence of AO. Abu-Mostafa et al.41, using 201 patients who underwent 301 extractions, also indicated that 0.2% CHX gel was more effective than 0.12% CHX solution. Mínguez-Serra et al.42 reviewed 12 clinical trials and reported similar results, and concluded that 0.2% CHX gel applied twice daily for seven days after tooth extraction was more effective than the use of 0.12% CHX mouth rinse. Torres-Lagares et al.43, in another study, showed that bioadhesive 0.2% CHX gel reduced the incidence of AO by up to 57.15% in patients with bleeding complications. Rodríguez-Pérez et al.44 reported that there were no differences between using 1% CHX and using 0.2% CHX gel twice daily for seven days with respect to reducing the incidence of AO in 88 subjects.

Barbar et al.45, in a randomized control trial study of 100 patients, showed a significant reduction in the incidence of AO using a single application of CHX gel following mandibular third molar surgery. Haraji and Rakhshan46 reported similar results regarding the effectiveness of a single-dose of intra-alveolar placement of 0.2% CHX gel in 45 patients. Jesudasan et al.47 worked with 270 patients and concluded that, although 0.2% CHX gel could reduce the incidence of AO, postoperative placement of a eugenol-based paste could eliminate AO completely. Yengopal and Mickenautsch48, in a systematic review, compared six regimens of using CHX for the prevention of AO and concluded that a single application of 0.2% CHX gel placed inside the alveolar socket following tooth extraction and participating in mouth rinsing with 0.12% CHX solution twice a day for seven days after operation are the most effective regimens for the prevention of AO. Dodson49, in a review study of 21 trials with 2,570 participants, showed similar results for these two regimens. Dodson49 also recommended that all members of the dental team be aware of the potential adverse side effects of CHX. Requena-Calla and Funes-Rumiche50 worked with 40 patients and applied 0.12% CHX gel, and reported no relationship between CHX gel and the reduction of AO incidence. However, Freudenthal et al.51, as part of their double-blinded randomized study with 100 extraction cases, did not verify the same observation and casted doubt upon the application of CHX gel for the prevention of AO. These authors claimed that patients' postoperative analgesic consumption reproduced the development of AO.(Table 1, Fig. 1)

The proangiogenic effects of CHX have not been previously evaluated. Saghiri et al.52 reported that 2% CHX may exhibit cytotoxic effects on dental pulp stem cells. Considering the levels of CHX and povidone iodine used routinely in the oral cavity, these results suggest that CHX has a higher cytotoxicity profile than povidone iodine. This observation might have some clinical relevance regarding the potential utility of povidone iodine in the prevention of AO53. CHX complications such as bad taste, alterations in taste, numbness in the tongue, and staining of dentures and oral cavity tissues have been reported3638. In addition, anaphylactic reaction to CHX has been recently observed54.

Hedström and Sjögren55, in a systematic review of 32 randomized controlled trials, showed that local treatment of the extraction site with tetracycline prompted a great reduction in risk for AO. Bosco et al.56 used local tetracycline for the prevention of AO in rats and concluded that tetracycline could reduce the occurrence of AO. This treatment also caused significant changes in the microbiota of the extraction site by decreasing the number of anaerobes while increasing the amount of tetracycline-resistant and multi-resistant microorganisms. Sanchis et al.57, in a postoperative study of 200 impacted mandibular third molar extractions, concluded that intra-alveolar placement of tetracycline compound did not affect the incidence of AO.

Bergdahl and Hedström58, in a randomized controlled trial of 119 patients, showed that the administration of 1,600 mg of metronidazole did not significantly reduce the incidence of AO. Reekie et al.59, in a randomized study of 302 patients seen in three general dental practices by general dental practitioners working in England during the time period of 2000 to 2003, concluded that topical metronidazole did not significantly reduce the incidence of AO. Neugebauer et al.60, in an intra-individual study on 100 patients, showed that antimicrobial photodynamic therapy can be used for the prevention of AO.

Ishihama et al.61, in a retrospective single-center review of 45 patients, concluded that the usage of azithromycin as a prophylactic agent for the prevention of AO did not significantly reduce the rate of AO. Bascones-Martinez et al.62, in a clinical trial of 400 women using tobacco and oral contraceptives, showed that azithromycin was significantly superior for post-extraction treatment versus saline for the prevention of AO.

Halpern and Dodson63, in their study of 118 subjects who used systemic antibiotics (e.g., penicillin or clindamycin for penicillin-allergic subjects) in an intravenous form, concluded a significant reduction in AO or surgical site infection occurred with drug administration. Ren and Malmstrom64, in a meta-analysis of 16 randomized controlled clinical trials including 2,932 patients, reported that systemic antibiotics used prior to surgery could effectively reduce the frequency of AO.

Wiśniewska et al.65, in a study of 80 patients, showed that lincomycin could significantly prevent the incidence of AO.

Olusanya et al.66, in a randomized experiment including 42 patients, employed a five-day regimen of oral 500 mg amoxicillin capsules and 400 mg metronidazole tablets three times daily. These authors concluded that, while a single bolus antibiotic prophylaxis may be effective in the reduction of pain, swelling, and trismus, in case of reducing the risk of AO, five-day postoperative consumption is advisable. Marcussen et al.67, in a systematic review of randomized controlled trials, reported that the consumption of a single oral dose of 2 g of amoxicillin could effectively reduce the risk of surgical site infection, while a single dose of 0.8 g of phenoxymethyl-penicillin did significantly reduce the risk of AO. Arteagoitia et al.68, in a systematic review and meta-analysis of 10 papers, including extractions performed in 1997, showed that the prophylactic use of amoxicillin for reducing the risk of AO was only effective when it was used in combination with clavulanic acid.(Table 1, Fig. 1)

There are few studies available to date that have investigated the proangiogenic effects of antibiotics used for the prevention of AO. Mathe et al.69 showed that tetracycline can increase the expression of vascular endothelial growth factor and prompt better revascularization of the treated tissues. Rawal and Rawal70 evaluated the nonantimicrobial properties of tetracycline and reported that it can regulate the angiogenesis processes, stimulate osteoblastic bone formation, and inhibit osteoclast function.

Manikandan et al.76 showed that eugenol is a phytochemical agent with remarkable abilities to alter the equilibrium between pro- and anti-angiogenic proteins and to disturb the balance between the stimulators and inhibitors of angiogenesis at the application site. Kobayashi et al.77 reported that PRP and PRF can act both as scaffolding and reservoirs for angiogenic factors during the wound-healing period. One of the limitations of the present study is its exclusive attention paid to the biomaterials used for AO treatment without the consideration of the quality or nature of the studies (i.e., in vivo, in vitro, case report, review).