Comparison of platelet‐rich fibrin with zinc oxide eugenol in the relief of pain in alveolar osteitis

Abstract Background and aims Alveolar osteitis (AO) is the most common painful post‐operative complication after tooth extraction. The common modalities used in the management of AO are lavage, placement of medicated dressings, analgesics, and antibiotics. The present study was undertaken to compare platelet‐rich fibrin (PRF) and zinc oxide eugenol (ZOE) for pain relief in AO. Methods All cases meeting the eligibility criteria received two different treatment modalities over a span of 18 months. At the analysis stage, the final sample size comprised 70 patients, with 35 patients appropriated in each group. Group A patients received ZOE and Group B received PRF. Pain scores were measured on “1st, 3rd, 5th, and 7th” days based on a visual analogue scale (VAS) and compared in both groups of patients. The collected data were analyzed using the chi‐square test, t test, and Mann‐Whitney U test. Results In patients treated with ZOE dressing, the average VAS scores observed were 7.4 ± 1.5, 5.1 ± 1.1, 3.4 ± 0.9, and 2.1 ± 0.7, respectively, on the “1st, 3rd, 5th, and 7th” follow‐up days. In patients treated with PRF, the average VAS score observed were 4.1 ± 1.2, 2.6 ± 0.9, 1.7 ± 0.9, and 0.8 ± 0.8 respectively. Conclusion Both ZOE and PRF were effective in pain control during the follow‐up period. However, the pain intensity measured as a pain score using VAS was, lower in the PRF group than in the ZOE group on all follow‐up days.

surgical site, curettage of the extraction socket, mechanical dislodgement of blood clot, fibrinolysis of blood clot, smoking, oral contraceptives, immune suppression, female gender, and vasoconstrictors. 2,[4][5][6][7][8][9] The emergence of AO as a common postoperative sequela of extraction has prompted surgeons to explore various treatment options, focusing on optimal healing and control over pain. It is fair to argue that the primary aim in the management of AO should be pain control until normal reparative processes are initiated. 10 The common modalities used in the management of AO are alveolar lavage, placement of medicated dressings, analgesics, antibiotics topical anesthetics, and obtundent, or their combinations. 1,2,5,9 Nevertheless, the application of dressing materials inside the extraction socket has been reported to delay wound healing and cause adverse reactions. 3,11,12 A plethora of pharmaceutical agents such as zinc oxide eugenol (ZOE), iodoform, chlorhexidine, butylparaminobenzoate, acemannan, guaiacol, chlorobutanol, neocone, and alvogyl are available for use in dry sockets. The sedative, antibacterial, and obtundent properties of ZOE have been utilized in the management of dry sockets, as intra-alveolar dressings. 13,14 Platelet-rich fibrin (PRF) is a second-generation platelet concentrate developed by Choukroun et al in 2001. 15 PRF is a tetra molecular polymer gel that incorporates platelets, leukocytes, cytokines, growth factors, and circulating stem cells into its matrix, which can accelerate physiologic wound healing and the formation of new bone. [16][17][18][19][20][21][22][23][24][25] The use of PRF has been postulated to accelerate the healing process of the extraction socket and in turn reduce postoperative pain. 26,27 The definitive management of dry sockets remains inconclusive.
It has been felt that a meaningful study must be carried out to evaluate the relative effectiveness of two different modalities used for pain management in AO. The present study aimed to compare ZOE and PRF for pain relief in AO.

Study design
The design of the study was single-blinded prospective study.

Sample selection procedure
All cases meeting the eligibility criteria received two different treatment modalities over 18 months. The methods of screening, grouping, interventions, follow-up, and analysis are summarized in the flow diagram ( Figure 1) In this study,

| Procedure
The following features were clinically diagnostic of AO.
1. Intense throbbing pain in relation to the extraction socket often radiates in nature and tends to increase in severity for a period between 1-and 3-days post-surgery.
2. Extraction socket denuded the blood clot with or without halitosis.
Group A patients received ZOE and Group B received PRF as the treatment modality. Pain score was measured on "1st, 3rd, 5th, and 7th" days based on a VAS and compared in both groups.
In group A patients, ZOE was used as an intra-alveolar obtundent dressing (Vishal Dentocare Private Limited, India).

| Statistical analysis
The T A B L E 2 Percentage distribution of the pain score between treatment groups  Table 2. The mean and median pain scores at different time intervals are shown in Table 3. On day 1, comparing the two groups, group A had a mean pain score of 7.4 ± 1.5, and group B had a mean pain score of 4.1 ± 1. 2. The pain relief obtained in the PRF group on day 1 was statistically significant (P < .01) ( Figure 3A).
On day 3, comparing the two groups, group A had a mean pain score of 5.1 ± 1.1, and group B had a mean pain score of 2.6 ± 0.9.
The pain relief obtained in the PRF group on day 3 was statistically significant (P < .01) ( Figure 3B).
On day 5, comparing the two groups, group A had a mean pain score of 3.4 ± 0.9, and group B had a mean pain score of 1.7 ± 0.9.
The pain relief obtained in the PRF group was statistically significant (P < .01) on day 5 ( Figure 3C).
On day 7, comparing the two groups, group A had a mean pain score of 2.1 ± 0.7 and group B had a mean pain score of 0.8 ± 0.8.
The pain relief obtained in the PRF group was statistically significant (P < .01) on day 7 ( Figure 3D).

| DISCUSSION
AO is one of the most common and unpleasant postoperative complications following extraction. It was first described by Crawford in 1896. Birn's hypothesis 4 is the most accepted explanation of dry socket to date expounding the significance of the localized fibrinolytic activity. According to this hypothesis, trauma and inflammation cause the release of tissue activators from adjacent tissues. Tissue activators convert plasminogen (present in the blood clot) to plasmin which causes lysis of blood clots and kininogen to kinin which causes pain. 4,12,14,29,30 In the present study, the maximum number of patients was group-30 to 39 years, and the minimum number was reported in the sixth decade. This is in agreement with previous studies where the common age group was reported in the range of 30 to 40 years. 14,16 However, some studies have reported a peak incidence in the second decade. 31,32 Sweet and Butler suggested an increased incidence of AO with the use of oral contraceptives and found a positive correlation  between them. 33 Catellani et al observed that this increased incidence could be due to the higher concentration of estrogen contained in them. 34 In the present study, 17 patients were men and 53 were women. Thus, the occurrence of AO showed a female preponderance, since patients taking oral contraceptives were excluded from this study, the predilection in female patients could not be associated with the use of oral contraceptives. This could be attributable to elevated endogenous estrogen levels during reproductive age.
The etiopathogenesis of AO remains inconclusive. Hence, the management of dry sockets lies in the paradigm between intraalveolar dressings and minimally invasive procedures.
The use of intra-alveolar dressings such as salicept patch, neocon, alvogyl, and ZOE have demonstrated positive outcomes regarding pain relief in AO patients. 3,9,14,35 However, each of these dressings is characterized by distinct merits and demerits. 36 Various studies have shown that PRF is a natural fibrin-based biomaterial that accelerates the healing mechanism of tissues and reduces inflammation. PRF is a fibrin matrix of trapped platelets, cytokines, and other cells that act as bio-resorbable membranes.
The activation and degranulation of these cells release various growth factors such as transforming growth factor-beta, platelet-derived growth factor, vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor, and so on. These factors initiate the healing process by stimulating cell migration and proliferation within the fibrin matrix. They also play a role in angiogenesis, chemotaxis, granulation tissue production, epithelization, and osteogenesis. 19,24,[38][39][40][41] Hussain et al concluded that PRF is as effective as ZOE in the management of AO for pain control and superior to ZOE in terms of socket healing and anti-inflammatory properties. 16 In a study comparing the efficacy of alvogyl and ZOE, Supe et al concluded that alvogyl required the least number of dressings and provided quicker and lasting pain relief and faster recovery to the patients. 9 Faizel et al compared neocone, alvogyl, and ZOE and reported that all three tested medicaments showed predictable outcomes. However, neocone emerged as a superior dressing in terms of faster and sustained pain relief, a smaller number of dental visits for dressing change, and better wound healing. On the other hand, ZOE was found to be the most cost-effective and easily available medication for dressing. 3 Kaya et al demonstrated the salicept patch with acemannan as its main ingredient as a viable alternative to alvogyl in the treatment of AO. 35 The present study demonstrated better pain relief using PRF than ZOE in contrast to previously reported studies. 14,16 In patients treated with ZOE dressing, the average VAS score observed were 7.4 ± 1.5, 5.1 ± 1.1, 3.4 ± 0.9, and 2.1 ± 0.7, respectively, on the "1st, 3rd, 5th, and 7th" follow-up days. In patients treated with PRF, the average VAS score observed was 4.1 ± 1.2, 2.6 ± 0.9, 1.7 ± 0.9, and 0.8 ± 0.8, respectively. Both ZOE and PRF were effective for pain control during the follow-up period. However, the pain intensity measured as a pain score using VAS was, lower in the PRF group than in the ZOE group on all follow-up days.
The authors attribute the better pain relief in the PRF group to faster wound healing associated with it. 16,27 The fibrin matrix in PRF promotes angiogenesis and enhances natural immunity, thus reducing inflammatory processes and pain. PRF also provides natural resurfacing of the dry socket wound, which ultimately results in the covering of the exposed nerve endings, thus providing a soothing effect. 31 Chakravarthi suggested that the kinins released from the dry socket may be antagonized by the various growth factors present in PRF, thereby causing pain relief. 26

CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.

TRANSPARENCY STATEMENT
Dr Satheesh Reeshma affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT
The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.