Effectiveness of the platelet-rich fibrin in the control of pain associated with alveolar osteitis: a scoping review

Abstract Objectives The aim of this scoping review was to determine the effectiveness of the platelet-rich fibrin in the control of pain associated with alveolar osteitis. Materials and methods Reporting was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews. A literature search was conducted in the PubMed and Scopus databases to identify all clinical studies on the application of platelet-rich fibrin in the control of pain caused by alveolar osteitis. Data were extracted independently by two reviewers and qualitatively described. Results The initial search returned 81 articles, with 49 identified after duplicates removal; of these, 8 were selected according to the inclusion criteria. Three of the eight studies were randomized controlled clinical trials, and four were non-randomized clinical studies, two of which were controlled. One study was case series. In all of these studies, pain control was evaluated using the visual analog scale. Overall, the use of platelet-rich fibrin resulted effective in the control of pain determined by alveolar osteitis. Conclusions Within the limits of this scoping review, the application of platelet-rich fibrin in the post-extra-extraction alveolus reduced the pain associated with alveolar osteitis in almost all the included studies. Nevertheless, high-quality randomized trials with adequate sample size are warranted to draw firm conclusions. Clinical relevance Pain associated with alveolar osteitis causes discomfort to the patient and is challenging to be treated. Use of platelet-rich fibrin could be a promising clinical strategy for pain control in alveolar osteitis if its effectiveness will be confirmed by further high-quality studies.


Introduction
Alveolar osteitis (AO) or "dry socket" is a widely recognized complication of dental extraction caused by a partial or total disintegrated blood clot within the extraction socket. Dry socket results in inflammation of exposed alveolar bone and delayed healing, accompanied by gradually increasing severity of pain which may radiate to the auricular and temporal regions [1]. The incidence of AO ranges between 1 and 30%, being more frequent in female patients after mandibular third molar extraction [2]. Many predisposing factors have been identified for the occurrence of this phenomenon including preexisting systemic diseases, drug and oral contraceptives assumption, operative techniques, and hygiene habits [1,3,4]. Strong halitosis, foul taste, edema of gingival Eugenio Pedullà and Alberto Bianchi contributed equally to this work. tissues with local lymphadenitis, and pain are frequent. Specifically, the severe, throbbing, referred pain is one of the most typical clinical manifestations [5]. Generally, pain associated with tooth extraction resolves in a few days by analgesics; when it persists for more days, it could be an indicator of the AO [5].
Since pain is the main and debilitating symptom of this pathology, several strategies have been proposed in order to avoid or reduce the pain associated with alveolar osteitis. The main therapeutic approaches include alveolar lavage, chlorhexidine mouthwash, application of topical gels, analgesics, cryotherapy, antibiotics, topical anesthetics and obtundent, or their combination, and placement of medicated dressings [6][7][8][9][10]. Therapeutic alternatives are numerous, heterogeneous, and challenging to compare [11].
Platelet-rich fibrin (PRF) is a second-generation platelet concentrate produced without biochemical blood manipulation [12,13]. It is constituted of three key elements: first, the platelets and their activated growth factors [14]; second, the leucocytes and their cytokines [15,16]; third, the density and complex organization of the fibrin matrix architecture produced by a natural polymerization [14]. The fibrin matrix seems responsible for the slow release of growth factors during the proliferation stage of wound healing and serves as a scaffold for cell migration and differentiation [17]. PRF is an important reservoir of numerous growth factors to promote angiogenesis, such as transforming growth factor b (TGF-b) and vascular endothelial growth factor (VEGF) [17]. In addition, PRF was found to reduce pain, swelling, and alveolar osteitis' occurrence, as well as improve soft and hard tissue healing after mandibular extractions by a stimulation of angiogenesis and increase of local perfusion during the healing process [18,19]. A modified form of PRF, called advanced PRF (A-PRF), was proposed. Because of its lower speed of centrifugation, A-PRF possesses a major number of platelets and growth factors with improvement in mechanical properties compared to the traditional leukocyte-PRF (L-PRF) [20].
Despite the benefits describing, some studies reported no significantly advantage in control of pain associated with AO when PRF was applied [21,22]. This scoping review aimed to determine the effectiveness of the PRF in control of pain associated with alveolar osteitis in order to provide an updated overview of the current knowledge and address the future research.

Materials and methods
This scoping review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews [23] and focused on the following research question: "What is the effectiveness of the PRF in control of pain associated with alveolar osteitis?"

Search strategy
A literature search was conducted in the PubMed and Scopus databases on 18/11/2022 to identify all pertinent studies investigating the effectiveness of the PRF in control of pain caused by alveolar osteitis. The following keywords were adopted for each database: ("alveolar osteitis" OR "dry socket") AND ("platelet rich fibrin" OR "PRF"

Eligibility criteria
All clinical studies (cohort studies, randomized clinical trials (RCTs), quasi-experimental studies, case report, and case series) investigating the effectiveness of PRF in pain control associated with alveolar osteitis were included. The exclusion criteria regarded the study design (in vitro and ex vivo studies, animal studies), article type (editorials, commentaries, short communication, and reviews), peerrevision (abstracts and preprint articles), and language (studies without an English abstract).

Data extraction
For each study, the following items: •

Results
The electronic search resulted in 81 articles. After duplicates exclusion, 49 abstracts were reviewed, and the full texts of 8 studies were screened. Finally, 8 studies were included for qualitative analysis (Fig. 1). All included studies are listed in the Table 1.
All studies were published after 2015 and investigated the potential application of PRF in the management of alveolar osteitis. For our purpose, we considered only the outcome of pain control management.
All the studies evaluated pain control by the visual analog scale (VAS) [18,21,22,[24][25][26][27][28]. The VAS consisted of 10 units in combination with a graphic rating scale, where the leftmost score of 0 represented absence of pain and the rightmost score of 10 indicated the worst possible, unbearable,   A-PRF+, advanced PRF Symptoms for diagnosis of dry socket include continuous throbbing type of pain; radiating to ear, temple, and neck; start of pain 1-3 days post extraction; foul taste; bad breath; pain not relieved even after medication. Signs include devoid of blood clot, infected or retained roots, localized swelling, lymphadenopathy [18] Blum's definition for AO diagnosis: patients with increasing postoperative pain severity in and around the lower permanent third molar extraction site in 3 days after the extraction and the total or partial breakdown of the blood clot in the socket with or without halitosis [24] excruciating pain. Chakravarthi et al. assessed the pain relief by recording also the analgesic intake [18]. Overall, almost all the studies showed that PRF reduced the pain associated with OA and guaranteed a fast pain relief [21,24,[26][27][28]. When compared with ZOE, PRF reduced the pain intensity in all follow-up days in the study of Reeshma et al. (2021) [27], while the PRF group showed slower and less pain remission at 1-, 3-, and 5-day in the study of Hussain et al. [22], with no difference at 7-day.
Finally, a significant decrease in pain was recorded in both the PRF and Alvogyl groups at the 3-day, with no differences between them [25].

Discussion
Pain is considered the most frequent and uncomfortable symptom of OA that requires an effective treatment [29]. Over the years, several strategies have been proposed for the management of pain associated with alveolar osteitis [6][7][8][9]. However, no standardized protocol for treating the associated pain has been established, and choosing the best treatment option is still a challenge for clinicians. PRF is an autologous fibrin-based biomaterial entangled with platelets, leukocytes, and their cytokines. More recently, the use of applying platelet-rich fibrin in the pain control of OA has been proposed [18,[21][22][23][24][25][26][27][28].
The aim of this scoping review was to summarize the available studies on the effectiveness of platelet-rich fibrin in the pain control of OA and offer a platform for further research.
Alveolar osteitis is a complex condition which may be challenging to be clinically standardized. Criteria of dry socket according to Chakravarthi's definition [18] include major symptoms like foul taste, bad breath, prolonged throbbing pain radiating to the ear, temple, and neck, beginning 1-3 days after the tooth extraction and not resolving after drug intake. Signs refer to lacking of a blood clot, infected or retained roots, local swelling, and lymphadenopathy. A minimum of two symptoms and one sign are necessary to make a diagnosis of alveolar osteitis. Similar is Blum's definition [6]. Only three studies explicated on the basis of which criteria the diagnosis of AO was performed [18,24,27].
Although three of the eight included studies were presented as randomized controlled clinical trials, the only study that specified the randomization procedure was that of Hussain et al. [22]. Similarly, no information was reported on strategies to guarantee the blinding of patients with regard to the treatment received and the operator responsible of pain assessment. Moreover, no control group was available in three of included studies [18,26,28], impairing the validity of the results obtained.
Gender, age, systemic condition, smoking status, extraction site, and surgical protocol are all factors able to impact the occurrence of postoperative complications including pain [30].
The included studies showed notable differences in participant selection. In almost all studies, the mean minimum age of the included population was 18 [21,24,26,28], and the maximum was 60 [18,21,22,25,27]. Age might be a determinant of surgical difficulty, due to relative root and bone stiffness which leads to more traumatic surgeries [30].
A pivotal aspect of clinical trials is to guarantee a representative sample of the population with the aim of avoiding variables that may alter the study. Systemic pathologies, such as diabetes, increase the risk of postoperative infections and delay the wound healing due to the alterations in the microvascular circulation. This alteration results in a reduced inflammatory response, and this could lead to an alteration in the perception of pain in alveolar osteitis [31]. For this reason, almost all studies excluded patients with systemic or immune disorders [18,21,22,24,[26][27][28]. In the study of Keshini et al. [25], preexisting systemic conditions were not reported as exclusion criteria. Smokers were excluded in three studies [22,24,27]. Smoking is a confounding factor because nicotine releases catecholamines which are responsible for vasoconstriction and tissue ischemia [21]. Thus, findings on smokers can be different from the general population and need caution in their interpretation.
Among the studies included, only the study of Keshini et al. [25] did not specify the gender. The majority of remaining studies exhibited a preponderance of women [22,24,[26][27][28]. Pain associated with AO is more common in females probably due to the fact that women in childbearing age are in a continuous sinusoidal fluctuation of estrogen levels able to modify the inflammation status and thus pain perception [32,33]. In addition, the use of oral contraceptives might raise plasma fibrinolysis and increase the risk for dry socket [30]. Nevertheless, females taking oral contraceptives are generally excluded from this kind of study [24,[26][27][28]. Thus, the preponderant occurrence of pain associated with AO in female patients is likely to be linked with the first mechanism [32,33].
The study of Yuce et al. [24] tested the A-PRF. The other studies did not specify the type of PRF tested. The A-PRF exhibited a more porous structure, permitting more space for trapped platelets and immune cells and consequently a higher and more pronounced release of growth factors in comparison with L-PRF [34].
Overall, the PRF preparation was performed following the standardized and validated Choukroun's technique [35]. This technique consists of 4 steps: blood sampling, centrifugation, fibrin clot sampling, and production of membranes, fragments, or swabs for extraction sites [35].
Four studies reported that the anatomical site was the third molar area [18,24,26,28]; the others did not specify which extraction site was assessed [21,22,25,27]. Of note, the molar region could require more frequently a surgical extraction. Surgical approach resulted in a 10-fold increase incidence of AO in comparison with non-surgical [36]. Indeed, the alveolar modifications caused by flap reflection and bone removal are more likely to cause AO when a surgical extraction is performed [37]. Moreover, the mandible has been reported to be more affected by AO than the maxilla probably due to more deliverance of direct tissue activators linked with bone marrow inflammation which occurred in more traumatic extractions [38].
Notable differences emerged in the sample size of included studies ranging from a minimum of 10 [18] to a maximum of 100 patients [26,28]. A small sample size may make it challenging to assess the true effect of a treatment due to the occurrence of a type II error for which the null hypothesis is incorrectly accepted and no difference between the study groups is reported [39].
Overall, most of the included studies reported a significant reduction in OA-associated pain ensuring a fast pain relief [21,24,[26][27][28]. The benefits observed in terms of pain control were probably linked with the faster wound healing promoted by PRF because of the increase in chemotaxis, angiogenesis, human osteoblast, and fibroblast proliferation, as well as differentiation in human bone mesenchymal stem cells [40,41]. In addition, PRF favors the natural resurfacing of the dry socket wound which covers the exposed nerve terminals determining a soothing effect [28]. Moreover, the growth factors antagonize the inflammatory kinins released from the dry socket promoting the pain relief [18]. Thus, PRF could be considered an adequate healing biomaterial for pain management [17]. PRF reduced pain less than the ZOE group [22] at 1-, 3-, and 5-day post-intervention and with no significant differences compared with Alvogyl [25]. Alvogyl is an intraalveolar dressing material, largely used in the management of dry socket because it quickly provides pain relief and soothing effect during the healing process [25]. This mechanism is imputable to the analgesic, anesthetic, and antimicrobial effects of eugenol, butamben, and iodoform, respectively [25].
Interestingly, PRF was compared with ZOE in OA-associated pain remission, with contrasting results [22,27]. ZOE is a commonly used obtundent material with antibacterial properties [22]. The different outcomes at 1-, 3-and 5-day post-intervention is probably due to the differences in sample size, enrollment population procedure, and demographical characteristics of patients involved [22,27].
Scoping review is a flexible approach introduced for investigating the available knowledge on a specific or new topic, for determining the search boundaries, and directing the future studies [42]. The use of platelet-rich fibrin in the control of pain caused by alveolar osteitis is a current topic for which the available studies are few. Consequently, the main purpose of this scoping review was exploring and defining the applications on PRF for pain associated with alveolar osteitis as well as underlining the limitations of the current research. For this reason, all available clinical studies were included independently from study design and quality conduct. Furthermore, the bias assessment of studies was not performed being beyond the purpose of scoping review and resulting more preferable for a systematic revision approach.
Some limitations have to be considered. First, the great variety in methodology of included studies made difficult a comparison among them. In addition, pain is a subjective experience, which means that it cannot be directly verified by those who are not experiencing it. This subjectivity generates a bias that is difficult to correct, since it is mainly due to the past experiences of individuals that can affect individual pain perception [43]. The application of dressing materials inside the extraction socket has been reported to delay wound healing and cause adverse reactions [7]; however, most of the studies reporting these findings are obsolete and thus poorly informative [44][45][46].
Although the application of platelet-rich fibrin in the postextraction socket is a time-consuming and invasive technique [22], it might be a promising strategy for the control of pain associated with alveolar osteitis being biocompatible, effective, and safe treatment [18,47]. Yet, high-quality randomized clinical trials on large sample size with adequate control groups are extremely warranted to evaluate the true benefits of the application of PRF in pain associated with alveolar osteitis.

Conclusions
Within the limits of the present scoping review, the application of platelet-rich fibrin in the post-extra-extraction alveolus reduced the pain associated with alveolar osteitis in almost all the included studies. Yet, high-quality randomized trials with adequate sample size are necessary to corroborate these findings.

Declarations
Ethics approval and consent to participate Not applicable.
Research involving human participants and/or animals Not applicable.

Conflict of interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.