Efficacy/Safety of the Use of Glucocorticoids in Oral and Maxillofacial Surgery

Citation: Nils, H.J.; Arce Recatala, C.; Castano, A.; Ribas, D.; Flores-Fraile, J. Efficacy/Safety of the Use of Glucocorticoids in Oral and Maxillofacial Surgery. Dent. J. 2023, 11, 239. https://doi.org/10.3390/ dj11100239 Academic Editors: Patrick R. Schmidlin and Gabriele Cervino Received: 4 July 2023 Revised: 8 September 2023 Accepted: 28 September 2023 Published: 17 October 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). dentistry journal Systematic Review Efficacy/Safety of the Use of Glucocorticoids in Oral and Maxillofacial Surgery Heilyn Joanna Nils 1,*, Cristina Arce Recatala 2, Antonio Castano 3, David Ribas 3and Javier Flores-Fraile 1 1University of Salamanca, 37008 Salamanca, Spain; [email protected] 2Valencia International University, 46002 Valencia, Spain; [email protected] 3University of Sevilla, 41004 Sevilla, Spain; [email protected] (A.C.); [email protected] (D.R.) *Correspondence: [email protected] Abstract: Introduction: Glucocorticoids, also known as corticosteroids or steroids, are drugs derived from cholesterol. They are synthesized by the adrenal cortex, along with other hormones, such as cortisol and aldosterone. Glucocorticoids are drugs recommended for patients undergoing surgery on the oral cavity, facial skeleton, and related cervical structures due to their high efficacy against inflammatory and immune processes. However, these drugs are restricted due to their multiple and serious adverse effects. The objective of this study was to verify the efficacy of corticosteroids administered in major surgeries of the oral cavity, as well as of the cervical and facial structures, based on the characteristics of the patient so as to select the best therapeutic strategy. Methods: Articles in the databases of PubMed, Nature Portfolio, Medline, Cochrane Library, and Google Scholar were thoroughly examined. Results: A total of 54 articles were selected to address the proposed objectives. The results obtained show that it is effective and safe to use glucocorticoids as pre- or postsurgical therapy in oral and maxillofacial surgery to control the processes of inflammation, pain, lockjaw, and edema. However, when referring to the use of these drugs, one must proceed with caution and pay particular attention when handling them. The concentration of the glucocorticoids used must be individualized, as well as the selection of the route of administration. Various studies show that, although the oral route is the most used route, the most effective route is the intramuscular route due to its easy absorption. However, for patients who have recurrent inflammatory and vesiculobullous ulcerative lesions, the topical route should be chosen to mitigate side effects, considering that recurrent applications must be made to prevent the worsening of the lesion and to avoid having to use medications enterally. In patients with cervicofacial infections, antibiotics continue to be the main drugs used to manage the condition in conjunction with corticosteroids. It is important to know the possible interactions of glucocorticoids with other medicines or food: it has been described that the interaction between Ritonavir, an antiretroviral drug that inhibits human immunodeficiency virus (HIV) proteases, and prednisone causes an increase in the concentration of prednisone, leading to possible toxicity in normally safe doses and, in many cases, iatrogenic Cushing’s syndrome. It is also important to know the systemic or topical adverse effects of the chronic or high-dose use of glucocorticoids. Conclusions: It can be concluded that by making adequate use of glucocorticoid therapy in oral and maxillofacial surgery to manage clinical manifestations, it is possible to attenuate the morbidities of treatment and intervention. Keywords: corticosteroids; anti-inflammatory postoperative oral surgery; dexamethasone; dentistry; dosage form design; route of administration; cervicofacial infection 1. Introduction Steroids are the most used medication, with high efficacy against inflammatory and immune diseases, pain, edema, and lockjaw [ 1 ]. Glucocorticoids are drugs derived from cholesterol (hence their name as steroidal drugs). They are synthesized by the adrenal Dent. J. 2023,11, 239. https://doi.org/10.3390/dj11100239 https://www.mdpi.com/journal/dentistry Dent. J. 2023,11, 239 2 of 20 cortex, along with other hormones, such as cortisol and aldosterone. Synthetic glucocorticoids are classified according to several criteria: according to the duration of action (short duration, 8–12 h; intermediate duration, 12–36 h; and long duration, more than 36 h); according to their glucocorticoid potential compared to the endogenous glucocorticoid hydrocortisone; and according to their mineralocorticoid activity or ability to mimic the mineralocorticoid effects of aldosterone, promoting water and sodium retention and favoring potassium elimination [2]. When describing the mechanism of action of these drugs, it must be stated that the adrenal cortex oversees the synthesis of glucocorticoids, cortisol, hydrocortisone, and corticosterone, hormones that are released throughout the day following a circadian rhythm and that have numerous effects at metabolic, cardiovascular, nervous system levels, etc. These steroid hormones exert their mineralocorticoid or glucocorticoid function through binding to two types of nuclear receptors: the glucocorticoid receptor (GR or type II in the old nomenclature) and the mineralocorticoid receptor (MR or type I). These act on different genes, producing changes (stimulation or inhibition) in protein synthesis and tissue response. The performance of these corticosteroids is regulated by the hypothalamuspituitary-adrenal cortex axis. Thus, the hypothalamic corticotropin-releasing hormone prompts the production of pituitary adrenocorticotropin, or ACTH, which then promotes cortisol output at the adrenal level. When cortisol levels are sufficient, and to avoid the excessive accumulation of cortisol, negative feedback to the axis occurs such that the release of CRH, ACTH, and cortisol is interrupted. Corticosteroids are analogs of endogenous glucocorticoids, and they prevent the entry of leukocytes into the inflammatory focus, disturb the action of fibroblasts and endothelial cells, and mitigate the performance or effects of numerous chemical mediators of inflammation [1,3]. As for the pharmacological effects of these drugs, it can be pointed out that they have anti-inflammatory actions, which are achieved through multiple mechanisms that include the inhibition of histamine release and consequent capillary vasodilation, the inhibition of prostaglandin synthesis, the inhibition of proinflammatory cytokines (COX2, PLA2, INOS IL, and TNF), and the increased synthesis of anti-inflammatory cytokines and annexin (which causes apoptosis). With regard to immunosuppressive actions, through a lymphocytic effect, T lymphocytes reduce the production of IL-2 and IFN γ , preventing the activation of Tc lymphocytes and natural killer (NK) cells. B lymphocytes, by contrast, are relatively resistant to the effects of glucocorticoids: they inhibit their proliferation only if they are administered before they are activated. At small doses, they do not affect the production of antibodies, but at high doses, an increase in catabolism and a slight decrease in synthesis are observed, perhaps due to indirect mechanisms [4,5]. The use of glucocorticoids is restricted due to their multiple and severe adverse effects. In turn, they are also very powerful antiallergens indicated in allergic processes, such as rhinitis, contact dermatitis, situations that occur with hives—and even in the treatment of anaphylactic shock once the patient has been stabilized with adrenaline—and skin diseases (psoriasis and atopic dermatitis, among others). Due to their immunosuppressive properties, they are also used in therapy for autoimmune diseases (e.g., systemic lupus erythematosus, psoriasis, and rheumatoid arthritis) and in the prevention of transplant rejection. They are also used in states of steroid deficiency, such as Addison’s disease, a disorder that manifests itself when the body does not produce enough of certain hormones secreted by the adrenal glands [6]. The adverse effects of glucocorticoids are a prolongation of their effects and include (a) intense muscle atrophy; (b) hyperglycemia, which can condition the appearance of diabetes mellitus, the appearance of cataracts, osteoporosis, peptic ulcer, delayed wound healing, and increased susceptibility to infectious processes; (c) iatrogenic Cushing’s syndrome—abnormal fat redistribution and fat accumulation in the abdominal region; and (d) the suppression of adrenal function, since it decreases with hypothalamus-pituitary- adrenal cortex axis activity, and a decrease in the production of endogenous glucocorticoids. It should be considered that the adrenal cortex atrophies in a period of 2–3 months, after Dent. J. 2023,11, 239 3 of 20 which treatment cannot be interrupted abruptly because it would lead to the appearance of adrenal insufficiency, which could be fatal. To address this, glucocorticoid doses are slowly decreased over weeks and even months [ 5 ]. The objective of this article is to review the efficacy of the administration of glucocorticoids using the various routes of administration and the appropriate doses of each drug. Focus question: presented in the “PICO” format. What is the effectiveness/safety of the use of glucocorticoids in patients undergoing oral and maxillofacial surgery without previous pathologies? Hypothesis: The use of corticosteroids is more effective (but not safe) in alleviating inflammation and pain processes in oral and maxillofacial surgery than the use of NSAIDs. 1.1. General Objective The objective of this paper is to study the effectiveness/safety of the use of glucocorticoids in oral and maxillofacial surgery in young and adult patients without other previous pathologies. 1.2. Specific Objectives 1. Identify the applications of glucocorticoids in oral and maxillofacial surgery in adolescents and adults. 2. Determine the appropriate dose to be administered in oral and maxillofacial surgery in adolescent and adult patients where there is no presence of other previous pathologies. 3. Examine the advantages and disadvantages of the different pharmaceutical forms of glucocorticoids. 4. Highlight the interactions of glucocorticoids with other drugs. 5. Describe the effectiveness when glucocorticoids are administered to attend oral manifestations and maxillofacial diseases in adults (aged 16–65 years). 6. Study the adverse reactions of glucocorticoids after prolonged use in patients undergoing oral and maxillofacial surgery. 2. Methodology 2.1. Review Type This work is a systematic review, and it was carried out following the PRISMA declaration (Preferred Reporting Item for Systematic Reviews and Meta-Analysis) and the criteria for the publication of a systematic review. Registration number is: CRD42023445218. The aim was to gather the information available in different databases to respond to the proposed objectives. A search was carried out in the period between 7 April 2023 and 2 June 2023. 2.2. Search Strategy Information was searched for in the PubMed, Nature Portfolio, Cochrane, Medline, and Google Scholar databases, using free terms, as well as MeSH terms, in the indicated cases and combining them with the Boolean AND and OR operators. During the search, thesaurus keywords limited to the English language were used, such as corticosteroids, anti-inflammatory postoperative oral surgery, dexamethasone, and dentistry. Likewise, parentheses were used to specify search combinations, and quotation marks were used to carry out searches with terms containing multiple words. In addition, books were examined. Finally, publication date filters were used, limiting the search so that it included articles published in the last 10–15 years (Figure 1). Dent. J. 2023,11, 239 4 of 20 Dent. J. 2023, 11, x FOR PEER REVIEW 4 of 20 Figure 1. Scheme of the methodology using a flowchart of identified, excluded and included studies. In the PubMed database, 742 results were obtained; when using the filters focusing on the last 10–15 years, 51 articles were obtained, of which 20 were selected. In the Nature Portfolio database, 1929 results were obtained. When using filters that covered the inclusion criteria, this was reduced to 9 articles, of which 3 were selected. In the same way, 52 articles were obtained from the Cochrane database, and 69 results were obtained from Medline. The search of these databases was carried out by applying Figure 1. Scheme of the methodology using a flowchart of identified, excluded and included studies. In the PubMed database, 742 results were obtained; when using the filters focusing on the last 10–15 years, 51 articles were obtained, of which 20 were selected. Dent. J. 2023,11, 239 5 of 20 In the Nature Portfolio database, 1929 results were obtained. When using filters that covered the inclusion criteria, this was reduced to 9 articles, of which 3 were selected. In the same way, 52 articles were obtained from the Cochrane database, and 69 results were obtained from Medline. The search of these databases was carried out by applying the filters already mentioned and by only looking for articles that responded to the proposed objectives; 1 article was chosen from each database. Finally, searches were carried out for the journals with the greatest impact in the Google Scholar search engine, with the most recent randomized clinical trials to sustain the vast study carried out on the subject in question. With our initial approach, 4080 articles were obtained, and by using filters that covered each inclusion criterion and the relevant dates, searching only in English, Portuguese, and Spanish, and rejecting those that were found to be duplicates, this was reduced to 37 articles, of which 27 (21 in English and 6 in Spanish) were useful in contributing information to this review. 2.3. Selection Criteria To carry out the systematic review adequately and accurately, selection criteria were applied (Table 1). Table 1. Summary of the selection criteria. Inclusion Criteria Exclusion Criteria Respond to the objectives set. Not related to the objectives. Study types: observational, randomized clinical trials. Full texts not available. Articles published in the last 10–15 years. Articles that do not meet the inclusion criteria or with little proven scientific evidence (PEDro scale less than 7). Articles are open access, free, and complete. Articles published in English, Spanish, Portuguese. Population between 10 and 65 years old/any race and sex. Valued with the PEDro scale higher than 7. 2.4. Study Selection and Quality Assessment Bias Analysis The main biases that must be considered during the search of databases are as follows: 3 Publication bias must be considered, specifically in studies whose results do not coincide with the prescribed interval. 3 The compilation of the data must be systematic and homogeneous; when there is heterogeneity in the obtained results, it hinders the combination and comparison when different populations are studied. 3 High heterogeneity may affect the validity of the results of the meta-analysis if included in this study, e.g., a difference between the age of the patients in each population and the results obtained. To assess the risk of bias in this systematic review, each piece of data must conform to the objectives set for the review. We used the Cochrane risk of bias tool to assess the methodologies of the examined studies, please see (Table 2). Dent. J. 2023,11, 239 6 of 20 Table 2. Cochrane risk of bias tool to assess the methodologies of the examined studies. Low risk (+), high risk (-) uncertainty (?). 1st Author, Year Bias from Random Sequence Bias Allocation Concealment Bias Blinding Participant and Personnel Bias Blinding Outcome Incomplete Outcome Data Selective Report Other Bias Bhandage 2018 [7] + + ? + + + + De la Cruz Carranza 2013 [8]+ + - + + + + Manriquez-Guzman 2013 [9]+ + - + + + + Chavez-Rimache 2020 [10]+ + + + + + + Nunez-Dias 2019 [11] + + + + + + + 3. Results Of the total number of studies analyzed, 50% were qualitative, 0% were observational, 25% were experimental, and 25% were studies with mixed methodologies (quantitative and qualitative). The main results of each of the reviewed articles are shown below (Figure 2). Dent. J. 2023, 11, x FOR PEER REVIEW 6 of 20 De la Cruz Carranza 2013 [8] + + - + + + + Manriquez- Guzman 2013 [9] + + - + + + + Chavez-Rimache 2020 [10] + + + + + + + Nunez-Dias 2019 [11] + + + + + + + 3. Results Of the total number of studies analyzed, 50% were qualitative, 0% were observational, 25% were experimental, and 25% were studies with mixed methodologies (quantitative and qualitative). The main results of each of the reviewed articles are shown below (Figure 2). Figure 2. Results of data extraction. 1. Identify the applications of glucocorticoids in oral and maxillofacial surgery in adolescents and adults (Table 3). Table 3. Summary of the main drug pathologies and routes of administration in oral and maxillofacial surgery. Pathology Drug Route of Administration Temporomandibular joint disorders. 10 mg/day methylprednisolone, betamethasone acetate, triamcinolone acetonide, and hydrocortisone. Intra-articular route. Limit application to 4 times a year. Oral lichen planus. Triamcinolone acetonide 0.1%, betamethasone sodium phosphate 0.1–0.05%, clobetasol 0.05%. Topical route. Two or three times a day if a lesion is present. Bell’s palsy. Prednisolone 1 mg/kg/day Orally. 7–10 days. Recurrent aphthous stomatitis. Hydrocortisone hemisuccinate 2.5 mg, Topical route on the lesion two or three times a day and before sleeping (gel or paste). 0% 20% 40% 60% 80% 100% Qualitative Observational Experimental Mixed Qualitative, 50% Observational, 0% Experimental, 25% Mixed, 25% Data extraction Figure 2. Results of data extraction. 1. Identify the applications of glucocorticoids in oral and maxillofacial surgery in adolescents and adults (Table 3). Currently, the vast therapeutic application of glucocorticoids, such as betamethasone, dexamethasone, methylprednisolone, triamcinolone, or prednisolone (resulting in the greater use of glucocorticoids and little to no use of mineralocorticoids), provides great benefits in acute and chronic conditions or ailments that have an allergic, inflammatory, or immunological basis [12,13]. Dent. J. 2023,11, 239 7 of 20 Table 3. Summary of the main drug pathologies and routes of administration in oral and maxillofacial surgery. Pathology Drug Route of Administration Temporomandibular joint disorders. 10 mg/day methylprednisolone, betamethasone acetate, triamcinolone acetonide, and hydrocortisone. Intra-articular route. Limit application to 4 times a year. Oral lichen planus. Triamcinolone acetonide 0.1%, betamethasone sodium phosphate 0.1–0.05%, clobetasol 0.05%. Topical route. Two or three times a day if a lesion is present. Bell’s palsy. Prednisolone 1 mg/kg/day Orally. 7–10 days. Recurrent aphthous stomatitis. Hydrocortisone hemisuccinate 2.5 mg, triamcinolone acetonide 0.1%, dexamethasone 0.5 mg. Topical route on the lesion two or three times a day and before sleeping (gel or paste). Behçet’s disease. Immunosuppressive therapy. In acute phase, prednisone 40–60 mg/day. Orally. Pemphigus diseases. Prednisone 0.5–1.5 mg/kg/day or 10–40 mg highly potent topical corticosteroids. Orally and topically, reducing or increasing the dose according to the severity of the lesion. Erythema multiforme. Clobetasol propionate rinses in aqueous solution. In case of aggravation of the lesion, prednisone 40–80 mg/kg/day, methylprednisolone 1 mg/kg/day (3 days). Topical route. Mouthwashes. Oral route in case of aggravation (1–2 weeks and reduce dose). Postherpetic neuralgia. Methylprednisolone 40 mg/10 day. Intramuscular route. Central giant-cell granuloma. Dexamethasone 0.5% (3 mg/mL/0) injections once a week for six weeks. Intramuscular route. * Temporomandibular joint disorders (TMJs): Preparations with ester (acetonide) that are insoluble in water release gradually and, therefore, have a longer effect. Formulations without ester (sodium phosphate) that are soluble in water release more quickly, and, therefore, their effect is shorter; such preparations include betamethasone sodium phosphate and dexamethasone [13–15]. * Oral lichen planus (OLP): Here, medium-potency topical corticosteroids are usually used; high-potency fluorinated drugs and, recently, halogenated corticosteroids have been incorporated due to their high potential. The great disadvantage and, therefore, inconvenience that results from using these topical medications is insufficient adherence to the mucosa. For recalcitrant erosive lichen planus erythematosus, where topical drug application is not effective, a more powerful systemic medication is used: prednisolone between 15 and 30 mg or until it reaches 35 mg between 5 and 7 days. Likewise, the injectable application of triamcinolone 10–20 mg 2–4 x/week for 2 weeks is also used [16–19]. * Bell’s palsy: This inflammation of the unknown cause of the facial nerve can be effectively treated by administering prednisolone 1 mg/kg/day, with a maximum dose of 60–80 mg for 7–10 days during the first week and a decrease in the dose in the following week. This protocol is carried out in patients with a normal immune response [20,21]. Oral Ulcerative and Vesiculobullous Lesions * Recurrent aphthous stomatitis (RAS): Canker sores derive from a non-infectious inflammation process. Topical and systemic steroids seek to limit the inflammatory worsening of this condition. Denture patients can mix steroids with an adhesive such as orabase. For more extensive lesions, a gauze with the steroid can be placed on the ulcer and left to act Dent. J. 2023,11, 239 8 of 20 for 15 to 30 min. For lesions in areas of accessibility or with a more complex visualization, a topical dexamethasone elixir of 0.5 mg is administered, applying it with a gauze on the pustules 4 × /day for 15 mts. In the presence of major thrush, administering prednisone systemically is recommended with an initial therapeutic approach of 40 mg/day with a duration of one week to fight the outbreak, gradually decreasing the dose after 7–14 days have elapsed [22,23]. * Behçet’s disease: Particularly manifested as a mucocutaneous condition with the appearance of oro-genital ulcers and skin lesions, this disease can be effectively managed with anti-inflammatory agents that modify the action of neutrophils; treatment is based on immunosuppressive therapy [24]. * Pemphigus diseases: There are two main groups that characterize these autoimmune blistering disorders: “The pemphigus diseases” and “The autoimmune blistering diseases of pemphigus”. In turn, we can classify them into three main subtypes: “Vulgar pemphigus”, “Foliaceous pemphigus”, and “Para neoplastic pemphigus”. For the pattern of pemphigus vulgaris, it is essential that therapy is based on systemic immunosuppression, choosing drugs such as corticosteroids. If there is resistance to improvement, the dose can be adjusted and increased up to 2 mg/kg/day. When topical therapy is used, the purpose of which is to alleviate inflammation and prevent secondary infections, calcineurin inhibitor corticosteroids, either combined or not combined with antibiotics, are administered. It should be noted that, when treating oral lesions, gels containing local anesthetics and appropriate care with a dental health professional should be incorporated [25–27]. For pemphigus foliaceus, topical doses between the range of 10 and 40 mg (one tube per day) have proven to be feasible for the use of prednisolone systemically. In seriously ill patients, systemic therapy should be used, with the corticosteroid of choice being prednisone at 0.5 mg/kg/day. This dose can be decreased 4–6 months after the initial treatment. The adjustment of this dose occurs at the start of maintenance therapy [ 28 , 29 ]. Finally, for neoplastic para pemphigus, glucocorticoids at a dose of 1–2 mg/kg/day are the quintessential treatment of choice due to their efficacy [18]. * Erythema multiforme: Patients can use a topical treatment; clobetasol propionate mouthwashes in an aqueous solution provide good management due to the contact time between the lesion and the drug. For patients who are not systemically involved, moderate- to-severe (ME) cases can be treated with systemic glucocorticoids. In patients with severe lesions, prednisone is recommended at 40–80 mg/kg/day for 1–2 weeks and then a rapid decrease in its dose. It is worth mentioning that prednisone at a dose of 0.5–1.0 mg/kg/day as initial systemic therapy or pulses of methylprednisolone at 1 mg/kg/day for 3 days have shown efficacy in the event of injury [30]. * Postherpetic neuralgia: Recently, researchers have suggested that the subsequent treatment to be followed should be based on a topical therapy of lidocaine or capsaicin and a systemic therapy based on gabapentin, pregabalin, and tricyclic antidepressants [ 31 ]. It is highly effective to use 40 mg methylprednisolone injections for 10 days, highlighting that there is great fear regarding its safety due to the possible risk of arachnoiditis or fungal meningitis [32]. * Central giant-cell granuloma (CGCG): There is still no complete understanding of its mechanism of action. Researchers have stated that administering an intralesional steroid injection will cause fibrosis and reossification of the lesion in the bone cyst due to the impediment of the excretion of lysosomal proteases, which inhibit osteoclasts and promote their apoptosis. The habitual treatment is surgical removal [ 33 ]. However, regarding the choice of corticosteroid, dexamethasone is recommended, by which, in order to obtain an optimal response, the patient must be disciplined in administering injections two or three times a week without interruption for three consecutive months [34]. * Other pathologies: Dent. J. 2023,11, 239 9 of 20 It is of great importance to refer to patients who present cervicofacial infections, where the use of corticosteroids or lack thereof could be beneficial. A brief review of studies carried out in the United Kingdom is presented below. Studies show that, given the high number of mortalities caused by cervicofacial infections, great interest has been generated in the use of steroids as adjuvants to reduce the serious effects of these conditions. These infections arise through different pathways, such as pharyngeal tonsils, teeth, salivary glands, esophageal trauma, and necrotic lymph nodes. However, they manifest in a similar way. Among them, we can mention peritonsillar abscess (PTA), periorbital cellulitis and abscess, pharyngitis, epiglottitis, supraglottitis, and DNSI (deep neck space infection). Usually, patients are subjected to medical and surgical treatments (intravenous broadspectrum antibiotics, or, when feasible, an incision is made, followed by drainage and aspiration), but what must be highlighted about this review is that, by incorporating corticosteroids as coadjutants, they minimize airway edema, lockjaw, and pain, simultaneously causing adverse effects, such as exacerbating infection and weakening the immune response, among other powerful complications in patients with possible systemic conditions or who are immunocompromised, thus creating controversy because of these unwanted manifestations [35]. The vast majority of studies suggest the following high doses for a short period of time, all administered intravenously (IV) [35]: Hydrocortisone at 200 to 1050 mg/daily; Dexamethasone at 8 to 10 mg/7 days; Methylprednisolone at 1 to 3 mg/kg/5–7 days (parapharyngeal abscess (IV); epiglottitis (IV); supraglottitis (IV). 2. Determine the appropriate dose to be administered in oral and maxillofacial surgery in adolescent and adult patients where there is or is not a manifestation of previous pathologies. Referring to the proper dosage when using corticosteroids, several factors must be considered: the doses, which must be specific to each patient depending on the pharmacokinetics of the different formulas; the possible presence of pathology or alteration that is suffered in the area of the body to be treated; the possible interactions of the drugs with non-steroidal agents and concomitantly administered steroids; and the patient’s response to treatment [36]. Various mechanisms are involved in the suppression of inflammation by corticosteroids, such as blocking the inflammatory process at an early stage or, in situations where the process is already well established, providing rapid resolution in favor of eliminating inflammation, highlighting the classification of the corticosteroids mentioned above. Below is a breakdown of the appropriate doses of the steroids used in oral and maxillofacial surgery, focusing on glucocorticoids, which are the preferred alternative (those with an intermediate effect and that are long-acting) to mineralocorticoids (Table 4) [37]. Table 4. Use of corticosteroids for temporomandibular joint (TMJ) conditions and other oral and maxillofacial injuries. The role of corticosteroids in today’s oral and maxillofacial surgery [2]. Drug Usual Dose Hydrocortisone (IV, IM, topical) 20 mg–240 mg/day Prednisone (orally) 5 mg–60 mg/day Prednisolone (orally) 5 mg–60 mg/day Methylprednisolone (orally, IV, IM) 10 mg–0 mg/day Triamcinolone (topical, orally) 10 mg–60 mg/day or 0.1 mg–0.3 mg Betamethasone (IV, IM, orally) 0.6 mg–7.2 mg/day Dexamethasone (IV, IM, orally) 0.75 mg–9.0 mg/day Dent. J. 2023,11, 239 16 of 20 meet the favorable systemic conditions for its use, is considered safe and effective for pain management, edema, inflammation, and lockjaw in oral and maxillofacial surgery. Studies in various populations show that considering the duration of administration, the route of administration, and the dose administered, the possible risks and side effects are limited. It should be noted that a recent study showed that the use of group B vitamins, administered intramuscularly as an adjuvant in corticosteroid therapy, showed an increase in the analgesic effect of a glucocorticoid in the population studied [10]. For decades, researchers have investigated the feasibility of the continued use of glucocorticoids and have found contrasting results regarding their safety. Likewise, regarding the pharmaceutical route of use, the intramuscular route of administration is one of the best choices since it has been proven to be more effective in reducing postsurgical pain and inflammation than the oral route, which is in contrast to other authors, who state that the oral route is their preferred alternative [10]. When we refer to the pathologies caused by cervicofacial infections, where the use of corticosteroids as an adjuvant to antibiotic therapy has begun to yield positive results, it is of great importance to know that, to carry out safe treatment and seek the best results, glucocorticoids should not be administered alone but rather always be accompanied by an antibiotic [35]. New trends are currently emerging, and these have identified a gene that generates the benefits of steroids without the appearance of side effects. Scientists have found that once the KLF15 gene (Krüppel-like factor 15) is activated, glucocorticoids frequently indicate improving muscular resistance and alleviating muscular dystrophy. This advance is especially important for diseases causing progressive muscle loss [54]. 5.1. Limitations The following are the limitations found when carrying out this systematic review: There are not enough articles that describe the effectiveness of the use of glucocorticoid therapy in populations between 16 and 65 years of age, either female or male. Systematic reviews need to be updated. Investigations into the newly emerging trends of therapies with glucocorticoids and adjuvants need to be carried out. 5.2. Future Perspectives The KLF15 transcription factor (Krüppel-like factor 15) is stimulated by glucagon and glucocorticoids, with this impulse occurring in the fasting state. However, insulin negatively regulates the expression of KLF15 under feeding conditions [54]. Skeletal muscle proactively regulates systemic nutrient homeostasis through transcriptional adjustments in response to physiological signals. These gene regulatory pathways are somewhat remarkable in their ability to serve in the treatment of metabolic diseases. Upon characterizing the KLF15 cistroma in vivo in skeletal muscle, it was evidenced that most of the binding of KLF15 takes place in distal intergenic regions and is linked to genes related to the circadian rhythm and lipid metabolism. We also identified the critical interdependence between KLF15 and the peroxisome-proliferator-activated receptors (PPAR δ ) nuclear receptor in the regulation of lipid metabolic gene programs. Furthermore, it was shown that KLF15 and PPAR δ are genome-wide, physically interrelated, and require each other to exert their transcriptional effects on target genes. This evidence indicates that KLF15 plays a vital role in metabolic adaptation through its activism on target genes and interactions with other nodal transcription factors such as PPARδ[54]. Inflammatory conditions, fibrosis, obesity, cardiovascular diseases, and cancer can be altered by factor KLF15. Knowing this information can aid in establishing the hidden molecular mechanisms behind the instigation of the gene transcription regulated by fasting, e.g., hepcidin’s role in the CRBN-KLF15 signaling pathway in hepatocytes [55]. Dent. J. 2023,11, 239 17 of 20 6. Conclusions Even though the information on the administration of corticosteroids is quite limited and, at the same time, somewhat controversial, it is necessary to recognize the success that most have achieved in assessments of their efficacy and high performance against inflammatory and immunological responses (even in cases of medical emergencies) in surgery, oral and maxillofacial surgery, and other health sciences in general. There is still profound uncertainty that surrounds health professionals today when trying to determine whether the adverse effects of the use of steroids could endanger the patient’s life or whether their use would provide benefits due to their anti-inflammatory and immunomodulatory properties when used in their proper doses. Studies have shown their ability to reduce morbidity, as well as the adverse effects that their prolonged use without a basis entails. It can be said that, for the most part, researchers promote the use of steroids, using the appropriate route of administration for each patient, as preventive, postoperative, or even maintenance therapy to prevent the recurrence or worsening of the injury or condition. In a certain way, due to certain systemic conditions in certain patients, the use of these hormones is a risk and is contraindicated, and alternative therapies that can be carried out with the greatest possible efficiency should be sought. The studies that were analyzed for cases of oral and maxillofacial surgeries mostly used dexamethasone (4–8 mg) as the main drug of choice, suggesting that the intramuscular route is more effective when seeking to attenuate unwanted clinical manifestations, such as facial edema, lockjaw, inflammation, and pain resulting from the intervention. For patients with cervicofacial infections, the use of high doses of corticosteroids (hydrocortisone (200 to 1050 mg); dexamethasone (8 to 10 mg); methylprednisolone (1 to 3 mg/kg), intravenously, in a short period of time at the same time as the administration of antibiotic therapy may be beneficial. Regarding the population between 10 and 16 years of age, no studies were found that could determine or provide clarity on whether the use of glucocorticoids is effective and safe in major surgeries of the oral cavity, facial skeleton, and cervical structures in this population. It should be noted that, in the population of adolescents and young adults in an age range of (10–16) or (18–35), postsurgical manifestations are subject to the duration of the surgery and whether an osteotomy is performed. It is vitally important to understand that once corticosteroid therapy has started, it cannot be stopped abruptly since the production of cortisol managed by the adrenal glands is diminished or practically stopped, which implies that the use of corticosteroids must be gradually withdrawn until the glands can once again begin to produce cortisol on their own. The use of these drugs provides the advantage that they can be used alone or combined with other medications for optimization and better results in terms of disease control and patient recovery. Nevertheless, it must be known that the interaction of glucocorticoids with certain medications, such as Ritonavir, can lead to possible toxicity and cause iatrogenic Cushing’s syndrome. Author Contributions: Conceptualization, H.J.N. and A.C.; methodology, H.J.N. and J.F.-F.; software, H.J.N.; validation, J.F.-F., A.C., C.A.R. and D.R.; formal analysis, H.J.N.; investigation, H.J.N.; resources, H.J.N.; data curation, H.J.N.; writing—original draft preparation, H.J.N.; writing—review and editing, H.J.N.; visualization, H.J.N.; supervision, J.F.-F., A.C., C.A.R. and D.R.; project administration, H.J.N.; funding acquisition, H.J.N. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. Dent. 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