Do Corticosteroids Still Have a Role in the Management of Third Molar Surgery?

Surgical removal of impacted lower third molars is one of the most commonly performed surgical procedures in any dental surgery worldwide. Although it is a minor surgical procedure, the common sequelae, which are pain, swelling and trismus, can severely affect patients’ quality of life during the immediate post-operative period [1]. These sequelae arise as a result of tissue inflammatory process, with cardinal signs of inflammation that include pain (dolor), heat (calor), redness (rubor), swelling (tumor) and loss of function (function laesa) [2]. There are considerable variations from patient to patient in the occurrence and severity of the inflammatory symptoms.

In the past, many different approaches, including drains, laser therapy and medications with enzymes, muscle relaxants or corticosteroids were clinically evaluated in an effort to minimize these post-operative sequelae [3‐6]. The last agent, namely the corticosteroids, have shown promising results. Corticosteroids are available as two main groups, the glucocorticoids and the mineralcorticoids. It is the glucocorticoids that are of interest here, because of their anti-inflammatory activities with little or no effect on fluid and electrolyte balance. The term corticosteroids will subsequently be used in this study to denote the former group of agents.

Corticosteroids are a class of chemicals that includes natural steroid hormones that are produced in the adrenal cortex of vertebrates as well as the synthetic analogues of these hormones. They are 21 carbon compounds having a cyclopentanoperhydro-phenanthene (steroid) nucleus and were first purified by Dr. William C. Kendall, who later on, together with Drs. Phillip S. Hench and Tadeus Reichstein, won a Nobel Prize for Physiology or Medicine. In 1948, Hench et al. successfully used cortisone and adrenocorticotropic (corticotropine) hormone to reduce the inflammatory process of rheumatoid arthritis [7]. Following this success, various other forms of corticosteroids have been synthesized as scientists found that the biologic properties of corticosteroids can be altered quantitatively and selectively by the substitution of certain chemical groupings and by minor configurational changes in molecular structure [3].

Dehydrogenation at the 1 position of the steroid nucleus gave rise to prednisone and prednisolone. This increased anti-inflammatory activity four to five times. During 1957, Arth et al. synthesized dexamethasone (9-alpha-fluoro, 16-alpha-methylprednisolone) which is a synthetic analogue of methylprednisolone in which a methyl group has been added at the carbon 16 position and a fluorine atom at the carbon 9 position [8, 9]. The addition of fluorine at the carbon 9 position greatly enhances the anti-inflammatory activity of the new compound. Dexamethasone has a milligram activity 5–10 times of predisone and prednisolone, and 30 times that of cortisone [10].

Corticosteroids are classified according to their duration of action. Short-acting glucocorticoids include cortisol (hydrocortisone) and cortisone, with duration of action less than 12 h and anti-inflammatory potency of 1. Intermediate acting glucocorticoids have duration of action of 12–36 h. They include prednisone and prednisolone with anti-inflammatory potency of 4, and 6-methylprednisolone and triamcinolone, both having anti-inflammatory potency of 5. Dexamethasone and betamethasone are long-acting glucocorticoids, with duration of action greater than 36 h and anti-inflammatory potency of 25 (Table 1) [11].

As seen in Table 1, to obtain a similar effect of 10 mg prednisolone, one needs to prescribe 8 mg methylprednisolone, 50 mg cortisone, 40 mg hydrocortisone (cortisol), or 1.5 mg betamethasone or dexamethasone. These doses are twice the equivalent to the physiological output of cortisol by the adrenal cortex in an average individual during an average day [12].

Corticosteroids reduce inflammation via the inhibition of phospholipase A2, which is the first enzyme involved in the conversion of phospholipids into arachidonic acid, therefore blocking the synthesis of other products such as prostaglandins, leukotrienes and substances related to thromboxane A2 [13]. In essence, corticosteroids stop the formation of these end products which is a broth of potent inflammatory mediators that causes the signs and symptoms described above [2]. They also have the ability to stabilize lysozyme membranes, decrease the release of inflammation-causing lysozymes, and decrease the permeability of capillary which thus prevents diapedesis, i.e. the initial leakage of fluids from the capillaries and loss of plasma protein into tissue space [3, 11]. There is also a decrease in the formation of bradykinin, a powerful vasodilating substance [3].

Strean is credited with publishing a paper which represented the first scientific approach to the general use of corticosteroids in dentistry [14]. Both Strean (together with colleague, Horton) and Spies et al. were the first to use (hydro)cortisone for the treatment of oral diseases related to local causes and oral manifestations of inflammatory systemic disease [15, 16]. However, it was an editorial by Kenny that first suggested the use of steroids for managing post-operative sequalae [17]. Following that, Ross and White confirmed this anti-inflammatory effect by using oral hydrocortisone against placebo in a double blind study involving third molar surgeries [18]. Since then, the use of corticosteroids for third molar surgery had been studied extensively in different formulations, dosings, routes and sites of administration. These corticosteroids include dexamethasone (per oral/p.o.), dexamethasone acetate (intramuscular), dexamethasone sodium phosphate (intravenous and intramuscular), methylprednisolone (p.o.), and methylprednisolone acetate and methylprednisolone sodium succinate (both intravenous and intramuscular) [19]. An attempt at undertaking a systematic review on the use of corticosteroids up to September 2011 by Herrera-Briones et al. turned into a narrative review due to the heterogeneity of many study designs, outcome measures, and routes of drug administration [20, 21]. Hence, this study does not attempt to replicate their work, but instead tries to answer some questions that arose from the systematic analysis. Quite a number of new reports have been published over the last 5 years, and we believe that some of them are able to address questions relating to the magnitude of the decrease in the clinical symptoms on the patients’ quality of life, the timing of drug administration, the efficacy of administrating into the masseter muscle as compared other sites of intramuscular administration, and the effect of enteral intake versus parenteral routes. This article aims to review only studies that were carried out in the past decade in an attempt to determine any consistent effects of corticosteroids on swelling, pain and trismus with the objective of answering the following questions:

We performed this review in the spirit of summarizing important facts and findings from various relevant studies and literature to provide a state of the art update on the use of corticosteroids in third molar surgery. The methodology used in this study is an adaptation from the protocol used by Ata-Ali et al. [13]. A Pubmed, Medline, EMBASE and Google search was undertaken of all controlled clinical trials on the effects of corticosteroids on pain, swelling and trismus after lower third molar surgery. The review was limited to studies published over the last 10 years (2006–2015). This review included only articles that compared the use of corticosteroids in any formulation, dose and route/site with another corticosteroid or negative/placebo control group. Articles were excluded if they contributed unclear data on the patient selection, treatment, route of administration, dose and surgical procedure, measurement of sequalae or inadequate data on outcomes. Articles that compared corticosteroids with other drugs, intervention or treatment were excluded, except when the corticosteroid was administered with an adjuvant therapy related to third molar surgery, namely an antibiotic. A total of 34 articles were finally included (Tables 2, 3, 4), with documentation of the following from each of them: year of publication, number of patients in the study and control groups, corticosteroids administered, dosage, route and timing of administration, analgesic efficacy, anti-swelling effect, and effect on trismus.

During the past 10 years, the commonly studied corticosteroids for use in third molar surgery were dexamethasone (17 reports), methylprednisolone (10 reports), prednisolone (2 reports) and betamethasone (1 report). Four other studies compared two different steroids. Corticosteroids had been administered via various routes that included intravenous, intramuscular (masseter, deltoid or gluteus), submucosal, endo-alveolar and oral.

Altogether, this review found that a single administration of corticosteroids was often effective in reducing post-operative pain, swelling and trimus, in contrast to previous reports that emphasized the need for pulse therapy or a longer duration of dosing to extend the benefits of the drug [12, 19, 52]. Although doses of corticosteroids will usually clear the blood stream in less than 24 h, the immunosuppresive anti inflammatory effects may persist up to 3 days, thus explaining why even a single dose is adequate for third molar surgery [59]. However, there have been three reports that found that corticosteroids were not better than negative control [32, 40, 44]. One possible explanation as to why these studies found that negative control was equally as good is possibly because the patients were stimulated through the hypothalamic-pituitary-adrenocortical pathways to increase their secretion of steroids, mostly hydrocortisone, during third molar surgery [59]. Another reason is the suboptimal dose provided, as reported by Kang et al. [44]. One way to determine the level of corticosteroids in the body is to measure them; another way is by checking the peripheral eosinophil count, as a study by Thorn et al. found that a fall in the peripheral eosinophil count is one of the most significant effects of cortisones on the cellular elements of the blood [60]. The magnitude of the fall varied with the dosage and route of administration. Ross and White reported the monitoring of peripheral eosinophil counts in their third molar study in 1958 [18], but no other researchers have done so since then. They reported an interesting fact discovered in the control group in which 6 patients (out of 22) were found to have a better than 50% reduction in their eosinophil counts, and, interestingly enough, all of these patients fell in the moderate edema group. This suggested that those patients produced excessive corticosteroids as a reaction to the trauma of surgery, hence resulting in less facial swelling.

Hydrocortisone (cortisol) is the natural corticosteroid produced by the body, with normal daily production in a normal adult being between 15 and 30 mg, but up to 300 mg can be supplied in times of crisis [12, 59, 61]. To achieve an anti inflammatory effect, corticosteroids have to be given at higher doses, above the basal secretion. However, there was not one single study that can answer the question on the best dosage, best route of administration and best time to provide corticosteroids. One fact that remains certain is that Kang et al. [44] in 2010 showed that prednisolone in doses of less than 20 mg was not effective. Therefore, a higher dose is suggested for clinical use. There follows a detailed discussion on the route of administration, dosage, and timing of the surgery, as well as the effects of corticosteroids on swelling, trismus and pain.

From these studies, it can be summarized that the use of corticosteroids in third molar surgery appears promising in reducing post-operative discomforts or sequelae. Fourteen studies reported the benefit of corticosteroids on all 3 sequelae, with 71.4% resulting from methylprednisolone use. It is almost certain that swelling and to some extent trismus will be significantly reduced with the use of corticosteroids. It appears that the potential analgesic effect of corticosteroids holds promise to enhance their further acceptance into routine dental practice, although their role in pain control remains debatable. More studies should therefore be carried out to confirm if the analgesic effect results from the synergistic effects with NSAIDs and/or local anesthetic agents. Assessment of the sequelae should be done with more accurate and precise assessment tools so that the results of these future studies will have an impact on the best route and corticosteroids to be used, taking into consideration its efficacy and side effects as well as cost and whether its usage is economically feasible to be adopted in routine practice.