sdarticle (2)

The use of corticosteroids and nonsteroidal antiinflammatorymedication for the management of pain and inflammationafter third molar surgery: A review of the literatureKing Kim, DMD,a Pardeep Brar, DMD,b Jesse Jakubowski,c Steven Kaltman, DMD, MD,d andEustorgio Lopez, DDS, MD,e Fort Lauderdale, FloridaDEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY, NOVA SOUTHEASTERNUNIVERSITY/BROWARD GENERAL MEDICAL CENTER

The use of medication to relieve pain and inflammation after removal of third molars has been exploredthoroughly in the literature. Narcotic analgesics, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, andcombinations of these all have a role in the postoperative management of pain and swelling within this group ofpatients. This article addresses the use of NSAIDs and corticosteroids after third molar surgery, along with a review ofthe literature, which is incorporated to provide practitioners helpful, quick, and reliable information regarding patients
undergoing third molar surgery. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:630-640)
The use of steroids in oral surgical procedures maypresent as an area of ambiguity for many practitioners.Some practitioners may consider the use of steroidsonly as a supplement in patients undergoing extensiveoral surgery procedures, but steroids such as dexameth-asone can be a valuable tool when performing moderateto moderately severe oral surgical procedures. The useof corticosteroids can decrease the severity of postop-erative sequelae in many patients and therefore de-crease morbidity after oral surgery. Many studies havedetermined the effectiveness of steroids after oral sur-gical procedures, but currently there is no standarddosing regimen for oral and maxillofacial surgeons tofollow.1 Most practitioners follow an empiric dosingstrategy that is often inadequate and provides a sub-therapeutic effect.

The objective of this review article is to provideinformation to oral and maxillofacial surgeons on thecauses of the common postoperative sequelae afterthird molar surgery, the mechanism of action of corti-costeroids, the use of nonsteroidal antiinflammatorydrugs (NSAIDs), a review of the literature evaluatingthe use of corticosteroids, the adverse effects and con-traindications of use with corticosteroids, and recom-

aChief Resident.bPrivate practice, Seattle, Washington.cDental student.dChairman.eDirector.Received for publication May 21, 2008; returned for revision Sep 30,2008; accepted for publication Nov 10, 2008.1079-2104/$ - see front matter© 2009 Published by Mosby, Inc.
doi:10.1016/j.tripleo.2008.11.005
630

mendations for the appropriate use of corticosteroidsafter dentoalveolar surgery.

COMMON POSTOPERATIVE SEQUELAE ANDCAUSES OF POSTOPERATIVE SEQUELAEAFTER ORAL SURGERY

Oral surgical procedures can vary in difficulty and inthe degree of trauma caused to the surrounding tissue.As the oral and maxillofacial surgeon performs a moreinvasive or difficult procedure, there will be an in-creased amount of trauma to the surgical site as well asto the surrounding tissues. The greater amount of tissueinjury leads to an increased amount of inflammation inthe perisurgical area. Swelling may be particularly sig-nificant when the surgery is prolonged and when largeamounts of bone, gingiva, and oral mucosa are manip-ulated. Careful surgical technique is effective in limit-ing tissue damage and swelling; therefore, attentionshould be taken to avoid prolonged periods of tissueelevation and retraction.

The classic signs of inflammation, which includepain, edema, erythema, and loss of function, commonlyoccur after routine or difficult surgical procedures. Theinflammatory process is necessary if healing is to occur,but often excessive inflammation causes the patientunnecessary pain, edema, and trismus. There are manymediators of inflammation, which include prostaglan-dins (PGs), histamine, bradykinin, and serotonin. Pros-taglandin and histamine levels are known to becomeelevated during inflammation.2 Bradykinin has a widespectrum of proinflammatory pharmacology, includingpotent pain-producing properties.3

Prostaglandins are derived from the precursor ara-
chidonic acid. Arachidonic acid is a major component

OOOOEVolume 107, Number 5 Kim et al. 631

of mammalian cell membrane phospholipids and isreleased from these phospholipids via cellular phospho-lipases that have been activated by mechanical, chem-ical, or physical stimuli. Arachidonic acid metabolismcan proceed along 1 of 2 major pathways: the cyclo-oxygenase pathway or the lipooxygenase pathway. Thecyclooxygenase pathway is responsible for providingPGE2,PGD2, PGF2�, PGI2, and thromboxane (TX) A2.The lipooxygenase pathway leads to the formation of afamily of compounds collectively called leukotrienes.The end products of these 2 pathways have a centralrole in the inflammatory processes occurring in injuredtissue. Agents such as aspirin or NSAIDs can suppressthe cyclooxygenase pathway, whereas glucocorticoidsmay act by inhibiting the activity of phospholipase A2,

thereby preventing the formation of the end products ofboth pathways.

NSAID USE FOR THE MANAGEMENT OFPAIN AND INFLAMMATION AFTER ORALSURGERY

NSAIDs decrease inflammation and fever while pro-viding analgesia by inhibiting the cyclooxygenase(COX) enzymes COX-1 and COX-2, important en-zymes which are needed for the production of inflam-matory mediators such as prostaglandins, prostacyclins,and thromboxanes. Refer to Fig. 1 to review the actionsof the COX-1 and COX-2 enzymes.

Preoperative administration of NSAIDs has been in-vestigated to determine efficacy in third molar oralsurgery patients. Some of the results of the studiesinclude delays in the onset of pain after surgery, de-creased peak pain intensity, and decreased postopera-tive swelling.5 These findings have special significanceconcerning the sequelae from surgical trauma, because

Fig. 1. Arachidonic acid cascade.4

the preoperative NSAID dose could decrease the

amount of postoperative analgesics needed, especiallymedications containing opiates, which tend to produceundesirable side effects.5 In addition, studies haveshown that an appropriate NSAID regimen may be allthat is required to manage postoperative pain. NSAIDshave been shown to provide an acceptable therapeuticoption for pain relief with fewer adverse effects thanthe opioid-analgesic combination drugs.6 Also, themany investigations done with management of acuteoral surgical pain in oral surgery patients indicate thata single dose of an NSAID is more effective thancombinations of aspirin or acetaminophen with an opi-oid, with fewer side effects.6

The side effects associated with the use of NSAIDsare numerous, but primarily they are related to gastro-intestinal (GI), hematologic, and renal disorders, aswell as the propensity to cause skin and mucosal reac-tions.7 It should be noted that most of the manifesta-tions of these adverse effects occur with chronic dosingof NSAIDs. Therefore, over a long period of time, thecontinuous inhibition of the COX enzymes becomesincreasingly significant.

The most profound adverse effect of the prolongeduse of traditional NSAIDs is GI disturbance. Becausethis class of drugs blocks both COX enzymes, thegastric protective functions produced from prostaglan-dins produced by the COX-1 enzyme are not present.This makes the GI tract susceptible to GI ulcers, dys-pepsia, and gastric bleeding.4 It has been found thatgastric and duodenal ulcers are prevalent (15%-30% ofpatients) at endoscopy in patients taking NSAIDs on aregular basis.8 Risk factors that have been associatedwith NSAIDs involve upper GI disturbances. Theseinclude previous ulcer or upper GI event, increasingage, concomitant anticoagulation, concomitant steroid
use, and the use of high dose or multiple NSAID use.8

OOOOE632 Kim et al. May 2009

Another adverse effect of NSAID use is increasedbleeding risk intraoperatively and postoperatively. Theinhibition of COX-1 in platelets by conventionalNSAIDs results in modulation of platelet function lead-ing to prolonged bleeding.9 This effect is longer lastingin aspirin compared with other NSAIDs, because aspi-rin irreversibly acetylates COX in the nonnucleatedplatelet.10 Studies suggest that most conventionalNSAIDs are associated with reduced platelet aggrega-tion in response to arachidonate and collagen and thatthere is a subsequent increase in bleeding time.9 Atheoretic concern is the fact that this prolongation ofbleeding time can promote intraoperative and postop-erative hemorrhage in dental surgical patients.10

The renal side effects of NSAIDs are also wellknown and equally concerning. Normal renal functionis partly dependent on prostaglandin synthesis, and it isbelieved that both COX-1 and COX-2 are important inproducing prostaglandins involved in reducing waterand sodium reabsorption which maintains proper dila-tion of the renal vasculature. With NSAID therapy,dose-dependent water and sodium retention manifestedby peripheral edema, elevation in blood pressure, andrarely congestive heart failure are thought to follow theinhibition of PGE2 synthesis.10 These NSAIDs are mostfrequently associated with a transient imbalance ofelectolyte and water levels that is generally mild inmost patients.9 It is estimated that serious renal prob-lems requiring hospitalization occur in 0.5%-1.0% oflong-term NSAID users.10

The use of NSAIDs in third molar surgery is welldocumented in the literature. There are numerous stud-ies which compare NSAIDs to other NSAIDs, NSAIDsto glucocorticoids, and NSAIDs to opioid analgesics. Inaddition, comparisons are made regarding routes ofadministration, timing of administration, and dosage.Common drugs which have been investigated include:ibuprofen, diclofenac, tramadol, ketorolac, and lomoxi-cam. Table I summarizes relevant studies in usingNSAIDs for patients undergoing third molar surgery.Table II compares the most commonly used NSAIDs.

MECHANISM OF ACTION OFGLUCOCORTICOIDS

The glucocorticoids are synthesized in the cortex ofthe adrenal gland. Glucocorticoids are corticosteroidswith a relatively greater effect on carbohydrate metab-olism than on water and electrolyte regulation. Despitethe name “glucocorticoid,” they have a very broadrange of effects on many metabolic activities. Glu-cocorticoid receptors are found in virtually every cell ofthe body and exert a wide range of physiologic actions
affecting virtually every organ system.
Glucocorticoids activate specific intracellular recep-tors after diffusing through target cell membranes. Areceptor-steroid complex is translocated to the cell nu-cleus and acts as a transcription factor for specific genesto either stimulate or inhibit their expression. It is at thiscellular level in which regulatory effects on the immunesystem, including effects on cytokines, are accom-plished. As a consequence of the time required forchanges in gene expression and de novo protein syn-thesis, most effects of corticosteroids are not immedi-ate, but become apparent after several hours. This factis of clinical significance, because a delay generally isseen before the beneficial effects of corticosteroid ther-apy become manifest.23

Suppression of each stage of the inflammatory re-sponse appears to be the major action of the glucocor-ticoids. There is a decrease in capillary dilatation, leu-kocyte migration, and phagocytosis, a decrease in thetotal number of circulating lymphocytes, basophils, eo-sinophils, and monocytes, and an inhibition of the for-mation of granulation tissue by retarding fibroblastproliferation and collagen synthesis. Their major role inreducing the inflammatory response is to inhibit theproduction of vasoactive substances such as prostaglan-dins and leukotrienes, as well as decreasing the numberof chemical attractants such as cytokines. There is alsoa generalized reduction in the secretion of lipolytic andproteolytic enzymes such as phospholipase, collage-nase, and elastase.

Glucocorticoids also stimulate the production of li-pocortin, which is an inhibitory protein of phospho-lipase A2. The inhibition of phospholipase A2 leads toa reduction in prostaglandins and leukotrienes. In ad-dition glucocorticoids inhibit the synthesis of COXwith a resultant inhibition of PGE2 and PGI2. The useof steroids is not curative, but palliative, and the aim isto decrease the severity of the symptoms a patient isanticipated to experience.23

ADVERSE EFFECTS AND CONTRAINDICATIONSTO GLUCOCORTICOID USE IN ORAL SURGERY

The potential for adverse effects with the use ofglucocorticoids depends on the intensity and durationof therapy. A single large dose or a short duration oftherapy causes few adverse effects. If therapy with aglucocorticoid is prescribed for �1 week, some signsof steroid toxicity may be seen as well as signs ofhypothalamic-pituitary-adrenal (HPA) axis suppres-sion. Adverse effects that are seen with glucocorticoidscorrelate with the dose and duration of therapy. Someadverse effects that can be seen include hyperglycemiaand glycosuria, myopathy, osteoporosis and osteone-crosis, suppression of growth, negative nitrogen bal-
ance, peptic ulcer, ocular effects, CNS effects, edema


Table I. Summary of several studies investigating the use of NSAIDs in oral surgery

Ref.No. of

patientsType ofsurgery Treatment groups Results Side effects

11 119 Removal ofbilateralimpactedthirdmolars

1. Ibuprofen 600 mg.2. Diclofenac 100 mg.3. Paracetamol 1 g with

codeine 60 mg.4. Placebo.

All given PO 1 h beforesurgery.

There was no significant differencein the extent of postoperativepain among the 4 groups, but theplacebo group had significantlyshorter times before their firstrequest for postoperativeanalgesics (median 17 min, range14-90 min) than the diclofenacgroup (median 32 min, range15-150 min).

There were, however, some side-effects, including nausea,vomiting, headaches, andgastrointestinal discomfort, butthere were no significantdifferences among the activeanalgesic groups regarding adverseevents either shortly afteroperation or at 6 or 24 h.


1. Preop (1 h before)diclofenac sodium 100mg.

2. Postop (immediatelyafter) diclofenac sodium100 mg.All given PO.

Patients served as their own controlgroup. Pain scores and mouthopening were observed for 1week after the operation and didnot show any differences.

No information regarding side effectspresented.


1. Diflunisal 1000 mg.2. Lornoxicam 16 mg.


Patients served as their own controlgroup. No statistically significantdifferences were found betweengroups regarding rescueanalgesic consumption andpostoperative pain scores.Preemptive administration ofboth NSAIDs proved to beeffective in the management ofpain after the surgical removal ofimpacted third molar teeth.

Side effects, including nausea,vomiting, allergy, andgastrointestinal adverse effects,were recorded.


1. 50 mg rofecoxib.2. 400 mg ibuprofen.3. Placebo.


There were no significant analgesicdifferences between rofecoxiband ibuprofen at any timeintervals after surgery. Rescuemedication use was significantlylower in the rofecoxib andibuprofen groups compared withthe placebo group; however,there was no significantdifference between the 2therapeutic groups.

No information was collectedregarding any possible side effectsof the medication.


1. IV ketorolac 30 mg, 30min before surgery withplacebo injection aftersurgery.

2. Placebo injection, 30 minbefore surgery and post-treated with IV ketorolac30 mg.

Patients served as their own controlgroup . Patients reportedsignificantly lower pain intensityscores in the ketorolac pretreatedsides compared with the post-treated sides (P � .003). Patientsalso reported a significantlylonger time to rescue analgesic(8.9 h vs. 6.9 h; P � .005), lesspostoperative analgesicconsumption (P � .007), andbetter global assessment for theketorolac-pretreated sides (P �.01). Pretreatment with IVketorolac has a preemptive effectfor postoperative third molarsurgery and extended the


analgesia by approximately 2 h.


Table I. Continued

Ref.No. of

patientsType ofsurgery Treatment groups Results Side effects

16 60 Removal ofbilateral

impactedthird

molars

1. Tramadol preop 100 mgIM 1 h before surgery.

2. Tramadol postop 100 mgIM immediately aftersurgery.

3. Saline before surgery.

The analgesic efficacy measured ascomplete relief of pain at 24 hwas 86% in the preemptivetramadol compared with 70%and 36% for postoperativetramadol administration andcontrol group. A significantreduction in the consumption ofanalgesics was seen inpreoperative group comparedwith the postoperative andcontrol groups.

Adverse events, such as drowsiness,dizziness, or nausea, were reportedequally across groups.


impactedthird

molars

1. Preop ibuprofen (400mg).

2. Preop codeine phosphate(30 mg).

3. Preop ibuprofen/codeine(400 mg/30 mg),

4. Preop placebo.5. Postop single doses of the

same combination ordiflunisal (250 mg).

Patients receiving the combinationor ibuprofen before surgery tooksignificantly longer betweensurgery completion and needingthe postoperative study treatmentthan patients receiving codeinephosphate or placebo. At 1.5-2 hafter postoperativeadministration, patients receivingthe combination after surgeryreported significantly greaterdecreases in pain severity thanthose receiving diflunisal.Patients taking the combinationafter surgery experiencedsignificantly better pain reliefthan patients taking diflunisal at1 and 2 h, but the reverse wastrue at 5 h.

�Side-effects reported were mild,with no significant differencesbetween the different treatmentgroups.


impactedlowerthird

molars

1. Immediate postopprednisolone 25 mg IM.

2. Immediate postopprednisolone 25 mg IM �diclofenac 100 mg IM.

3. Immediate postop placeboIM.

Groups 1 and 2 suppressed pain atthe 7th postoperative hourcompared with control. Groups 1and 2 also had less postoperativeswelling compared with controlat postoperative day 2. Group 2had a smaller loss of mouthopening at days 2 and 7compared with groups 1 and 3.Group 2 had less swelling atpostoperative day 7 than groups1 and 3.


19 72 Removal ofsingle

impactedlowerthirdmolar

1. 50 mg rapid-releasetablet, 100 mg sustained-release tablet ofdiclofenac, and 40 mg IVmethylprednisolone.

2. 50 mg rapid-releasetablet, 100 mg sustained-release tablet ofdiclofenac, and 40 mg IVsaline.All given 20 min beforesurgery.

Double-blind, randomized, placebo-controlled study. IV administrationof methylprednisolone in additionto PO diclofenac before surgerygave statistically significant (P �.05) greater pain relief thandiclofenac alone for the first 4 h.There was no significantdifference after the first 4 h orduring the 2 days after surgery.The need for additional analgesicsduring the day of operation andthe 2 days after was less in themethylprednisolone � diclofenacgroup than in the diclofenacgroup. Maximal mouth openingwas equally decrease in bothgroups from a mean of 50 mm to

Number of side effects recorded waslow in both groups.

36 mm

antiinfl


and hyperkalemia, altered distribution of body fat, in-creased susceptibility to infection, suppression of pitu-itary and adrenal function, and poor wound healing.24

These effects are most commonly seen with long-termglucocorticosteroid therapy and are very rarely seenwhen administering steroids for �5 days.

There is, however, a very unusual side effect whichhas been documented to affect patients immediatelyafter administration of intravenous dexamethasone.This side effect is perineal pruritis. This side effect hasa female predilection, lasts 30-45 s, and has been shownto occur with dosages between 6-8 mg.25-27 The mech-anism of this phenomenon is poorly understood. Onehypothesis is that the perineal itching and burning isrelated to the phosphate ester of dexamethasone, be-cause the same perineal irritation has been described

Table I. Continued

Ref.No. of

patientsType ofsurgery Treatment groups

20 40 Removal of4symmetricalimpactedthirdmolars

1. 32 mgmethylprednisolone 12 hbefore and 12 h aftersurgery and 400 mgibuprofen the day ofsurgery and the 2 daysfollowing, 3�/day.

2. Placebo of identicalappearance.

Pa

21 30 Removal of4 thirdmolars

1. 50 mg either diclofenacor placebo before surgery.

2. 50 mg diclofenac and 10mg prednisolone orplacebo before surgery

Pr

Table II. Comparison of the most commonly used NS

DrugReccomended adult

dosage (mg)

Ibuprofen 200-400 q 4-6 hDiclofenac 50 q 8 hDiflunisol Initial 500-1000 then 250-500 q 8-12 hRofecoxib Initial 50 then 25 qdKetorolac 10 q 4-6 hAspirin 325-650 q 4-6 hAcetaminophen 325-650 q 4-6 hNaproxen Initial 500 then 250 q 6-8 h

with hydrocortisone-21-phosphate and prednisolone

phosphate. Treatment of this side effect is administra-tion of dexamethasone diluted in 50 mL fluid over 5-10minutes.28

The HPA axis suppression was investigated by Wil-liamson et al.29 by administering 8 mg dexamethasoneto patients undergoing the removal of impacted thirdmolar teeth. A significant difference was found be-tween preoperative values of 11-deoxycortisol and val-ues 3 days after surgery. No difference was found whencomparing preoperative values of 11-deoxycortisolwith values 7 days after surgery. An initial suppressionof the normal feedback mechanism of the HPA axiswas observed, and this was followed by a completereturn of normal functioning by the seventh postoper-ative day.

Systemic and topical glucocorticoids are absolutely

Results Side effects

erved as their own controlAfter use of ibuprofen/prednisolone, ultrasonication showed a reductionling of 56% (P � .001)ed with the placebomeasurement with a tapee showed a 58% (P �duction in swelling. Thenalog scale showed a

on of 67.7% inrative pain comparedacebo.

Side-effects reported were mild, withmore seen in placebo group.

ive administration of 50lofenac could relieve painelling more than the. Additional 10 mgolone could further reduceg. The combination ofnac and prednisolone has

analgesic andammatory effect.

No side effects were recorded

9,22

mum dailyage (mg)

Duration ofaction (h)

Onset ofaction (h)

Plasmahalf-life (h)

1,200 4-6 .5-1 2-4150 4-6 1.5-2 1-1.5

1,500 8-12 �1 8-1275 24 2-3 1740 6-8 �10 min 2-6

4,000 4-6 20-30 min 3-64,000 4-6 �1 1-31,250 �7 1 12-17

tients sgroup.methylexaminin swelcompargroup;measur.001) revisual areductipostopewith pleoperatmg dicand swplaceboprednisswellindiclofea better

AIDsMaxi

dos

contraindicated in patients with ocular herpes simplex,


primary glaucoma, healed or incompletely healed tu-berculosis, or acute psychosis. Relative contraindica-tions include Cushing syndrome, diverticulitis, recentintestinal anastomosis, active or latent peptic ulcer,renal insufficiency, hypertension, diabetes mellitus, os-teoporosis, myasthenia gravis, psychotic tendencies,and acute or long-standing infections.29 It is clear fromthe list of adverse effects and contraindications that therisk/benefit ratio of steroid use must be consideredbefore initiation of therapy.2

REVIEW OF LITERATURESeveral studies have been conducted to evaluate the

efficacy of corticosteroids in reducing the postsurgicalsequelae experienced after oral surgical procedures,particularly after the removal of impacted third molarteeth. The literature contains studies that have usedmethylprednisolone, betamethasone, and dexametha-sone at various dosages and routes of administration. Asummary of the results of these studies can be viewedin Table III.

Huffman30 in 1977 administered 40 mg and 125 mgdoses of methylprednisolone intravenously before theremoval of bilaterally impacted maxillary and mandib-ular third molar teeth. Subjective criteria were used toevaluate the patients 24 h, 48 h, and 7 days aftersurgery. There was a statistically significant reductionin the postoperative edema in those patients givenmethyprednisolone at both 24 and 48 h. There wassome reduction in postoperative edema associated withan increase in dose from 40 to 125 mg, although thisfinding was not statistically significant. Minimal edemastill developed in the cases that used steroids.

Braxendale et al.31 gave patients 8 mg dexametha-sone or placebo orally 2 h before surgery. Patients inthe dexamethasone group had significantly lower painscores 4 h after surgery than the placebo group. Therewas no significant difference between the groups on thefirst postoperative morning. Pain was reported using avisual analog scale.

Beirne and Hollander32 found a significant reductionin pain and swelling, but not trismus, after the admin-istration of 125 mg methylprednisolone administeredintravenously. Swelling was measured using photo-graphic and face-bow techniques. Pain was measuredby the number of pain pills that the patient reportedbeing used. The patients in the experimental groupreported less pain on the day of surgery than the controlgroup. On the day after surgery there was no statisti-cally significant difference between the pain reports inthe 2 groups. The patients in the experimental groupused significantly less medication on the day of surgerythan the control group, but the 2 groups showed no
significant differences in the total number of pain pills
taken after surgery. Facial swelling was significantlyreduced in the experimental group when measured bythe photographic and face-bow techniques on the dayfollowing surgery. The experimental group had an in-crease in swelling on the second and third days ofsurgery, but this remained less than the swelling in thecontrol group.

Schmelzeisen and Frolich33 in 1992 investigated theuse of 6 mg dexamethasone given orally once 12 hbefore and once 12 h after osteotomy of 2 impactedthird molar teeth. On the first day after surgery thedifference in cheek swelling was 54.3% as measured bytape, 46% measured with a gauge, and 29% measuredby sonographic measurement of the cheek diameter inthe first molar area. Limitation in jaw opening wasreduced in the experimental group by 17.7%. Pain asassessed by visual analog scale was reduction by about50% in the dexamethasone group. The amount of an-algesics required after surgery was reduced by 37%with dexamethasone administration. The effect of thedrug was most pronounced on the first postoperativeday, when most of the swelling occurs, and the effectwas less obvious as the swelling subsided.

Skjelbred and Lokken34 injected 9 mg betametha-sone intramuscularly. Patients were evaluated on thethird and sixth postoperative days, with a reduction inswelling of 55% and 69%, respectively. Measurementswere made using a mechanical device. Pain assess-ments made with a visual analog scale were signifi-cantly lower in the steroid group.

Neupert et al.35 evaluated the use of 4 mg dexameth-asone given intravenously in 60 patients. No differ-ences in swelling and daily pain were noted, but trismusand global pain were significantly affected by the ste-roid. This study may have used a subtherapeutic dose,and the method used to measure swelling may lacksensitivity.

Schaberg et al.36 evaluated the effectiveness of meth-ylprednisolone for the reduction of postoperative facialedema in 39 patients who underwent either a Le Fort Iosteotomy or a transoral vertical osteotomy. Patientswere evaluated by computerized tomographic examina-tion performed preoperatively and at 24 and 72 h aftersurgery. Le Fort I osteotomy patients receiving meth-ylprednisolone had a reduction in facial edema by 61%at 24 h after surgery, and 10% at 72 h postoperatively.Patients undergoing transoral vertical osteotomy had areduction in facial edema by 38% at 24 h and 45% at72 h after surgery.

In a prospective, randomized, controlled, double-blind study of 61 patients, Dionne et al.41 demonstratedthat preoperative dosing of dexamethasone in the thirdmolar oral surgery model reduced inflammation during
the postoperative period but was insufficient as an

e surge


analgesic. It was shown, however, that postoperativeadministration of intravenous ketorolac suppressed the

Table III. Summary of results of several studies that hasurgical procedures

ReferenceNo. of

patients Type of surgery Treatment admini

30 129 Removal of bilateralimpacted third

molars

1. Placebo (n � 44).2. MP 40 mg (n � 43. MP 125 mg (n �

IV immediately besurgery.


molars

1.2 mg BM PO on thbefore surgery and thPO QID to a total of


molars

6 mg DM PO 12 hrssurgery and 6 mg DMafter surgery.


molars

1. 8 mg DM PO.2. Placebo.

Medication wasadministered 2 h bsurgery.


molars

9 mg BM IM before


molars

9 mg BM IM 3 h afte


molars

4 mg DM IV before


molars

16 mg MP PO eveninsurgery and 20 mg Mbefore surgery.


molars

1. 125 mg MP IV.2. Placebo IV.

Medications wereadministered befor

pain response and was effective in reducing both pain

and inflammation. This study used probes to quantifyand measure levels of inflammatory markers at the sites

estigated the use of corticosteroids before and after oral

Results

Reduction in postoperative edema in those patients given MP(P � .005 at both 24 and 48 h after surgery). There wassome reduction in postoperative edema associated with anincrease in dose, but this was not statistically significant.There was an insignificant difference between the 3 groupsat 7 days.

ngmgg.

Patients served as their own control group. The control grouphad 5.6 times as much edema as the BM group, and therewas a significant reduction in the requirement for painmedication in the BM group and less than one-half theamount of trismus in the BM group compared with thecontrol. 4% of the BM group developed alveolar osteitis.

hPatients served as their own control group. Decrease in

cheek swelling compared with control at 24 h was 54.3%(P � .001) as measured by tape, 46% (P � .001) by agauge in the first molar area, and 29% (P � .056) bysonographic measurement of cheek diameter. Limitation ofjaw opening was reduced by 17.7% (P � .002) after DM.Pain assessed by visual analog scale was reduced by 50%by DM (P � .01). 76% of patients preferred perioperativeDM over the control.

Pain scores after 4 h were significantly lower in the DMgroup (P � .005). There was no significant differencebetween the groups on the first postoperative morning.Significantly more patients had severe swelling andsignificantly fewer patients had mild swelling in theplacebo group compared with DM (P � .05). The %reduction in mouth opening was similar in both groups.

. Patients served as their own control group. The meanreduction in swelling on the third and sixth postoperativedays was 55% (P � .001) and 69% (P � .001),respectively. The mean reduction in mouth opening abilityfrom the preoperative state was 44% after placebo and23% after active drug (P � 0.001). Pain assessments werelower after the corticosteroid injection.

ry Patients served as their own control group. The meanreduction in swelling on the third and sixth postoperativedays was 47% and 14%, respectively. The mean reductionin mouth opening on the third postoperative day was 46%after placebo and 18% after active drug.

. Patients served as their own control group. No differences inswelling and daily pain. Trismus and global pain weresignificantly altered in the steroid group.

e Patients served as their own control group. Swelling wasreduced by 42% at 24 h and 34% at 48 h after surgery. Bythe third day the difference was only 19%. Trismus or theneed for analgesic medication was not affected by thisdose of MP.

ry.

Patients were assigned randomly to 2 treatment groups. Oneday after surgery, the MP group reported significantly lesspain than the control group (P � .05). The MP group hadsignificantly less swelling than the control group.

ve inv

stered

2).43).fore

e evenien 1.214.4 m

beforePO 12

efore

surgery

r surge

surgery

g beforP IV

of tissue injury (lower third molar extraction sites).

.


They showed that PGE2 and TXB2 levels were bothreduced in the patients treated with ketorolac, but onlyTXB2 levels were reduced in the dexamethasonegroup. They postulated that PGE2, the primary prosta-noid responsible for the peripheral pain response, wasnot suppressed adequately by dexamethasone to pre-vent the sensitization of peripheral nociceptors. Fur-thermore, the investigators proposed that dexametha-sone inhibits COX-1 associated with TXB2 productionin certain cell types and has little effect on inhibitingCOX-1 PGE2 production in other cell types. Ketorolacsuppressing peripheral PGE2 levels and pain greaterthan dexamethasone also may indicate that PGE2 levelsmay need to be reduced below a certain critical levelbefore analgesia can be produced.41

RECOMMENDATIONS FOR THE APPROPRIATEUSE OF CORTICOSTEROIDS FOLLOWINGDENTOALVEOLAR SURGERY

There are several synthetic analogues of glucocorti-coids available to the practitioner. The drugs vary intheir glucocorticoid potency, relative mineralocorticoidpotency, duration of action, and plasma half-life. Referto Table IV for a comparison of the most commonlyused agents. Plasma half-lives of the various syntheticglucocorticoids vary from 1 h to approximately 4 h.However, plasma half-life is not a good indication ofthe duration of biologic activity of each steroid. Dura-tion of action is best reflected in the period of adreno-corticotropic hormone suppression by the pituitarygland after the administration of a single dose of glu-cocorticoids. The glucocorticoid potency of hydrocor-tisone is very similar to the naturally occurring cortisol,whereas methylprednisolone and dexamethasone are 4

Table III. Continued

ReferenceNo. of

patients Type of surgery Treatment admini

41 61 Removal of bilateralimpacted thirdmolars

1. 8 mg DM PO andsurgery/placebo atonset.

2. 8 mg DM PO andsurgery/30 mg ketpain onset.

3. Placebo beforesurgery/placebo atonset.

DM, Dexamethasone; MP, methylprednisolone; BM, metamethasone

to 20 times more potent, respectively.

Common preparationsSteroids for dentoalveolar surgery are available for

oral, parenteral, and intramuscular (IM) use. The mostcommonly used agents are oral dexamethasone (Dec-adron) and intravenous (IV) or IM dexamethasone so-dium phosphate (Decadron Phosphate). Dexametha-sone acetate, a longer-acting IM preparation, is alsoavailable. A 0.75 mg dose of dexamethasone is equiv-alent to 20 mg cortisol (hydrocortisone) and to 25 mgcortisone. The biologic half-life of dexamethasone is36-54 h, and it is considered to be a long-acting steroid.Methylprednisolone is another commonly used cortico-steroid in dentoalveolar surgery. It is available orally inseveral strengths and is marketed under the trade nameMedrol. It can be used IM or IV as methylprednisolonesodium succinate, and this is marketed as Solu-Medrol.A longer-acting IM form, methylprednisolone acetate,is available as Depo-Medrol. A 4 mg dose of methyl-prednisolone is equivalent to 20 mg cortisol (hydrocor-tisone) and to 25 mg cortisone. The biologic half-life ofmethylprednislone is 18-36 h, and it is considered to bean intermediate-acting steroid. Betamethasone, a long-er-acting agent, is also available in oral, IM, and IVpreparations.23

DISCUSSIONThe use of NSAIDs in managing oral surgical pa-

tients has been well described. From the literatureavailable, it is apparent that the combination of anotherdrug with an NSAID is often more effective in control-ling postoperative pain and swelling in third molarsurgery than an NSAID alone. For example, the com-bination of diclofenac and prednisolone offers a bettertherapeutic outcome regarding pain and swelling, as

Results

ore

oret

Patients were assigned randomly to 3 treatment groups.Tissue samples collected at 20 min postoperative intervalson buccal aspects of lower third molar extraction socketsyielded decreased levels of TXB2 in DM treatment groupscompared with placebo. Group 2 showed significantdecrease in both TXB2 and PGE2 levels in the first 60min after ketorolac administration compared with groups 1and 3. Average time for requesting postoperative analgesicwas 119.3 min. No difference in time to pain onset amongall 3 groups. Pain intensity was similar in all 3 groups inthe immediate postoperative period. Administration ofketorolac in group 2 patients resulted in a rapid analgesicresponse with an analgesic effect being statisticallysignificant compared with groups 1 and 3 (P � .01).

stered

IV befpain

IV beforolac a

pain

documented in various studies.18,20,21 It is important,


therefore, that combination drugs be recognized andavailable to maximize the benefit of these antiinflam-matory medications.

Most studies advocate the use of NSAIDs for pre-venting postoperative pain,18,19 while glucocorticoidsfor controlling postoperative swelling and tris-mus.2,18,40 This is attributable to the role of prostaglan-dins in local pain and the inhibition of these prostaglan-dins in preventing the onset of pain. Glucocorticoidsexert their action at virtually every step in the inflam-matory process, which leads to decreased capillary di-latation, decreasing circulating lymphocytes, inhibitingfibroblast proliferation, and inhibiting prostaglandinsand leukotrienes. The suppression of these factors ex-erts a profound effect on tissue inflammation and thusoffers a potent therapeutic tool in managing patientspostoperatively.

Glucocorticoids are effective agents in reducing theextent of the common postoperative sequelae of pain,edema, and trismus after dentoalveolar surgery. To beeffective, these drugs must be given in adequate doses.A dose of corticosteroids must equal or exceed thephysiologic amounts released by the body. Normaldaily output of cortisol is 15-25 mg/day, but up to 300mg of cortisol can be released in a time of crisis. A doseexceeding this limit would suppress the inflammatoryprocess to a greater extent than the body could by itself.The authors of this paper suggest a dose equivalent to300 mg cortisol for maximum effect. Doses of 125 mgmethylprednisolone, which is equivalent to 625 mg ofcortisol have been used in previous clinical trials with-out adverse side effects.

Postoperative edema peaks 48-72 h after surgery.Most glucocorticoids used in oral surgical proceduresdo not exert their effect beyond 24 h if given as a singledose. To maintain their antiinflammatory efficacy, ste-roid doses should be maintained for a minimum of 3days and a maximum of 5 days to maximize theirbenefit and minimize their risk of causing delayedhealing and HPA axis suppression. The ideal route of

Table IV. Comparison of commonly used glucocortico

DrugEquivalent glucocorticoid

potency (mg)M

Cortisone 25Hydrocortisone 20Prednisone 5Prednisolone 5Methylprednisolone 4Triamcinolone 4Dexamethasone 0.75Betamethasone 0.6

administration is intravenous. Steroids given through

this route can provide an immediate pharmacologicresponse, reduces patient noncompliance, and providesa more predictable response. The oral route of admin-istration gives a delayed onset of action, can create anerratic response due to the pharmacokinetics of thedrug, and relies on patient compliance. However, theoral route does provide a convenient, economic, andsafe route of administration of drug to most patients.

The intramuscular route of administration has aslower onset of action than the intravenous route, andthe rate of absorption is highly dependent on the rate ofblood flow to the site of administration. The onset ofaction is still faster than the oral route, and long-actingdepot preparations can be injected. Corticosteroids arenot indicated for routine use. Rather, they should beused for more complex oral surgical procedure in whichtrauma is categorized as moderate to severe. Oral sur-gical procedures involving the removal of at least 1partial bony or full bony impacted third molar toothfalls into this category, as do long surgical procedureswhich create a considerable amount of soft and hardtissue trauma.

REFERENCES1. Alexander RE, Throndson RR. A review of perioperative corti-

costeroid use in dentoalveolar surgery. Oral Surg Oral Med OralPathol Oral Radiol Endod 2000;90:406-15.

2. Gersema L, Baker K. Use of corticosteroids in oral surgery.J Oral and Maxillofac 1992;50:270-7.

3. Hargreaves KM, Costello A. Glucocorticoids suppress levels ofimmunoreactive bradykinin in inflammed tissue as evaluated bymicrodialysis probes. Clin Pharmacol Ther 1990;48:168-78.

4. Haas, DA. An update on analgesics for the management of acutepostoperative oral surgical pain. J Can Dent Assoc2002;68:476-82.

5. Jackson DL, Moore PA, Dionne RA, Hargreaves KM. Preoper-ative nonsteroidal antiinflammatory medications for the preven-tion of postoperative oral surgical pain. J Am Dent Assoc1989;119:641-7.

6. Dionne RA, Berthold CW. Therapeutic uses of nonsteroidalantiinflammatory drugs in oral and maxillofacial surgery. CritRev Oral Biol Med 2001;12:315-30.

corticoid potency(relative)

Duration ofaction (h)

Plasma half-life(min)

1 8-12 600.8 8-12 900.25 24-36 600.25 24-36 2000 24-36 1800 24-36 1200 36-54 2000 36-54 200

idsineralo

7. Bannwarth B. Comparative safety of traditional nonsteroidal


antiinflammatory drugs and COX-2 selective inhibitors. PresseMed 2002;31(39 Pt 2):7-9.

8. Laine L. Gastrointestinal effects of NSAIDs and coxibs. J PainSymptom Manage 2003;25(2 Suppl):32-40.

9. Isakson P, Hubbard R. Analgesics: nonsteroidal anti-inflamma-tory drugs. In: Evers AS, Maze M (editors). Anesthetic pharma-cology: physiologic principles and clinical practice. Livingstone(PA): Churchill; 2004. p. 435-55.

10. Desjardins PJ, Hersh EV, Trummel CL, Cooper SA. NonopioidAnalgesics, Nonsteroidal antiinflammatory drugs, and antirheu-matic and antigout drugs. In: Yagiela JA (editor). Pharmacologyand therapeutics for dentistry, 5th ed. St. Louis (MO): Mosby;2004. p. 331-64.

11. Joshia A, Pararab E, Macfarlanea TV. A double-blind random-ised controlled clinical trial of the effect of preoperative ibupro-fen, diclofenac, paracetamol with codeine and placebo tablets forrelief of postoperative pain after removal of impacted thirdmolars. Br J Oral Maxillofac Surg 2004;42:299-306.

12. Bridgman JB, Gillgrass TG, Zacharias M. The absence of anypre-emptive analgesic effect for nonsteroidal antiinflammatorydrugs. Br J Oral Maxillofac Surg 1996;34:428-31.

13. Pektas ZO, Sener M, Bayram B, Eroglu T, Bozdogan N, DonmezA, et al. A comparison of pre-emptive analgesic efficacy ofdiflunisal and lornoxicam for postoperative pain management: aprospective, randomized, single-blind, crossover study. Int J OralMaxillofac. Surg 2007;36:123-7.

14. Morse Z, Tump A, Kevelham E. Ibuprofen as a pre-emptiveanalgesic is as effective as rofecoxib for mandibular third molarsurgery. Odontology 2006;94:59-63.

15. Ong KS, Seymour RA, Chen FG, Ho RCL. Preoperative ketoro-lac has a preemptive effect for postoperative third molar surgicalpain. Int J Oral Maxillofac Surg 2004;33:771-6.

16. Pozos-Guillen A, Martinez-Rider R, Aguirre-Banuelos P, Perez-Urizar J. Pre-emptive analgesic effect of tramadol after mandib-ular third molar extraction: a pilot study. J Oral Maxillofac Surg2007;65:1315-20.

17. Hill CM, Carroll MJ, Giles AD and Pickvance N. Ibuprofengiven pre- and post-operatively for the relief of pain. Int J OralMaxillofac Surg 1987;16:420-4.

18. Buyukkurt, MC, Gungormus M, Kaya O. The effect of a singledose prednisolone with and without diclofenac on pain, trismus,and swelling after removal of mandibular third molars. J OralMaxillofac Surg 2006;64:1761-6.

19. Hyrkas T, Ylipaavalniemi P, Okarinen VJ, Paakkari I. A com-parison of diclofenac with and without single-dose intravenoussteroid to prevent postoperative pain after third molar removal.J Oral Maxillofac Surg 1993;51:634.

20. Schultze-Mosgau S, Schmelzeisen R, Schmele H. Use of ibupro-fen and methylprednisolone for the prevention of pain and swell-ing after removal of impacted third molars. J Oral MaxillofacSurg 1995;53:2.

21. Lin TC, Lui MT, Chang RC: Premedication with diclofenac andprednisolone to prevent postoperative pain and swelling afterthird molar removal. Zhonghua Yi Xue Za Zhi 1996;58:40.

22. Wynn RL, Meiller TF, Crossley HL. Drug information handbookfor dentistry. Hudson (OH): Lexi-Comp; 2007. p. 31–5, 149-54,485-89, 494-97, 853-58, 934-39, 1148-51.

23. Trummel CL. Antiinflammatory drugs. In: Yagiela JA, NeidleEA, Dowd FJ, editors. Pharmacology and therapeutics for den-tistry. Mosby; 1998. p. 297-319.

24. Nesbitt LT. Minimizing complications from systemic glucocor-
ticosteroid use. Curr Ther 1995;13:925-39.
25. Andrews D, Grunau VJ. An uncommon adverse effect followingbolus administration of intravenous dexathethasone. J Can DentAssoc 52:309-11, 1986

26. Taleb N, Geahchan N, Ghosn M, Brihi E, Sacre P. Vulvarpruritus after high-dose dexamethasone. Eur J Cancer Clin Oncol1988;24:495. Letter.

27. Czerwinski AW, Czerwinski AB, Whitsett TL, Clark ML. Ef-fects of a single, large, intravenous injection of dexamethasone.Clin Pharmacol Ther 1972;13:638-42.

28. Perron G, Dolbec P, Germain J. Perineal pruritis after I.V.dexamethasone administration. Can J Anesth 2003;50:749-50.

29. Williamson LW, Lorson EL, Osborn DB. Hypothalamic-pitu-itary-adrenal suppression after short-term dexamethasone ther-apy for oral surgical procedures. J Oral Surg 1980;38:20.

30. Huffman GG. Use of methylprednisolone sodium succinate toreduce postoperative edema after removal of impacted thirdmolars. J Oral Surgery 1977;35:198-9.

31. Baxendale BR, Vater M, Lavery KM. Dexamethasone reducespain and swelling following extraction of third molar teeth.Anaesthesia 1993;48:961-4.

32. Beirne RO, Hollander B. The effect of methylprednisolone onpain, trismus, and swelling after removal of third molars. OralSurg Oral Med Oral Pathol Oral Radiol Endod 1986;61:134-8.

33. Schmelzeisen R, Frolich JC. Prevention of postoperative swell-ing and pain by dexamethasone after operative removal of im-pacted third molar teeth. Eur J Clin Pharmacol 1993;44:275-7.

34. Skjelbred P, Lokken P. Post-operative pain and inflammatoryreaction reduced by injection of a corticosteroid: a controlledtrial in bilateral oral surgery. Eur J Clin Pharmacol 1982;21:391-6.

35. Neupert EA, Lee JW, Philput CB, Gordon JR. Evaluation ofdexamethasone for reduction of postsurgical sequelae of thirdmolar removal. J Oral Maxillofac Surg 1992;50:1177-82.

36. Schaberg SJ, Stuller CB, Edwards SM. Effect of methylpred-nisolone on swelling after orthognathic surgery. J Oral Maxillo-fac Surg 1984;42:356-61.

37. Hooley JR, Francis FH. Betamethasone in traumatic oral surgery.J Oral Surgery 1969;27:398-403.

38. Skjelbred P, Lokken P. Reduction of pain and swelling by acorticosteroid injected 3 hours after surgery. Eur J Clin Pharma-col 1982;23:141-6.

39. Milles M, Desjardins PJ. Reduction of postoperative facial swell-ing by low-dose methylprednisolone: an experimental study.J Oral Maxillofac Surg 1993;51:987-91.

40. Olstad OA, Skjelbred P. Comparison of the analgesic effect of acorticosteroid and paracetamol in patients with pain after oralsurgery. Br J Clin Pharmacol 1986;22:4.

41. Dionne RA, Gordon SM, Rowan J, Kent A, Brahim JS. Dexa-methasone suppresses peripheral prostanoid levels without anal-gesia in a clinical model of acute inflammation. J Oral MaxillofacSurg 2003;61:997-1003.

Reprint requests:

Dr. King KimOral and Maxillofacial SurgeryOral and Facial Surgical Center/Baptist Memorial Golden TriangleHospital300 Hospital DriveColumbus, MS 39705
[email protected]
mailto:[email protected]

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