REVIEWARTICLE

Maximizing the Safety of NonsteroidalAnti-inflammatory Drug Use for PostoperativeDental Pain: An Evidence-based ApproachK. S. Ong, DDS,* and R. A. Seymour, PhDt*Department of Oral and Maxillofacial Surgery, National University of Singapore; tDepartment of Restorative Dentistry, University ofNewcastle upon Tyne

This article reviews the use of nonsteroidal anti-inflammatory drugs (NSAIDs) forpostoperative dental pain. An evidence-based approach is used to evaluate the clin-ical studies to date on the safe use of these drugs in dental patients. No drugs arewithout adverse effects or are perfectly safe, but their safe use in clinical practicewould entail maximizing the therapeutic efficacy and minimizing the adverse effects.Therapeutic recommendations are made after reviewing the evidence for the safeuse of NSAIDs in postoperative dental pain.

Key Words: Third molar surgery; Surgical pain; Analgesia; Complications.

onsteroidal anti-inflammatory drugs (NSAIDs) areamong the most widely used medications in the

world.' Their introduction into clinical practice has im-proved dramatically the management of acute pain indentistry.2 However, due to the widespread use of thesedrugs, there are concerns about NSAIDs-induced tox-icity, which can be a significant health hazard.3 No drugsare without adverse effects or are perfectly safe, buttheir safe use in clinical practice would entail maximizingthe therapeutic efficacy and minimizing the adverse ef-fects. An evidence-based approach is used in this reviewto analyze critically the evidence available about the safeuse of NSAIDs in acute postoperative dental pain. Themandibular third molar surgical model is used for theanalysis. This is a well-validated, well-documented, andhighly sensitive model to assess therapeutic relief ofmoderate to severe pain by analgesics includingNSAIDs.4A literature review for evidence-based studies on the

use of NSAIDs in postoperative dental pain was done.Evidence from other pain models and general conceptsof NSAIDs were also included when appropriate. Stud-ies were identified by computer search with MEDLINE(1986-2001), EMBASE (1986-2001), Cinahl (1986-

Received March 4, 2002; accepted for publication October 14,2002.Address correspondence to Dr Cliff K.S. Ong, 435 Orchard Road,

Suite 11-02, Wisma Atria, Singapore 23887; cliffong@pacific.net.sg.Anesth Prog 50:62-74 2003© 2003 by the American Dental Society of Anesthesiology

2001), and the Cochrane Library (Issue 1, 2001). Abroad free text search with restriction to publication inEnglish was undertaken using all variants of terms"NSAIDs," "third molar surgery," "postoperative den-tal pain," and "adverse effects." A hand search of rel-evant books or journals not indexed by the above in-dexes was also done.

RESEARCH-BASED EVIDENCE INPOSTOPERATIVE DENTAL PAIN MODEL

A recent review paper by Swift5 states that NSAIDs areeffective analgesics for postsurgical dental pain and thatthe adverse effects associated with NSAIDs are rarelyseen when used for this purpose. Gastrointestinal tox-icity, bleeding, renal toxicity, and potential of allergicreactions were identified as possible risks for the dentalpain model. However, Swift5 did not use an evidence-based approach. An evidence-based approach will beused in this review in order to determine the strengthof the information available to prove whether the aboveclaims about NSAIDs are supported with actual evi-dence.The evidence for analgesic efficacy and adverse ef-

fects of NSAIDs in the dental pain model will be dis-cussed in relation to the following: (a) choice of NSAIDs,(b) dosage of NSAIDs, (c) routes of administration of

ISSN 0003-3006/03/$9.50SSDI 0003-3006(03)

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Anesth Prog 50:62-74 2003

NSAIDs, (d) preemptive effect of NSAIDs, and (e) spe-cific complications during dental surgery due to NSAIDs.

Twenty-six third molar surgical randomized controlledtrials (RCTs) with a total of 5742 analyzed patients pub-lished between 1986 and 2001 were selected.6-31 Theinclusion criteria used were randomized allocation totreatment groups, which included the NSAIDs and pla-cebo, and a standard outcome measure for pain to allowcomparison of results. Analgesic efficacy and adverseeffect outcomes were summarized and synthesized qual-itatively in these 26 RCTs (Table 1). Of these 26 RCTs,6 were general anesthesia (GA), 19 were local anesthe-sia (LA), and 1 was a conscious sedation model. Thesedifferent types of studies are presented in a smaller sum-mary table (Table 2). When scientific literature in a par-ticular area of the dental surgical model was not avail-able, evidence from other pain models was includedwhen appropriate. Evidence was classified into 3 levels:RCTs (level I); case-control/epidemiologic studies (levelII); and incomplete or inconsistent scientific literature(level III).

CHOICE OF NSAIDs

Many NSAIDs have been tested for their analgesic effi-cacy in the dental surgical model. This includes ibupro-fen, diclofenac, naproxen, ketoprofen, and others.-31All the 26 RCTs reviewed supported the analgesic effi-cacy of the different NSAIDs in the dental surgical mod-el. Analgesic efficacy was found to be as effective or

more efficacious when compared with paracetamol, as-

pirin, or an opioid. No single case of serious adverseevents was reported following the administration of thedifferent NSAIDs in these 26 RCTs comprising 5742analyzed patients. A serious adverse event is defined as

hospitalization for life-threatening events like gastroin-testinal bleeding or renal failure.32 Only minor adverseeffects were reported in these RCTs, and none of theserequired any treatment.A landmark study on chronic pain was conducted in

the United Kingdom by Beardon et al.33 These research-ers examined the outcome of 57,715 prescriptions to25,959 patients whose inpatient and outpatient medicalrecords were all linked to the large Tayside database inDundee, Scotland. The study showed that the fractionof serious adverse events attributable to all NSAIDs(pooled) was 24-38%, increasing with age of patientand dose of NSAIDs. Hence there is clear level I evi-dence that NSAIDs are efficacious and have an extreme-ly safe profile in the acute dental surgical model whencompared with the chronic pain model. However, itshould be noted that most of the dental surgical studiesare single-dose studies followed by a short-term use of

medication, which may be NSAIDs as well, over thenext few days of recovery. As the duration of therapy isa risk factor for adverse effects of NSAIDs, it is expectedthat the duration produced very little in the way of ad-verse effects in this model.34

In the chronic pain model, significant differences inadverse effects were found between the differentNSAIDs. Henry et al35 recently published a meta-anal-ysis of 12 control epidemiologic studies (level II evi-dence) comparing the relative risks of gastropathy re-ported with the different NSAIDs. Ibuprofen was asso-ciated with the lowest relative risk of gastrointestinal (GI)toxicity. The 11 comparator drugs in this analysis wereassociated with a 1.6- to 9.2-fold increase risk of ad-verse events compared with ibuprofen. Aspirin (1.6) anddiclofenac (1.8) were among the lowest risk, whereaspiroxicam (3.8) and ketoprofen (4.2) were the highest.However, evidence from the 26 RCTs shows that thechoice of the different NSAIDs does not seem to pro-duce any significant difference on the adverse effects inthe dental surgical model. Again, this may be due to theshort-term usage of these drugs.When severe pain is expected, some NSAIDs may

provide analgesia as efficacious as morphine. There isevidence in the dental surgical model that parental ke-torolac23 and lornoxicam'5 are efficacious in severepain. Norholt et al15 has shown in a well-designed RCTof 252 patients that intramuscular (IM) 8 mg of lornox-icam is at least as effective as 20 mg of morphine IM,and more effective than 10 mg of morphine IM for thetreatment of severe postoperative third molar surgicalpain. Furthermore, lornoxicam was better toleratedthan morphine, and a lower incidence of adverse effectswas observed than that of morphine. The majority ofthe adverse events reported for lornoxicam were of mildseverity and associated with discomfort from the site ofinjection. However, all of the patients (100%) on 20 mgof morphine and 87% of patients on 10 mg of mor-phine experienced opioid-related adverse events. Thisstudy provides level I evidence that NSAIDs can be usedreliably in lieu of opioids in cases when severe dentalsurgical pain is expected.

Anecdotal evidence suggests that there is considerablevariability in the pain relief obtained from NSAIDs.36,37Such variability may be explained in terms of differencesbetween agents with respect to either pharmacodynam-ic actions, pharmacokinetic parameters, or a combina-tion of both. Stereoisomerism, where preparations existas racemic mixtures and where only 1 enantiomer isactive, may also be important. However, chiral inversionfrom inactive to active enantiomer may occur and maybe rapid or slow.When dealing with high-risk patients, COX-2 selective

inhibitors may be useful. Theoretically, by specifically in-

Ong and Seymour 63

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Table 2. Summary of Types of Studies*

Percentage ofPatients

Number Number ReportingTypes of of of Minor AdverseStudies Studies Patients Effects (M)

GA 6 1163 14.7LA 19 4379 9Conscious sedation 1 200 6Total 26 5742 -* LA indicates local anesthesia, and GA, general anesthesia.

hibiting COX-2 activity, COX-2 inhibitors are intendedto have anti-inflammatory and analgesic effects withinthe therapeutic dose range without blocking the physi-ologic function of the COX-1 isoform.38 Rofecoxib andcelecoxib are the 2 COX-2 selective NSAIDs that havebeen approved by the US Food and Drug Administra-tion for acute pain management. Morrison et a139 hasrecently reviewed 6 RCTs of 1284 patients on the an-algesic effect of rofecoxib in the third molar surgicalmodel. Rofecoxib was compared with either 400 mg ofibuprofen or 550 mg of naproxen sodium. In these stud-ies, 50 mg of rofecoxib consistently provided analgesicefficacy similar to that of the comparator NSAIDs andwith minimum adverse effects. Available data also sug-gest that celecoxib has analgesic efficacy in patients withpostsurgical dental pain, but it is generally less effectivewhen compared with standard doses of naproxen andibuprofen.4041 Based on studies in the dental surgicalpain and dysmenorrhea model, rofecoxib appears tohave greater analgesic efficacy than celecoxib.2 How-ever, COX-2 inhibitors are currently not recommendedas the first line of therapy in acute pain, as the clinicalexperience with these drugs has been limited.42 Yet theymay be useful in patients previously deemed at high riskto receive conventional nonselective NSAIDs, such asan elderly patient undergoing major surgery.

Theoretically, a drug that consists of a combinationof an NSAID and opioid (eg, ibuprofen and codeine/hydrocodone) should give a better analgesic effect thanibuprofen or codeine/hydrocodone alone. However,many studies of third molar surgical pain have not beenable to show that NSAIDs plus opioid is better thanNSAIDs alone.43 44There has been 1 study showing thatan ibuprofen-codeine combination has a better analge-sic effect than ibuprofen alone, but with a higher inci-dence of side effects due to the opioid.45 Although manystudies show that single-entity NSAIDs demonstrate an-algesic superiority when compared with opioid combi-nations, the combinations are still very popular amongclinicians and patients. A plausible explanation is thatopioids not only have the potential to act antinocicep-

Table 3. Some Selected Alternatives for Use of NSAIDsAgainst Pain After Oral Surgery*

Optimal AdultDose Dosing Maximum

(Oral Route, Interval DoseAgent mg) (h) per Day (mg)

Ibuprofen 400 4-6 3200Naproxen 500 12 1250Flurbiprofen 50 6-8 300Ketoprofen 50 6-8 300Diclofenac 50 6-12 20Ketorolac 10 4-6 40Meclofenamatesodium 100 6-8 400

Etodolac 200 6-8 1000Rofecoxib 50 24 50

* Adapted and modified from Sunshine and Olson.67

tively, but may also reduce the affective/emotional com-ponent of pain.

DOSAGE OF NSAIDS

All NSAIDs seem to have a ceiling effect or plateau withrespect to analgesia, above which an increase in dosewill only prolong the duration of action and increase theincidence of unwanted effects.46 Multiple case-controlstudies in the chronic pain models have shown that asthe dose of NSAID increases, the risk of complicationincreases proportionally from two- to threefold for pa-tients using lower doses to greater than sevenfold forpatients on high-dose NSAIDs.47Many RCTs, including the dental surgical model, have

found that a dose of 400 mg of ibuprofen is the optimalanalgesic dose for adults.1,21 These studies have dem-onstrated that the analgesic effect of ibuprofen does notincrease with doses above 400 mg, probably as the re-sult of the ceiling effect. Schou et al"l have demonstrat-ed in a well-designed RCT of 304 third molar patientsthat a single dose of 400 mg of ibuprofen provided themaximum pain relief and longest duration of analgesiceffect compared with 50, 100, and 200 mg of ibupro-fen. Similar results have also previously been reportedin single- and multiple-dose studies.21,30,31 The optimalanalgesic dose for many other NSAIDs used in dentalsurgical pain has also been evaluated (Table 3). Hencelevel I evidence entails that the recommended optimalanalgesic dose of NSAIDs should be used for maximumanalgesic efficacy and minimum adverse effects.

ROUTES OF ADMINISTRATION OF NSAIDS

Many doctors used IM or rectal NSAIDs, even when theoral route could be used. Reasons for choosing these

Ong and Seymour 69

70 Safety of NSAID for Postoperative Pain

routes were pharmacokinetic-based-that is, the rate ofdrug absorption may impact efficacy and the onset ofanalgesia. Tramer et a148 did a systematic review com-paring the analgesic efficacy of NSAIDs given by differ-ent routes for acute and chronic pain. Twenty-six RCTs(2225 analyzed patients) published between 1970 and1996 were reviewed. The authors concluded that thereis a lack of evidence for any difference in analgesic ef-ficacy of NSAIDs given by different routes. However,the IM and rectal routes were more likely to have spe-cific local adverse effects. The IV route also reported tohave more postoperative bleeding.One of the trials24 compared 150 mg of diclofenac

taken orally with IM 50 mg plus 100 mg orally of diclo-fenac in a third molar surgical model. The drugs weregiven as a premedication using a well-designed, doubledummy RCT, and the group sizes were large (50 pergroup). No difference was found between the 2 routesof administration with respect to analgesic efficacy.Since there is adequate evidence of a lack of differencein the analgesic efficacy between the different routes,the safest and simplest one should be used when pos-sible.

PREEMPTIVE EFFECT OF NSAIDS

Preemptive analgesia is the assumption that an anal-gesic given before noxious stimulus has effects that longoutlasts the presence of the analgesic in the body. Theclinical implication would be more effective pain man-agement, reducing postoperative pain and analgesic re-quirements.49There is convincing evidence in the general surgery

model that opioids have a preemptive effect.49 Howev-er, the evidence for a preemptive effect of NSAIDs isconflicting. To date, the only RCT in the third molarsurgical model did not support that NSAIDs have anypreemptive effect. One hundred milligrams of diclofenacsodium was tested for any preemptive effect in 21 pa-tients in a randomized, crossover trial.50 No significantdifference was found in the pain scores. However, thisnegative study did not provide any statistical informationon the confidence interval or the power estimation. Thesample size may not have been large enough to detectsignificant differences. The results from a previous studydone by Campbell et al51 indicated that at least 30 pa-tients would be needed in this surgical model in orderto detect a significant difference in pain. This is basedon the assumption that a difference of 10 mm in thevisual analogue scale is clinically significant between the2 sides in each patient, with a type I alpha error of .05and a type II beta error of .01.By contrast, it has been shown that IV 60 mg of ke-

torolac has a preemptive effect in an RCT of 60 totalhip replacement surgery patients.52 However, 1 con-founding factor in this study was a large disparity be-tween the number of male and female subjects, withmore women in the control group. The authors alsoadmitted that no information was available concerningthe preoperative level of pain and analgesic consump-tion in the patients. These factors may have introducedbias into this study.The evidence for the preemptive effect of NSAIDs is

conflicting. However, the consensus of experts recom-mends that it is advantageous to give NSAIDs preemp-tively to prevent pain53 (level III evidence). Administra-tion of the NSAIDs 1-2 hours prior to pain onset allowsfor absorption and distribution of the drug to establisheffective blood levels at the site of action, rather thanhaving the patient experience pain and administer theNSAID after onset.53 There may be advantages in con-sidering the use of COX-2 inhibitors as a medication ofchoice in preemptive analgesia compared with COX-1inhibitors because of the minimal thromboxane ef-fects.54 In theory, this will cause minimal postoperativebleeding problems when compared with COX-1 inhibi-tors, particularly when multiple dental extractions ormore major oral surgery is to be done. A recent studyreported that a 10-day administration of rofecoxib hadno effect on the antiplatelet activity of low-dose aspirin,as measured by serum thromboxane B2 activity andplatelet aggregation.55 This suggests that rofecoxibcould be safely used in patients taking prophylactic as-pirin without the additional risks of bleeding problems.

COMPLICATIONS IN DENTAL SURGERY DUETO NSAIDS

Many complications and serious adverse events can oc-cur with chronic treatment of NSAIDs. Clear evidenceexists for these serious adverse events in the chronicpain models as exemplified by the Beardon et a133 study.However, there are no epidemiologic studies of seriousadverse events in the dental surgical model. There is atheoretical risk of serious adverse events that could oc-cur with the use of NSAIDs in this model. These will bediscussed using other models as appropriate.

Postoperative Bleeding

Because NSAIDs inhibit the cyclooxygenases, they alsodecrease the production of thromboxane A2, a potentplatelet-aggregating agent, thus increasing the risk ofpostoperative bleeding. Many authors have suggestedwithholding NSAIDs or to stop aspirin therapy preop-eratively in order to prevent excessive postoperative

Anesth Prog 50:62-74 2003

Anesth Prog 50:62-74 2003

bleeding.3 The published clinical studies present conflict-ing data. An increased frequency of bleeding episodeswas reported after abdominal surgery in patients treatedwith indomethacin.56 No significant increase in bloodloss was found in patients receiving diclofenac concur-rent with hip replacement, transurethral resection ofprostate, or gynecologic laparotomies.57-59 A separatestudy, however, reported increased hemorrhage afterprostate surgery in patients who received preoperativeaspirin or NSAIDs.60The effect of aspirin on postextraction bleeding has

been evaluated in an RCT consisting of 39 patients re-quiring dental extractions who were on long-term pro-phylactic aspirin.61 The authors divided the patients ran-domly into 2 groups: those who stopped aspirin therapybefore extraction and those who continued the aspirintherapy. In both groups, a local hemostatic method wassufficient to control postextraction bleeding. The au-thors concluded that low-dose aspirin therapy does nothave any significant effect on postextraction bleedingand should not be stopped before the procedure. How-ever, it should be cautioned that this may not be true formore major oral surgical procedures.The evidence for postoperative bleeding related to

NSAIDs is conflicting. However, the consensus of ex-perts recommends that NSAIDs should not be admin-istered when the risk of postoperative bleeding is high,particularly when an anticoagulant or corticosteroid hasalso been administered42 (level III evidence). It should benoted that aspirin is an irreversible inhibitor of plateletcyclooxygenase, whereas ibuprofen and most otherNSAIDs are reversible. Hence when platelets are ex-posed to aspirin, they are rendered ineffective and re-covery depends on replacement, which may take 4-8days. Platelets exposed to ibuprofen can regenerate cy-clooxygenase, and the effects only last 8-12 hours.There may be a place for COX-2 inhibitors for pa-

tients at risk of bleeding because of the minimal throm-boxane effects.54 This will, in theory, cause minimalpostoperative bleeding problems when compared withCOX-1 inhibitors.

GI Tract ComplicationsFrom the standpoint of morbidity and mortality, GI ad-verse effects undoubtedly constitute the most importantgroup of adverse effects. Indeed, GI ulceration and hem-orrhage are more significant than all other NSAID ad-verse effects combined in cases of chronic use.47 Dys-pepsia, nausea, and diarrhea are the other common mi-nor adverse effects.3 Evidence from the 26 RCTs sup-ports that the above are also common minor adverseeffects in the dental pain model.Concomitant anticoagulant or corticosteroid use, ad-

vance age, and prior peptic ulcer history increases therisk of GI tract ulceration significantly.42 This has beenconfirmed uniformly in many case-control studies, andit has been suggested that the risks increase markedlyafter more than 5 days of continuous therapy, particu-larly in the elderly.42 Hence for dental surgical pain,NSAIDs usage should be limited to 5 days only. In pa-tients at high risk for NSAID gastropathy, the coadmin-istration of misoprostol has been shown to provide ef-fective protection against both gastric and duodenal ul-cer. This agent is known to reduce acute gastric damagesignificantly, and in a large placebo-controlled, doubleblind study has been shown to reduce the incidence ofcomplicated peptic ulcer disease by 40%.62

Allergic Complications

By blocking the cyclooxygenase with NSAIDs, phos-pholipids may be preferentially shunted toward the li-poxygenase pathway with resultant enhanced produc-tion of leukotrienes. These agents contribute to asth-matic and anaphylactoid reactions typically associatedwith NSAIDs.63 Aspirin-induced bronchoconstriction oc-curs in only 5-10% of asthmatic patients, but it may besevere or even fatal. It is recognized that there is a cross-reaction with aspirin-induced bronchoconstriction andother NSAIDs.63 There is evidence that meclofenamicacid is unique in that it inhibits the production of bothprostaglandins and leukotrienes and may therefore be asafer choice for patients with anaphylactoid reactions toNSAIDs.64 A careful drug history in this group of pa-tients will usually highlight those patients at risk.

Renal ComplicationsAcute renal failure can occur in patients on NSAIDs,most commonly those with a decreased effective circu-lating volume, and in particular those with congestiveheart failure and renal insufficiency.65 In patients whoare at risk, acute renal failure can develop with the firstdose of NSAIDs. It is likely that higher doses and longeracting NSAIDs entail greater risk.66 These results werepredicted by the results of clearance studies in suscep-tible patients showing that short-acting NSAIDs, such asibuprofen, resulted in sharp decreases in the glomerularfiltration rate (GFR), but that these decreases in GFRreturned to base-line levels within the dosing interval ofthe NSAID.66 In other words, if the dosing interval wassufficiently short, patients were able to recover renalfunction before the next dose was administered. Overall,no global adverse effect on the kidney occurred whenassessed as a 24-hour determination of the GFR. Theseobservations predict that long-acting NSAIDs would pre-clude renal recovery during the dosing interval, and

Ong and Seymour 71

72 Safety of NSAID for Postoperative Pain Anesth Prog 50:62-74 2003

thereby cause persistent and more clinically importantdecreases in GFR. This hypothesis is supported by theepidemiologic study (level II evidence) that there is ahigher risk of functional renal failure with NSAIDs hav-ing a half-life > 12 hours.66 In the dental surgical pa-tients who are at risk of renal failure, it is probably saferto give NSAIDs of short duration, rather than one witha long duration of effect.

Drug Interactions

All drugs can have potential serious interactions withother drugs that the patient may be taking concurrently.It is important to avoid polypharmacy where possible.There can be significant drug interactions with NSAIDsthat may impact their safe use for dental pain. The fol-lowing are some examples of possible drug interactionswith NSAIDs: (a) NSAIDs antagonize the antihyperten-sive effects of angiotension-converting enzyme (ACE) in-hibitors (the risk of renal impairment or hyperkalemia isincreased when patients are treated with these 2 classesof drugs simultaneously); (b) warfarin levels are likely tobe increased if patients are treated with NSAIDs andanticoagulants, because of competition for protein bind-ing sites; (c) the antidiabetic effects of the oral sulfonyl-ureas are increased by the coadministration of NSAIDs;(d) the risk of peptic ulceration with associated perfo-ration and bleeding is increased in patients taking bothNSAIDs and corticosteroids; (e) in patients taking di-uretics, nephrotoxicity is increased, which is likely to bebecause of reduced extracellular fluid volume (the di-uretic effect is antagonized and an elevation in serumpotassium can occur); and (f) methotrexate levels can beincreased due to the direct competition for renal excre-tion of methotrexate and NSAIDs.

DISCUSSION

There are different pain models and varying methodsfor studying analgesic agents. The dental pain impactionmodel has been chosen in this review, and the analgesicstudies were single-dose studies or multidose studies. Itshould be noted that the majority of the RCTs reviewedin this article are single-dose analgesic studies. Single-dose studies are good and appropriate because they areexcellent predictors of analgesic efficacy and can beused to determine the optimal analgesic dosage andtime-effect of that drug as well as its relative efficacy toknown standards. However, single-dose studies could befaulted for not measuring the cumulative effects of adrug over several doses or days. There is some rationalefor quickly eliminating an agent for use in acute pain

that on the very first dose does not have any advantageover the standard treatments.

Recently, there has been a growing recognition of theimportance of augmenting the traditional approach ofsingle-dose analgesic studies with multidose efficacy tri-als. This multidose model more closely approximatesthe "real life" clinical setting. Patients with pathologicpain typically require more than 1 dose of medicationto alleviate their pain. In addition, information concern-ing the optimal dosing frequency and the side effect pro-file can best be obtained from multidose studies. Dentalpostoperative pain is a good model for both single-doseand short-term multidose study. Pain arising from thissurgical procedure usually persists for 3-4 days. How-ever, the usefulness of this model in a short-term mul-tidose study is underscored, as there are very few mul-tidose studies for this model to date. More multidoseanalgesic studies in this model should be done in thefuture to better delineate the safety profile of analgesics.

CONCLUSION

NSAIDs are safe for use in the clinical practice of post-operative dental pain. Level I evidence has shown thatit is efficacious in dental surgical pain and produces min-imum adverse effects. The choice of NSAIDs can bebased on professional preference and the patient's pre-vious response. For patients at risk of NSAIDs toxicity,the shortest duration NSAIDs with the lowest optimalanalgesic dose over the shortest term should be used.The oral route should be used whenever possible. Theadministration of NSAIDs preemptively can be useful toestablish effective blood levels before the pain starts.

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