Vol. 119 No.

3 March 2015

Clinical implications of prescribing nonsteroidal

anti-inammatory drugs in oral health careda review
Ravleen Nagi, BDS, MDS,a B.K. Yashoda Devi, BDS, MDS,b N. Rakesh, BDS, MDS, PhD,c
Sujatha S. Reddy, BDS, MDS, PhD,d and Deepa Jatti Patil, BDS, MDSe
Nonsteroidal anti-inflammatory drugs (NSAIDs), including both the traditional nonselective NSAIDs and the
selective cyclooxygenase (COX)-2 inhibitors, are widely used for their anti-inflammatory and analgesic effects. They are
routinely prescribed in dental practice for the management of pain and swelling. Their use in treating acute dental pain and
chronic orofacial pain, as adjuncts to the treatment of periodontal disease, and to minimize edema following surgical
procedures is well documented. However, long-term utilization of nonselective NSAIDs could increase the risk of
gastrointestinal symptoms, ranging from mild (e.g., dyspepsia, nausea, or vomiting) to serious gastric problems (e.g., gastric
bleeding or perforation). Therefore, selective COX-2 inhibitors have been developed with fewer GI side effects but the recently
identified cardiovascular adverse reactions limit their routine use in dental practice. Another major concern for oral physicians
is NSAID-induced mucosal lesions and prolongation of bleeding time during invasive dental procedures. This article reviews
therapeutic and analgesic uses of NSAIDs in dentistry. The various issues surrounding NSAID-induced adverse reactions and
their implications in dentistry are also discussed. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:264-271)

The primary goal of oral health care providers is to

relieve dental pain for the optimal well-being of patients. Nonsteroidal anti-inammatory drugs (NSAIDs)
provide important analgesic and anti-inammatory
benets to millions of patients. They are widely used
therapeutic agents for the treatment of a wide spectrum
of pathophysiologic conditions. Due to their effectiveness in reducing mild to moderate pain, they are
commonly prescribed in dental practice.1
Vane discovered that aspirin and related drugs act by
inhibiting prostaglandin (PG) biosynthesis.2 The
principal pharmacologic effects of NSAIDs are
attributed to their ability to inhibit PG activity by
blocking the activity of both cyclooxygenase 1 (COX1) and COX-2.2,3 Although NSAIDs relieve symptoms, they are not without potentially signicant
adverse effects. The most noteworthy adverse effect is
upper gastrointestinal (GI) toxicity. Cardiovascular
a
Senior Lecturer, Department of Oral Medicine and Radiology, D.J.
College of Dental Sciences & Research, Modinagar, Ghaziabad, Uttar
Pradesh, India.
b
Senior Professor, Department of Oral Medicine and Radiology,
Faculty of Dental Sciences, MS Ramaiah University of Applied
Sciences, MSRIT Post, Mathikere, Bangalore, Karnataka, India.
c
Associate Professor, Department of Oral Medicine and Radiology,
Faculty of Dental Sciences, MS Ramaiah University of Applied
Sciences, MSRIT Post, Mathikere, Bangalore, Karnataka, India.
d
Professor and Head, Department of Oral Medicine and Radiology,
Faculty of Dental Sciences, MS Ramaiah University of Applied
Sciences, MSRIT Post, Mathikere, Bangalore, Karnataka, India.
e
Senior Lecturer, Department of Oral Medicine and Radiology,
Swami Devi Dyal Dental College and Hospital, Panchkula, Haryana,
India.
Received for publication May 4, 2014; returned for revision Oct 28,
2014; accepted for publication Dec 2, 2014.
! 2015 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2014.12.002

264

(CV) safety is a major concern and has resulted in

NSAID withdrawal in many patients. Therefore, dentists should assess the risk and benets of each medication, taking into account the medical history and
analgesic requirement of each individual. These drugs
should be prescribed in appropriate doses and durations
to reduce or avoid NSAID-associated complications.4
This review discusses the mechanisms of action,
therapeutic uses, and potential side effects associated
with the use of NSAIDs in dental practice.

MECHANISM OF ACTION
NSAIDs act as nonselective inhibitors of the tissue
COX, which exists in two well-known subtypes: COX1 and COX-2. COX catalyzes the formation of PGs and
thromboxanes (TXA2) from arachidonic acid. COX-1 is
constitutively expressed in various tissues, whereas
COX-2 is a largely inducible form found predominantly
in the kidneys and the central nervous system.COX-1
generates PGs for the bodys housekeeping functions,
such as gastric mucosal integrity, platelet homeostasis,
and regulation of renal blood ow. TXA2 generated
initiates platelet aggregation. COX-2 synthesizes
proinammatory PGs that mediate pain and inammation at the site of tissue damage, such as in pulpitis,

Statement of Clinical Relevance

Acute pain is the most common complaint that
causes patients to seek help from oral health care
professionals. Nonsteroidal anti-inammatory drugs
are routinely prescribed but have been associated
with adverse reactions. Therefore, consideration of
the medical history and the analgesic requirement of
patients are essential.

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Nagi et al. 265

Fig. 1. Mechanism of action of nonsteroidal anti-inammatory drugs (NSAIDs).

periodontitis, or pain from surgery. Thus, the therapeutic anti-inammatory effects of NSAIDs are primarily due to COX-2 inhibition, whereas undesirable
side effects are due to COX-1 inhibtion.5
Commonly used nonselective or traditional NSAIDs
block both COX-1 and COX-2, but serious GI effects
have been reported with their long-term use. This has
led to the development of selective COX-2 inhibitors
(rofecoxib, celecoxib, valdecoxib), also known as the
coxibs, which have an improved gastric safety prole. In addition, selective inhibitors of COX-2 depress
prostacyclin (PGI2), an atheroprotective agent, but not
COX-1ederived TXA2, a proaggregatory and vasoconstrictor mediator, which might predispose patients
to heart attack and stroke6 (Figure 1).

ANALGESIC AND THERAPEUTIC USES OF

NSAIDS IN DENTISTRY
The introduction of NSAIDs into clinical practice has
dramatically improved pain management in dentistry.7
Drugs available for pain management belong to two
major groups: the non-narcotic analgesics (NSAIDs and
acetaminophen) and the opioids (or narcotics). The most
commonly used non-narcotic analgesics in dentistry are
available as over-the-counter medications. Unlike opioid
analgesics, NSAIDs exhibit the ceiling effect to analgesia,
with no tolerance or physical dependence and possess
both anti-inammatory and analgesic actions.8
NSAIDs are the mainstay therapy for acute dental
pain. They have also been evaluated for treatment of

chronic orofacial pain; as an adjunct in the treatment of

periodontal disease; and to minimize postoperative
edema, endodontic pain, and bone pain from oral cancer.9 Ibuprofen is the prototypical nonselective NSAID
and represents the gold standard against which new
analgesic agents are evaluated. Shorter-acting (4-6
hours and 6-8 hours) nonselective NSAIDs are more
appropriate for treating acute dental pain with fewer GI
side effects when used on a short-term basis. Recently
introduced selective COX-2 inhibitors are being widely
prescribed by health care professionals to manage
chronic pain in certain conditions, such as temporomandibular disorders (TMDs), due to their improved
gastric tolerability in conjunction with the comparable
efcacy of nonselective NSAIDs.10,11 Table I lists the
NSAIDs commonly used in dental practice.
Prescribing considerations
NSAIDs have been established as the drugs of rst choice
for the management of mild-to-moderate dental and
postoperative pain. They are usually more effective when
prescribed in adequate doses before the synthesis of PGs at
the site of inammation (within 2 hours of tissue injury).
Therefore, clinicians should consider an initial loading
dose, such as double the maintenance dose, which will
allow therapeutic levels to be reached more rapidly.12,13
Another consideration for the use of NSAIDs is
reduction of pain after surgery; therefore, NSAIDs are
prescribed on a regular basis for the rst 1 to 2 days
following a surgical procedure, such as every 4 hours,

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266 Nagi et al.

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March 2015

Table I. Nonsteroidal anti-inammatory drugs (NSAIDs) used in dentistry drug dosages have been veried. No
revisions necessary
Group

Generic name

Dosing form

Adult dose

Pediatric dose

Salicylic acid derivatives

Aryleacetic acid
derivatives

Aspirin
Diclofenac
Aceclofenac

Tablets
Tablets/suppositories/
injection

325-650 mg, q4h

50 mg/8 h PO
75 mg/24 h IM

Propionic acid derivatives

Ibuprofen

Tablets
Liquid

Ketoprofen
Naproxen

Tablets
Tablets
Liquid

Indole derivatives

Indomethacin

Capsules

Oxicam derivatives

Piroxicam

Tablets/suppositories

Pyrazolones

Metamizol

Capsules, solution for

injection, suppositories

Pyrrolo-pyrrole derivative

Ketorolac

Tablets/IM injection

200-400 mg/q4-6h
20-40 mg/cc solution q46h
25-50 mg q8-12h
1.5-2 mg/kg/d in 3-4 doses
250-500 mg/q8-12h
10 mg/kg/d in 2 doses
125 mg/5 mL solution
q8-12h
200-400 mg/q6-8h
Not recommended under
14 years (hepatotoxic)
40 mg/d on rst day 20
0.2 to 0.3 mg/kg/d
mg/d on following days
Maximum daily dose
15 mg
500-1000 mg/q6-8h
1-3 years 250 mg/q6-8h
Maximum 6 g/d PO
3-11 years 250 mg/q6h
2 g/8 h IV
10 mg/q4-6h
Not recommended under
IM: 30 mg q6h
16 years (nephrotoxic)
(limit 5 days)
100-200 mg q12h
Safety not evaluated in
children
325-650 mg/q4-6h
10 mg/kg q4h
1 g/8 h
15 mg/kg q6h

Selective COX-2 Inhibitors Celecoxib

Tablets

Para-aminophenol
derivatives

Tablets/intravenous
infusion/suspension/
suppositories

Acetaminophen/
paracetamol

10-15 mg/kg/dose q4-6h

2 to 3 mg/kg/d in divided
doses 2-4 times daily
Maximum daily dose
200 mg
20 mg/kg/d in 3-4 doses

q4-6h, every 4 to 6 hours; q8-12h, every 8 to 12 hours; mg/kg/d, milligrams per kilogram per day; PO, per oral; IV, intravenous; IM, intramuscular;
COX, cyclooxygenase.

as opposed to an as needed basis. The analgesic can

be taken on an as-needed basis following this initial
period.13 Table I provides the recommended doses of
NSAIDs used in dentistry. One of the limitations of
NSAIDs is that they have a ceiling effect; thus, after
an analgesic ceiling has been reached, an increase in
the dose only increases the side effects without
achieving additional analgesia. However, this problem
can be overcome by adding synergistic medications,
for example, adding acetaminophen to ibuprofen or
acetaminophen to diclofenac.8
Although NSAIDs are effective analgesics, at times
nociceptive pain in the moderate to severe range may
require additional analgesia by combining an opioid
analgesic (hydrocodone, oxycodone) with an
NSAID.12,13 Combination therapy has the advantages
of the anti-inammatory properties of NSAIDs and a
possible decrease in NSAID-induced adverse effects.
Table II lists the various NSAIDeopioid combination
analgesics used for treating dental pain.
NSAIDs and endodontic pain
NSAIDs have been shown to be very effective for
managing pulpal and periradicular pain. Pain during

endodontic therapy is usually controlled with local

anesthesia, but post-treatment pain continues to be a
challenge for the dental clinician because of either
insufcient relief of pain or unacceptable side effects.
Ibuprofen (200-400 mg; every 4-6 hours), acetaminophen or paracetamol (325-650 mg; every 4-6 hours)
are commonly prescribed by dentists to reduce pree
and posteendodontic treatment pain (see Table I).
Combination of ibuprofen and acetaminophen
provides additive analgesia for treating intense
endodontic pain.14
NSAIDs and orthodontic pain
NSAIDs are usually prescribed by orthodontists to
manage pain resulting from application of force to biologic tissues during orthodontic treatment. NSAIDs
block PG synthesis and result in slower tooth movement.
Acetaminophen is the drug of choice for orthodontic
pain without affecting orthodontic tooth movement.15
NSAIDs in temporomandibular disorders
Short-term use of oral (naproxen, ibuprofen) and topical
NSAIDs, such as ibuprofen and diclofenac, may provide
temporary relief from jaw discomfort in patients with

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Nagi et al. 267

Table II. Nonsteroidal anti-inammatory drugs (NSAIDs) and opioid combination dosing regimen for dental pain
Dosing form

Dosage

Acetaminopheneparacetamol codeine

NSAID opioid combination

Tablets/liquid

Acetaminopheneparacetamol hydrocodone

Tablets/liquid

Ibuprofen hydrocodone

Tablets/liquid

Ibuprofen oxycodone

Tablets/liquid

Acetaminopheneparacetamol oxycodone

Tablets/liquid

Aspirin codeine

Tablets/liquid

Acetaminopheneparacetamol tramadol hydrochloride

Tablets

Acetaminophen 300 mg
Codeine: 30 mg q4-6h, as needed
2 tablets q4-6h, as needed
Acetaminophen 500 mg
Hydrocodone 5 mg q4-6h, as needed
2 tablets q4-6h, as needed
Ibuprofen 200 mg
Hydrocodone 7.5 mg q4-6h, as needed
2 tablets q4-6h, as needed
Ibuprofen 400 mg
Oxycodone 5 mg; 1 tablet qid, as needed PO
Acetaminophen 325-500 mg
Oxycodone 2.5-7.5 mg; 2 tablets q4-6h, as needed PO
Aspirin 325 mg
Codeine 30 mg; 1-2 tablets q4-6h, as needed PO
Acetaminophen 325 mg
Tramadol 37.5 mg; 2 tablets q4-6h, as needed

q4-6h, every 4-6 hours; qid, four times a day; PO, per oral.

TMDs. NSAIDs, such as ketoprofen, ibuprofen, and

piroxicam, can be incorporated into transdermal creams
for application on the skin over the painful muscle or
joint.16 The combination of NSAIDs and physical therapy
administered for 4 weeks has been proven to be an
effective primary treatment for disk displacement
without reduction and without osseous changes.17
NSAIDs in oral cancer pain
PGs, especially PGE2, appear to have an important role
in the pathogenesis of cancer. Overexpression of COX-2
is thought to contribute to carcinogenesis by stimulating
cell proliferation, inhibiting apoptosis, and enhancing
angiogenesis. Therefore, nonselective NSAIDs and selective COX-2 inhibitors may prevent carcinogenesis by
decreasing cell proliferation and inducing apoptosis.18
NSAIDs in combination with opioids have long been
part of the analgesic pharmacopoeia in the treatment of
mild to moderate pain from oral cancer. Benzydamine
hydrochloride oral rinse is used for prophylactic
treatment of radiation-induced oral mucositis.19
NSAIDs and periodontal bone loss
Numerous clinical studies have shown that PGE2 levels
are elevated at the sites of ongoing attachment loss and
alveolar bone loss. PGE2 has been found to be a
potentially signicant mediator of periodontal disease
progression, which suggests NSAIDs as a therapeutic
possibility for preventing alveolar bone resorption in
progressive periodontitis.20,21 Dentifrices and mouthwashes that contain NSAIDs, such as urbiprofen,
naproxen, and ibuprofen, are available in some
markets.20 PGs have also been implicated in the periimplantitis, suggesting the role of NSAIDs in controlling implant failure.22

SIDE EFFECTS OF NSAIDS

Gastrointestinal alterations
The link between gastroduodenal mucosal injury and
NSAIDs is well recognized. PGs modulate virtually
every aspect of mucosal defense, and this is evident
from the increased susceptibility of the GI mucosa to
injury following chronic use of an NSAID.23 Increasing
age, stress, Helicobacter pylori infection, smoking,
alcohol use, and a history of ulcer are some of the
predisposing factors for NSAID-induced gastropathy.24 Studies have shown that a signicant
proportion of patients experience upper GI symptoms,
usually dyspepsia, and lesions ranging from petechial
hemorrhages to bleeding peptic ulcers, as seen on
endoscopy.23,25 In dental practice, NSAIDs are prescribed for a shorter duration in patients of all age
groups to treat acute pain or as a prophylactic measure.
The most frequently experienced GI side effects are
dyspepsia, diarrhea, and abdominal pain.26
Mechanism of NSAID-induced gastropathy. There
are two major components to the pathogenesis of
NSAID-induced gastropathy. NSAIDs cause direct
damage through topical irritant effects and indirect
damage through systemic inhibition of PG synthesis.27
PGs reduce gastric acid secretion and increase mucous
production, and thus, the ability of an NSAID to cause
gastric damage correlates well with its ability to
suppress gastric PG synthesis.28
Selective COX-2 inhibitors in gastroenterology. Recently, high Gl risks have been reported with
chronic use of traditional NSAIDs, such as piroxicam,
ketoprofen, and ketorolac; low-dose ibuprofen offers
the lowest risk. Selective inhibitors of COX-2 were
expeditiously developed with the notion that they
would inhibit inammatory PG synthesis (thus reducing

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268 Nagi et al.

edema and pain) but not gastric PG synthesis (thus not

causing ulceration). They are associated with reduction
in GI risks, associated with most NSAIDs at equivalent
doses, and offer the opportunity for safe and effective
treatment of patients who are at risk of developing GI
complications.29
Cardiovascular adverse effects
CV safety of NSAIDs is a highly controversial topic due
to past research suggesting an increased CV risk with all
nonselective NSAIDs and selective COX-2 inhibitors
except naproxen (1000 mg daily) and low-dose
ibuprofen ("1200 mg daily).30 Clinical trials have
found that ibuprofen and naproxen may attenuate the
antiplatelet effects of low-dose aspirin, which is used
for prevention of myocardial infarction and other CV
diseases.31 It is an important consideration in patients
with a high risk of CV disease, but the clinical
implication of the interference by NSAIDs on the
antiplatelet effect of aspirin is still unclear. Therefore,
further studies are required to characterize the CV
effects of aspirin in people taking NSAIDs.
Adverse cardiovascular events with selective COX-2
inhibitors. PGs are thought to play an important role in
normal CV homeostasis. The development of imbalance between PGI2 and TXA2 may be a key factor in
the genesis or progression of myocardial ischemia.
Selective COX-2 inhibitors are not an acceptable substitute for aspirin in patients who need antiplatelet
therapy for cardioprotection because these agents do
not inhibit TXA2 production. By selectively decreasing
PGI2 production without inhibiting TXA2 production,
selective COX-2 inhibitors, theoretically, might
decrease the vasodilatory and platelet antiaggregatory
effects of PGI2 without inhibiting the vasoconstrictor
and platelet aggregatory effects of TXA2.32 In response
to ndings of increased risk of thrombotic CV events,
rofecoxib was taken off the market in September
2004, valdecoxib was withdrawn in April 2005, and a
black box warning was designated for celecoxib.5,32
Hepatotoxicity
The hepatotoxicity of NSAIDs was identied nearly 70
years ago, leading to the withdrawal of several drugs
from clinical use.33,34 There are two main clinical patterns of hepatotoxicity from NSAIDs.34 The rst is
acute hepatitis with jaundice, fever, nausea, and
greatly elevated transaminases and sometimes
eosinophilia. The alternative pattern is with serologic
(antinuclear factorepositive) and histologic (periportal
inammation with plasma and lymphocyte inltration
and brosis extending into the lobule) features of
chronic active hepatitis.

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March 2015

Nonselective NSAIDs, such as diclofenac, sulindac,

and aspirin, have been reported to be more commonly
associated with hepatotoxicity.33 Aspirin-related hepatotoxicity is a dose-related phenomenon associated with
intrinsic salicylate hepatotoxicity and generally only
occurs when aspirin is used in full anti-inammatory
doses (i.e., not 75-300 mg, as used in antiplatelet indications). The United Kingdom Medicines Control
agency has recommended that children under 16 years
should not be given aspirin because of its linkage with
Reye syndrome, the rare but potentially fatal disorder
found almost exclusively in children and adolescents.35
The newer selective COX-2 inhibitors (e.g., celecoxib, nimesulide) are also associated with hepatotoxicity.36,37 although celecoxib is said to have lesser
potential for hepatotoxicity.38 Patients who develop
NSAID-induced hepatotoxicity must be advised to
stop taking NSAIDs permanently. Acetaminophen remains the analgesic of choice for these patients, even in
the presence of jaundice.35
Renal effects and hypertension
Studies have conrmed the relationship between analgesic use and renal damage. Regular use of NSAIDs
increases the risk of kidney disorders. Acute deterioration of kidney function occurs in 0.5% to 1% of patients who regularly take NSAIDs.39 Phenacetin was
proven to cause analgesic nephropathy, and was
banned in the United States and has been replaced by
acetaminophen.40
Nearly all NSAIDs have been found to increase
blood pressure in normotensive and hypertensive individuals and could also attenuate the antihypertensive
effects of diuretics and angiotensin-converting enzyme
inhibitors. The pathogenesis is believed to be renal
vasoconstriction secondary to the inhibition of vasodilatory PGs, thus increasing peripheral resistance and
blood pressure.41 COX-2 expression has also been
found to be upregulated in the salt depletion status in
renal ischemia. Some evidence indicates that specic
COX-2 inhibition may induce electrolyte imbalance,
and abnormal blood pressure in renal ischemia, ultimately leading to uid and sodium retention.40
Dermatologic adverse effects
NSAIDs are among the most commonly prescribed
drugs in medical practice due to its ability to inhibit
both lipoxygenase (LOX) and COX pathways. Chronic
use of NSAIDs has been found to result in various
adverse cutaneous reactions. Photosensitivity is a
commonly overlooked adverse effect associated with
benaxoprofen, piroxicam, diclofenac, and benzydamine.42 Among the currently marketed NSAIDs,

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piroxicam appeared to have the greatest association

with serious adverse reactions, such as StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can affect the oral health of patients.
Thus, health care providers should be aware of the signs
and symptoms of SJS and TEN.43
NSAID use in pregnancy
Removal of the source of pain using local anesthesia is
the optimal management of dental pain during pregnancy. The U.S. Food and Drug Administration (FDA)
includes most NSAIDs in Category C (drugs that can be
used before 30 weeks of pregnancy) and Category D
(drugs that can be used starting at 30 weeks of pregnancy). Starting at 30 weeks of pregnancy, NSAIDs
should be avoided by pregnant women as ineffective
contractions during labor and premature closure of the
ductus arteriosus may occur due to inhibition of PG
synthesis.26 If, however, postoperative pain is present,
an analgesic may be necessary and should be
prescribed. Acetaminophen at recommended doses
(maximum allowed dose 4000 mg per day) is
considered safe and well tolerated during all stages of
pregnancy; however, due to the risk of kidney
damage or liver toxicity with overdose, it is avoided,
if possible.26,44
Miscellaneous adverse reactions
Systemic effects observed with NSAID use are fever,
increased susceptibility to infection, and lymphadenopathy. 45 Aspirin has complex effects on the blood sugar and
can give rise to both hypoglycemia and hyperglycemia.
Diclofenac prolongs diabetes mellitus with long-term
use. Salicylates may reduce hyperglycemia in some patients with diabetes, independently of insulin.46

DENTAL IMPLICATIONS OF NSAID USE

Most pain in the dental setting is acute pain arising from
preoperative conditions (infection, inammation) or
from a dental procedure (surgery, inammation). An
effective model for assessing the efcacy of analgesics
to treat acute pain is third molar extraction.9 Combining
ibuprofen with acetaminophen provides dentists with an
additional therapeutic strategy for managing acute
postoperative dental pain. This combination has been
reported to provide greater analgesia without
signicantly increasing the adverse effects.47
Studies have found that selective COX-2 inhibitors
are as efcacious as nonselective NSAIDs in treating
acute dental pain with less GI toxicity.10 It has also been
suggested that for this short period, the risk of
developing serious upper-GI toxicity with nonselective
NSAIDs is very low and the currently available selective

MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATE

Nagi et al. 269

COX-2 inhibitors are appropriate for prolonged treatment of chronic pain associated with TMDs and orofacial pain; however, their high cost and CV toxicity limit
the routine use of these pharmacotherapeutics.11
Dental management of cardiac patients on aspirin
therapy remains a challenging issue for dental professionals. Low-dose aspirin (75-300 mg daily) is
routinely used as a prophylactic clotting inhibitor in
cardiac patients to prevent CV disease outcomes.
However, it has been found to increase the risk of
bleeding after dental extractions and also appears to
affect periodontal assessments by prolonging bleeding
on probing.48,49 Earlier recommendations suggested
discontinuation of aspirin use for 7 to 10 days, but the
current recommendation is up to 3 days of discontinuation before invasive dental procedures.49 However,
recent studies have reported that the riskebenet
analysis favors continuing aspirin anticoagulant
therapy even during dental extractions, as bleeding
can be safely controlled with local homeostatic
measures except in a small number of patients in
whom embolic events may prove fatal.50,51
Mucosal lesions can occur with any of the NSAIDs.
They can occur alone (e.g., aphthous ulcers) or in association with nonmucosal disorders (e.g., SJS and
TEN). Use of NSAIDs (diunisal, fenclofenac, and
indomethacin) can result in lichenoid reactions of the
oral mucosa, and diclofenac and piroxicam can cause
pemphigus vulgaris. Prolonged contact of the mucobuccal area with aspirin for relief of dental pain has
been found to be associated with epithelial necrosis and
ulceration.52

ADVERSE DRUG INTERACTIONS IN DENTAL

PRACTICE
Drug interactions with use of NSAIDs have been well
documented. Concurrent use of NSAIDs and corticosteroids could increase the risk of GI bleeding, which is
a potential concern for dentists, particularly with longterm utilization of these pharmacotherapeutics.53
Sufcient evidence exists to support the occurrence of
interactions among NSAIDs, antihypertensives, and
diuretics. Antihypertensives and diuretics stimulate
the release of the vasodilator PGI2. NSAIDs may
potentially reduce the efcacy of antihypertensive
drugs. In patients taking diuretics, nephrotoxicity is
increased, which is likely to be the result of reduced
extracellular uid.41
Health care professionals should advise patients
regarding the appropriate concomitant use of aspirin
and ibuprofen, which might render aspirin less effective
when used for its antiplatelet cardioprotective effect.30
High-dose aspirin, mephenamic acid, and ketoprofen
increase the hypoprothrombinemic effects of warfarin
by displacing it from the protein-binding site. Levels of

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270 Nagi et al.

methotrexate, which is used in cancer chemotherapy,

can be increased due to the direct competition for renal
excretion between methotrexate and NSAIDs.53
Serotonin reuptake inhibitors are indicated for the
treatment of depression, and they impair the ability of
platelets to obtain serotonin from the bloodstream
thereby inhibiting platelet aggregation independent of
the arachidonic acid pathway. The concomitant use of
NSAIDs and serotonin reuptake inhibitors may
induce toxicity with respect to Gl bleeding.54

FUTURE DIRECTIONS
Currently, nitric oxideereleasing NSAIDs are being
developed in the hopes that they would exhibit reduced
GI toxicity relative to the traditional NSAIDs; they
represent a promising new class of drugs that will
provide safer and more effective therapies for a number
of inammatory disorders. They also have been found
to possess antineoplastic properties that stimulate cell
necrosis and angiogenesis.18,55 Other novel areas of
research include the preassociation of NSAIDs with a
zwitterionic phospholipid to prevent interactions between the NSAID and the mucosa; chiral NSAIDs; and
ibuprofen formulated as a racemic mixture. It has been
found that GI damage is caused by S isoform and that
the R isoform is safer.55
Recently, a third cyclooxygenase, COX-3 that exists
in the central nervous system has been identied.
Acetaminophen and the low concentration of some
NSAIDs are more specic to COX-3, and this selective
inhibition will lead to the discovery of more potent
drugs for controlling pain and fever.56 A newer
nonsteroidal drug, licofelone, which is a competitive
inhibitor of 5-LOX and COX isoenzymes, decreases
the production of the proinammatory PGs involved in
gastric damage. It is currently in clinical development
and its use is expected to reduce the incidence of GI
toxicity to a considerable extent.57
CONCLUSION
NSAIDs continue to be the most appropriate choice for
the management of acute and chronic pain in dentistry,
but their use has been limited by their propensity to
cause GI and other associated adverse effects. It is
important for physicians to give each NSAID an
appropriate therapeutic trial before an alternative is
tried. NSAIDs are generally safe and effective when
benets and risks are carefully assessed and patients
are appropriately instructed and monitored. In the
future, more clinical trials should be encouraged to
explore the potential of the new emerging NSAIDs to
achieve greater safety and analgesic efcacy in treating
dental pain.

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March 2015
We would like to thank our Principal, Dr B.N. Sreenivas
Murthy, BDS, MDS, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, MSRIT Post, Mathekere,
Bangalore, Karnataka for his support and guidance.

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Reprint requests:
Ravleen Nagi, BDS, MDS
Senior Lecturer
Department of Oral Medicine and Radiology
D.J. College of Dental Sciences & Research
Niwari Road
Modinagar
Ghaziabad, U.P.
India
ravleennagi@yahoo.in