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J Am Dent Assoc, Vol 136, No 10, 1439-1448.
2005 American Dental Association


CLINICAL PHARMACOLOGY
Clinical implications of cyclo-oxygenase2
inhibitors for acute dental pain
management
Benefits and risks
MICHAEL SPINK, D.D.S., M.D., SAUL BAHN, D.M.D., M.S.D. and ROBERT
GLICKMAN, D.M.D.
ABSTRACT
Background.Cyclo-oxygenase2 inhibitors (COX-2
i
) demonstrate analgesic efficacy for
patients who require gastrointestinal safety. The authors discuss the potential benefits and
risks of these novel, but expensive, analgesics when used in dentistry.
Methods. The authors conducted a MED-LINE search focused on the subject headings of
common analgesic drugs and COX-2
i
, using peer-reviewed journals limited to the English
language. They selected for review 127 articles that met the criteria. They also tried to
identify any randomized controlled trials pertinent to dentistry and indicative of evidence-
based medicine.
Results.When comparing COX isoforms (COX-1 and COX-2), the authors found that
overlapping and mutually exclusively properties coexist. COX-2
i
originally were developed
to minimize interference with the gastroprotective properties of the COX-1 isoform, while
selectively preventing prostanoid synthesis expressed solely at sites of bodily trauma or
other inflammation. COX-2
i
were found to provide pain relief equal to or slightly exceeding
that offered by many mild narcotics. They may avoid some of the serious side effects that
can occur with even short-term use of nonselective nonsteroidal anti-inflammatory drugs.
Conclusions.The pharmacodynamics of COX-2
i
reveal an agent that includes analgesic,
anti-inflammatory and gastroprotective properties but also allows for an undesirable
disruption of the delicate hemodynamic balance.
Clinical Implications. Symptomatic and asymptomatic gastroparietic patients who do not
have severe cardiovascular, cerebral or renal ischemic disease benefit from use of COX-2
i
.
Long-term use of these agents in medically compromised patients may prove disastrous.
Key Words:Cyclo-oxygenase2 inhibitors; pain management; dental pain;
analgesics
Cyclo-oxygenase2 inhibitors (COX-2
i
) selectively bind to the COX-2 isoform
responsible for synovial inflammation and tissues with high cellular
transformation.
1,2
These inhibitors originally were approved only for analgesia and
anti-inflammation in patients with rheumatoid arthritis (RA), osteoarthritis (OA) and
gynecologic disorders such as dysmenorrhea. Patients with these conditions often
need long-term analgesic therapy owing to their diseases progressive or chronic
natures that previously could not be controlled safely or efficiently with other non-
steroidal anti-inflammatory drugs (NSAIDs), analgesics or narcotics. Before COX-
2
i
, patients were exposed to the harmful side effects often seen with the long-term
use of nonselective NSAIDsgastric perforations, ulcers, and bleeding (the so-
called "PUB" side effects)or a chance of addiction with the use of long-term
narcotics.
3

Cyclo-oxygenase2 inhibitors widen the spectrum of pharmacological management in
specific patient populations.
COX-2
i
offer greater safety with similar efficacy than the simpler analgesic agents in
lowering peak noxious levels in many patients with pain management problems, including
acute dental pain (Table ).
4
Although COX-2
i
are expensive, they are a more suitable
medication than NSAIDs for either prophylactic or postoperative analgesic treatment of
symptomatic patients with significant gastric disease. These agents are available for the
dental armamentarium and may be prescribed incorrectly by dentists. Therefore, we
conducted this literature review to evaluate the benefits and risks of these COX-2
i
when
used as analgesics for medically compromised patients who are seeking dental treatment.
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TABLECOX-2
i
* USED IN PAIN MANAGEMENT.
CYCLO-OXYGENASE ISOFORMS AND THEIR
INFLUENCES ON VITAL SYSTEMS
During a traumatic, infectious, ischemic, toxic or autoimmune injury to an endothelial cell
membrane, a cascade of phospholipids metabolites propagate from the cells ruptured
membranes. COX is the enzyme that catalyzes the formation of special polyunsaturated
fatty acids called "prostanoids" from arachidonic acid in a rate-limiting step.
5
These short-
lived metabolites are second messengers for both inflammation and normal organ
homeostasis, resulting in the formation of important prostanoidsprostaglandin E
2
(PGE
2
),
prostaglandin I
2
(PGI
2
) and thromboxane A
2
(TXA
2
).
Purification of COX, a key enzyme in inflammation, occurred in 1976. Only in the last
decade did modern laboratory techniques distinguish the "dichotic" roles of COX and
isolate the COX-2 isoform.
68
A study of the isoforms specific roles in inflammatory
molecular biology clarified their differing physiological and functional activities, as well as
their roles regarding homeostasis and pathology. Previously, biochemists believed that
expression of COX-1 was constitutive, and that COX-2 occurred only during pathological
states.
9
However, in this article, we will show the tightly coupled physiological and
pathological roles of COX-1 and COX-2.
Platelets express COX-1, which converts arachidonic acid to its metabolite TXA
2
; TXA
2
is
specifically associated with inflammation and platelet aggregation. Therefore, COX-1
expression not only is constitutive in all nonpathological tissue, but it also is responsible for
prostaglandin repopulation after tissue injury.
10
Reciprocally, COX-2 is constitutively
expressed in tissues associated with cellular transformation, as well as during
inflammation.
11

Therefore, studies comparing these two COX isoforms found that both overlapping and
mutually exclusive properties coexist.
1214

COX-2
i
were developed to selectively prevent prostanoid synthesis expressed only at bodily
trauma or inflammation sites. Theoretically, these agents should not diminish the gastro-
and nephroprotective properties of the COX-1 isoform.
15

Manufacturers have promised that COX-2
i
can offer pain relief equal to that of nonselective
NSAIDs and even some low-potency narcotics. This might lead to the avoidance of some
of the PUB side effects that can occur even with short-term use of nonselective NSAIDs.
The true pharmcodynamics of COX-2
i
reveal a unique and undesirable hemodynamic
sequelae that jeopardizes the homeostasis of vital structures such as the kidneys,
gastrointestinal (GI) tract, heart, brain and vasculature.
16

GI consequences. In GI tissue metabolism, COX-1 releases PGI
2
and PGE
2
. These two
prostaglandins are responsible for gastric mucosal protection through vasodilatation,
stimulation and secretion of gastric duodenal mucous, as well as bicarbonate, thereby
forming a protective barrier to excessive acid production. These protective prostaglandins
help preserve the stomachs mucosal integrity. If nonselective NSAIDs disrupt the
prostaglandins cascade, GI cytoprotection no longer exists.
17
There is an even higher risk
of ulcerative disease in elderly people who take anticoagulants or corticosteroids.
1822
There
are conflicting results with long-term celecoxib use.
2325

Although not a panacea, COX-2
i
improve safety for most patients who require specific GI
watchfulness.
2630
One report verifies a significant decrease in gastric and duodenal ulcers at
three and six months using endoscopy when comparing COX-2
i
with nonselective
NSAIDs.
31
Other data suggest that COX-2 expression interferes somewhat with wound
healing, especially at the base of GI ulcers. Thus, COX-2
i
possibly could delay ulcer
healing and be counterproductive for patients with pre-existing or developing ulcers.
32

Vascular consequences.Celecoxib also adversely affects the cardiovascular system.
31

COX-2 is an essential enzyme for PGI
2
synthesis in the myocardium, central nervous
system and peripheral vasculature.
33
The PGI
2
metabolite has important wound healing,
antithrombotic and vasodilator properties needed for vascular homeostasis. Alteration of
COX-1 and COX-2 disrupts this vascular homeostasis. COX-2 inhibition, therefore,
counteracts the procoagulant COX-1 production of TXA
2
. If myocardial and vascular
prostacyclin do not exist during a procoagulative state, TXA
2
remains unopposed (Figure ).
This may result in a proliferation of thrombi, because COX-2
i
could have no antiplatelet
activity at therapeutic dosages. PGI
2
is important in limiting thrombotic events, especially
in patients at higher risk of experiencing comorbidities such as arterial stenosis and
atherosclerosis.
34,35
One trial specifically supports these thrombotic dangers of COX-2
i
.
36

Another randomized controlled trial disproves that COX-2
i
promote myocardial and
cerebral infarction.
37


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Figure.Diagram of cyclo-oxygenase (COX) hemodynamics. COX-2 inhibition creates
an undesirable alteration in the bodys hemodynamics, possibly leading to
coagulopathic events such as stroke and heart attack.
Concomitant administration of warfarin and rofecoxib also can stimulate a hemorrhagic
stroke.
38
The metabolism of warfarin occurs by cytochrome CYP2C9the same enzyme
that rofecoxib inhibits. Selective patients taking celecoxib and warfarin show substantial
inhibition of CYP2C9, resulting in higher plasma concentrations of warfarin and a possible
state of hypoprothrombinemia.
39,40
If a patient is hypertensive with comorbidities that
necessitate warfarinsuch as atrial fibrillation or prosthetic value replacementcelecoxib
or other COX-2
i
seem to be an inappropriate choice for analgesia.
Renal consequences.Prostanoids are not directly responsible for renal blood flow in
healthy kidneys.
41
However, PGI
2
significantly influences the renal system of medically
compromised adults, especially patients with diabetes, arteriosclerosis or other causes of
renal insufficiency. COX-2 inhibition decreases PGI
2
and PGE
2
modifiers of glomerular
filtration in compromised kidneyscausing sodium retention, promoting peripheral edema
and hypertension, and lowering renal perfusion. There also exists an upregulation of COX-
2 in nephrotic inflammation. Since COX-2 maintains basal renal function in a compromised
kidney, its inhibition promotes renal ischemia.
42

The consequence of coxibs, both nonselective and COX-2, is a dose-dependent elevation of
blood pressure and peripheral edema in patients. COX-2
i
can even induce congestive heart
failure in some compromised patients who are concomitantly taking beta-adrenergic block
drugs or angiotensin-converting enzyme (ACE) inhibitors for hypertension.
43
Therefore,
use caution when combining "nephro-effecting" drugs in patients with elevated serum
creatinine levels.
Bone consequences. In the orthopedic literature, NSAIDs are known to impair fracture
healing.
44,45
Because of confounders such as smoking, which also is a known impedance to
osteogenesis, orthopedists are uncertain if COX-2
i
demonstrate a similar pharmacological
propensity. However, a periodontal study evaluated COX-2
i
, as well as constituents vital to
intrabony periodontal defect repair (such as enamel matrix proteins), and found no
differences in pocket depths of patients taking COX-2
i
compared with control subjects.
46

Other researchers find that COX-2
i
prevent the progression of periodontitis in human
cultured gingival fibroblast and rodent alveolar bone.
47,48
These results suggest that COX-2
i

may be bone-sparing.
Pulmonic consequences. Prostaglandins provide pulmonary vascular tone in both
physiological and inflammatory states. An animal study suggests that bronchiolar
epithelium and the veins of hilar smooth muscle constitutively express COX-1, and smaller
smooth muscle arterioles express COX-2; both isoforms promote pulmonic vasoregulation
in states of homeostasis and inflammation.
49
In tissues with chronic inflammation, COX-1
inhibition leads to a metabolic shift to the leukotriene pathway.
50
Nonselective NSAIDs
inhibit both COX-1 and COX-2 in the lungs, thus promoting excessive leukotrienes,
leading to profuse airway edema from this sequential chemotaxis and cytokine release.
People with a history of asthma or with nasal polyps often report a hypersensitivity to
aspirin and other NSAIDs. Most patients with hypersensitivity to NSAIDs or with asthma
can tolerate rofecoxib.
51,52
Patients who report having had aspirin-induced asthma now can
receive rofecoxib without respiratory embarrassment.
53
This analgesic choice is a safe
alternative to aspirin desensitization or narcotic use.
Allergic manifestations, including severe life-threatening anaphylaxis, often are adverse
drug reactions (ADRs) to sulfonamides. Celecoxib is a sulfonamide derivative, and it
possesses some small sulfa-allergic potential, according to a couple of reports.
54,55

Although one cohort study shows that celecoxib has 80 percent more ADRs than rofecoxib
at a relative risk of 1.8, such reactions are not clinically significant.
56
Another study
suggests that the risk of experiencing allergic reactions when taking celecoxib is
comparable with that of a placebo and other NSAIDs.
57

The manufacturers warn that valdecoxib, a benzene-sulfonamide, is contraindicated for
patients with a history of asthma, urticaria or allergic-type reactions after taking aspirin or
other NSAIDs.
58
One valdecoxib report describes a passive cutaneous anaphylaxis.
59

Another study suggests that there is small potential for severe, rarely fatal, anaphylacticlike
reactions possible in such NSAID-sensitive patients.
60

CYCLO-OXYGENASE2 INHIBITORS VERSUS
COMMON ANALGESICS
NSAIDs and acetaminophen. Pharmacia (Morpeth, England) compared ibuprofen and
diclofenac efficacy with that of celecoxib for OA in its Celecoxib Long-term Arthritis
Safety Study.
61
An important criticism of this study was the allowance of concomitant low-
dose aspirin use for cardiovascular prophylaxis, which when consumed with celecoxib
inactivates aspirins anti-TXA
2
effects and stratifies the data outcomes for hypertension,
infarction and GI ulcer. Although celecoxib showed a reduction in GI adverse events even
with concomitant aspirin use, this reduction was not compared on a long-term basis. In
dental extraction models, a dosage of celecoxib 400 mg was inferior to that of ibuprofen
400 mg for controlling postoperative pain.
62

Merck (Whitehouse Station, N.J.) presented the Vioxx Gastrointestinal Outcomes Research
study, which was aimed at evaluating rofecoxib versus naproxen efficacy in RA.
63
This
study documents a reduction in GI adverse events by rofecoxib use. Another study targeted
the analgesic similarity between rofecoxib, ibuprofen and naproxen.
64
Rofecoxib 50 mg has
analgesic effects equivalent to naproxen 550 mg or ibuprofen 400 mg.
65
The analgesic
effect is reproducible, more effective than placebo and comparable in effect with maximal
single doses of NSAIDs.
Practitioners appropriately prescribe the selective NSAIDs to not interfere with
anticoagulation in patients who have GI discomfort or who are prone to GI bleeding.
Aspirin has the longest anticoagulation history and is the most notorious analgesic to
produce the PUB complications. It acetylates platelet COX permanently, inactivating this
enzyme for the platelets life span of seven to 10 days. This reaction prevents the formation
of TXA
2
, a potent platelet aggregator. Bleeding is a response to irreversible acetylation of
platelets and interference of mucosal integrity. Death can occur from GI perforation or
bleeding, especially in patients with Mallory-Weiss syndromes slitlike tears.
Choline magnesium trisalicylate (CMT) is an alternative salicylate derivative that is
somewhat more gastroprotective and safer hemodynamically than aspirin. CMT is
complementary to morphine for the treatment of metastatic bone pain.
66
However, no
studies to date have compared CMT with COX-2
i
.
Nimesulide is a newer NSAID that provides greater selectivity to COX-2 than to COX-1. It
possesses antipyretic and anti-inflammatory properties similar to other NSAIDs without
significantly affecting cytoprotective prostaglandin in the gastric mucosa. Theoretically,
proton-pump inhibitors or prostanoid analogs given with nonselective NSAIDs also could
provide cytoprotection. One study showed that rofecoxib 50 mg provides better
postoperative analgesia than doesnimesulide 200 mg.
67

Acetaminophen is hemodynamically safe and provides effective relief for mild pain. Short-
term side effects are minimal as compared with narcotic combinations, except for in
patients who misuse alcohol. Acetaminophens most beneficial property is that it does not
affect platelets either reversibly or irreversibly. It is unlike COX-2
i
, which bind reversibly
only to COX-2. However, in a clinical trial of acetaminophen use in patients undergoing
extraction of impacted third molars, about 75 percent of patients required analgesic rescue
medication.
68
Thus, acetaminophen possesses an analgesic ceiling effect. It also
demonstrates one specific crucial disadvantage: severe hepatic damage even at therapeutic
doses in chronic alcohol users.
69
Therefore, dentists should be cautious when prescribing
acetaminophen to alcoholics, owing to the possibility of severe liver toxicity even at normal
doses.
70
Unlike acetaminophen, rofecoxib is metabolized by the both the liver and the
kidneys. It rarely is contraindicated for patients with liver dysfunction who need successful
pain management. However, patients with gallbladder disease or a history of
cholecystectomy will have impaired absorption and altered excretion because of biles role
in rofecoxibs pharmacodynamics.
71

Injectable analgesics. Pediatric dentists and oral surgeons in a hospital environment can
prescribe injectable analgesics such as morphine, fentanyl, ketorolac, meperidine, tramadol
and parecoxib for postoperative pain management. These patients may be patients who are
recovering from extensive restorative dentistry, have experienced facial trauma, have
undergone orthognathic or other maxillofacial surgery, or are experiencing moderate to
severe pain. However, injectable analgesics have disadvantages. There are vast
inconsistencies seen with the analgesic efficacy of narcotics such as fentanyl and morphine.
Narcotics undesirable side effectssuch as constipation, nausea and vomiting, dizziness
and sleepinessincrease the benefits of the COX-2
i
.
72
Likewise, some practitioners limit
the use of ketorolac during surgery, owing to the possibilities of renal ischemia, GI
perforation or enhanced postoperative bleeding. However, these adverse events can be
avoided if clinicians use ketorolac only for select patients and limit the prescription to less
than five days.
73

Parecoxib is a prodrug of valdecoxib and the first injectable COX-2
i
. Parecoxib 40 mg
intravenously or intramuscularly (IM) is equivalent in efficacy to ketorolac 30 to 60 mg IM
after impacted third-molar extractions.
74
Injectable COX-2
i
also show a longer analgesia
duration than do ketorolac and morphine. Further, patients receiving paracoxib did not need
rescue medication, unlike patients receiving ketorolac or morphine. Another study
confirmed that parecoxib 50 mg is as effective as and longer acting than ketorolac 30 mg in
an impactedthird-molarextraction model.
75

For treating postoperative dental pain, meperidine is a poor overall analgesic. A
randomized controlled trial shows that adverse events are more likely to be experienced
with meperidine than with ketorolac.
76
Seizure potential and the possibilities for
professional abuse limit the perioperative use of meperidine.
77
The majority of anesthesia
training programs reported a suspected or confirmed staff incident of drug dependence with
meperidine or fentanyl two decades ago, though now the trend is a decreased tendency in
its medical use and abuse.
78,79
Another disadvantage of meperidine is its fatal interaction
with monoamine oxidase inhibitors that causes the serotonin syndrome, a hyperpyrexic
crisis.
80
Yet, one anesthesia teaching adage about meperidine is valuable
81
; meperidine
provides a dose-dependent effect on shivering by inhibiting opoid receptors.
82
No studies
compare COX-2
i
with meperidine.
A synthetic analog of morphinetramadolacts both as a opiate receptor agonist similar
to other narcotics and as a norepinephrine and serotonin reuptake antagonist. In severe
acute pain, a trial indicates that parenteral tramadol is less effective than morphine. In
postoperative patient-controlled analgesia, tramadol is equally effective as meperidine.
83

Oral tramadol is only as effective as codeine for acute dental pain. Tramadols common
adverse effects include dizziness, nausea, xerostomia and sedation. There exists some
potential for addiction and abuse with tramadol in health professionals.
84
Similar to
meperidine interactions, a toxic hyperserotonergic stateserotonin syndromecan occur
when tramadol is combined with serotonin reuptake inhibitors, a group of
antidepressants.
8587
Another study evaluated oral tramadol and acetaminophen
combinations (T/APAP) against hydrocodone and acetaminophen combinations
(H/APAP).
88
Investigators found that T/APAP provides more rapid, effective and
comparable analgesia with greater tolerability. However, the cost of T/APAP was not
addressed in the article. Tramadol is a moderately effective, but expensive, alternative to
other analgesics in some clinical situations.
Narcotic combinations and other unique analgesics. COX-2
i
provide equal
efficacy as narcotic combinations, such as codeine with acetaminophen when the
appropriate dosage is given.
8992
Rofecoxib reveals a greater overall peak and duration of
analgesic effect with a similar onset as codeine with acetaminophen.
93
In a comparison of
valdecoxib with an oxycodone and acetaminophen combination, valdecoxib demonstrated a
longer duration of action and a better tolerability profile than did an oxycodone and
acetaminophen combination.
94

Owing to the moderate-to-severe pain that results from oral surgical procedures, H/APAP
are commonly written prescriptions. It is tempting to compare the COX-2
i
agents with
hydrocodone and acetaminophen combinations. However, no peer-reviewed journal article
has compared these two entities. Two notable, but rare, side effects of these narcotic
combinations are deafness and fulminating hepatic failure.
9597

Etodolacan NSAID with greater COX-2 selectivity than COX-1had lower scores on
visual analog pain scales and fewer adverse events than tramadol and diclofenac after
coronary bypass surgery.
98
The study, however, excluded all patients with elevated
creatinine levels. This criterion emphasizes COX-2dominant adverse effects in the
compromised vasculature, especially in patients with significant renal insufficiency.
Meloxicam also possesses a more selective COX-2 enzymatic activity than COX-1 at
therapeutic dosages.
99
It does not significantly interfere with platelet aggregation.
100

Although meloxicam distributors warn against the potential risks of dose-dependent GI
ulcerations and hemorrhage, some studies have found little clinical evidence of
ulceration.
101,102
Investigators caution against prescribing meloxicam to patients with a
history of GI bleeds from other NSAIDs. The most common adverse GI events in healthy
patients are dyspepsia, diarrhea, abdominal pain, nausea and vomiting. All these endpoints
are significantly less as compared with diclofenac. Meloxicam is equally effective as a
placebo in a postendodontic model.
103

Potential uses for COX-2
i
. COX-2 and cancer have an intimate relationship. Early
studies showed that elevated levels of COX-2 were linked to early tumor development.
Further, blocking COX-2 decreased tumor progression such as invasion, angiogenesis and
metastasis.
104106
Evidence suggests that COX-2 inhibition may prevent degeneration of
neurons as in Alzheimers disease and defuse malignancy, which arises from familial
adenomatous polyposis.
107109

Peripheral nerve injury. In neuronal inflammation, there is an elevation of prostanoid
expression. However, peripheral nerve regeneration appears to be hampered by
nonselective NSAIDs but by not COX-2
i
.
110
A proposed neuropathic injury model implies
that prescribing post-operative COX-2
i
for patients recovering from third-molar nerve
injury may not further impede peripheral nerve regeneration, unlike NSAIDs do in the
laboratory.
Head and neck cancer. The COX-2 pathway plays an important role in head and neck
cancers, too. Tumor samples show that COX-2 expression and PGE
2
production are
statistically significant to tumor angiogenesis and lymph node metastatic events.
111
COX-2
activity also parallels that of vascular endothelial growth factor (VEGF), messenger RNA
and protein expression in these tumor specimens. Appropriately, indomethacin and
celecoxib can lower VEGF, PGE
2
and COX-2 concentrations.
COX-2 overexpression even exists in premalignant conditions, such as oral leukoplakia and
in situ squamous cell carcinoma of the head and neck.
112
Investigators theorize that COX-2
may adversely modulate apoptosis and immune surveillance along with angiogenesis.
Using COX-2
i
, specifically celecoxib, researchers suppressed nascent tumorgenesis, tumor
progression and metastases by inhibiting PGE
2
.
113
The data suggest that these analgesics
possess similar chemo-preventive properties to retinoids. They may be more effective in
preventing cancer if combined.
114
Therefore, COX-2
i
are a possible regimen in the treatment
of patients with head and neck cancer.
Temporomandibular disorder. Practitioners treat patients who have
temporomandibular disorders (TMD) with a variety of therapies, including prolonged use
of analgesics. The mainstays for treatment of outpatient TMD include an NSAID and splint
therapy but may include muscle relaxants, sedatives, psychotropics and steroids along with
physical therapy. Difficulties in pharmacological and surgical management of TMD often
arise. Owing to the longevity of TMD treatment, COX-2
i
soon became beneficial to such
patients, because they limit PUB side effects.
115

Animal models with induced temporomandibular joint arthritis display reduced
concentrations of a known inflammatory-related neuropeptidecalcitonin gene-related
peptidewhen they are given rofecoxib.
116
Other investigators welcome COX-2
i
in the
dental armamentarium for the treatment of other chronic orofacial pain, but caution about
their cost and problems with medically compromised patients.
117

FUTURE DEVELOPMENTS
Ideal analgesic. Practitioners often prescribe an analgesic that is appropriate for patients
morbidities and lifestyles.
118
However, the ideal analgesic would encompass all patients
needs (Box ). Investigators suggest that rofecoxib would be a superior anti-inflammatory if
it possessed its own COX-2 selectivity but had the pharmacokinetics of ibuprofen.
119

Another improvement might be a supplement for COX-2
i
lack of anxiolysis that directs the
prescription of morphine derivatives.
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BOXPROPERTIES OF AN IDEAL ANALGESIC.
Optimal pain relief also should be within the patients budget. The cost of analgesics is an
important concern to all, but especially to the elderly. The average cost of coxibs is almost
$2.50 per dose. However, there also are potential costs for aspirin-use side effects
antiulcer medication, surgical repair and hospital stays.
120
Patients with occult GI ulcer,
asymptomatic renal disease or undocumented hypertension truly are affected by NSAID
economics.
The 2004 removal of the rofecoxibVioxx from the market by Merck, the subsequent jury
finding that Merck was liable for the death of a man who took Vioxx, and the discussions
in the lay and professional literature demonstrate the economic forces that can sublimate
clinical evidence and danger.
New COX-2
i
agents. Most NSAIDs block both COX-1 and COX-2, while others
selectively inhibit COX-2 more than COX-1.
121123
Pharmaceutical companies are
attempting to improve on past clinical trials by decreasing drug side effects and increasing
drug potency. The emerging drugs, called second-generation coxibs, include etoricoxib,
parecoxib and valdecoxib. Etoricoxib is a new drug designed to treat OA. It has been
approved in the United Kingdom for symptomatic relief of many afflictions, including
acute dental pain. Merck has begun a large trial for cardiovascular patients and hails
etoricoxib as the most selective coxib in development. Deracoxib is a novel coxib that has
been approved for postoperative pain relief in dogs.
124
Theoretically, selective drugs are
more accurate in sparing patients the clinical sequelae of GI ulceration. Their
cardiovascular, renal and hepatic dangers just recently are being well-appreciated.
However, none of these second-generation COX-2
i
are clinically more effective than
rofecoxib and celecoxib.
125

COX-3. Research describes a third COX isoenzyme called COX-3. Researchers
hypothesize that COX-3 is either a variant of COX-1 or COX-2; this is known as the COX-
1b and COX-2b hypothesis.
36
It is known that COX-3 functions along a continuum of
homeostasis properties, either active by itself or combining with COX-1 or COX-2 to
obtain a physiological effect.
126
Laboratory models suggest this isoenzyme is responsible
for the resolution phase of inflammation. Acetaminophen inhibits the COX-3
isoenzyme.
127129

CONCLUSIONS
The literature is replete with articles disproving the original hypothesis that COX-1 is
simply a housekeeping enzyme necessary for the production of prostaglandins needed for
homeostasis, while the COX-2 isoform exists only in patho-physiological states.
Investigators warn that blocking COX-2 may create a state of potential platelet aggregation,
thrombosis and vasoconstriction in some compromised patients. Although NSAID and
narcotic analgesic combinations are successful analgesic regimens for most healthy
patients, COX-2
i
widen the spectrum of pharmacological management in specific patient
populations. COX-2
i
may be more than 200 times as expensive as generic aspirin and
ibuprofen, but only a few dental patients with chronic pain require COX-2
i
analgesia and
anti-inflammatory activity on a long-term basis. Only patients who cannot tolerate first-line
nonspecific analgesic medications benefit with COX-2
i
for acute and chronic pain control.
FOOTNOTES

Dr. Spink is a resident, Department of Oral and Maxillofacial Surgery, Bellevue Hospital, First Ave.
at 27th St., New York, N.Y. 10016, e-mail "ms210@nyu.edu". Address reprint requests to Dr. Spink.

Dr. Bahn is a professor, Department of Oral and Maxillofacial Surgery, College of Dentistry, New
York University, New York City, and an attending clinician, Department of Oral and Maxillofacial
Surgery, Bellevue Hospital Center, New York City.

Dr. Glickman is a professor and the chair, Department of Oral and Maxillofacial Surgery, College of
Dentistry, New York University, New York City, and an attending clinician, Department of Oral and
Maxillofacial Surgery, Bellevue Hospital Center, New York City.
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