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J Am Dent Assoc, Vol 137, No 4, 480-487.
© 2006 American Dental Association
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CLINICAL PRACTICE

JADA Continuing Education

The use of COX-2 inhibitors for acute dental pain

A second look



Michaell A. Huber, DDS and Geza T. Terezhalmy, DDS, MA


   ABSTRACT
TOP
 ABSTRACT
PHYSIOLOGY OF COX ISOENZYMES
 ANALGESIC EFFICACY OF COX-2...
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background. On the basis of their perceived better safety profile compared with other analgesic agents, cyclo-oxygenase-2 (COX-2) inhibitors have been prescribed frequently as first-line agents to treat acute dental pain. However, recently identified cardiovascular adverse reactions associated with these drugs mandate a reappraisal of their use in dental practice.

Types of Studies Reviewed. The authors reviewed 18 clinical studies that evaluated the efficacy of a COX-2 inhibitor for the treatment of acute dental pain. All of the studies used the widely established third-molar surgical extraction model to induce postsurgical inflammatory based pain, and all were randomized, double-blinded and placebo-controlled. However, numerous vagaries in overall study design made direct comparisons difficult.

Results. None of the studies established any of the COX-2 inhibitors as clearly better than ibuprofen, the current gold standard for the treatment of surgically induced dental pain. However, in single-dosing scenarios, the COX-2 inhibitor often demonstrated a longer duration of action compared with ibuprofen.

Clinical Implications. The evidence to date fails to demonstrate any therapeutic advantage to using a COX-2 inhibitor to treat acute dental pain compared with ibuprofen. In the rare event that a COX-2 inhibitor may be appropriate, the clinician must inform the patient of the potential risks, and the drug should be used for the shortest possible time.

Key Words: Acute dental pain; cyclo-oxygenase-2 inhibitor; adverse drug events; ibuprofen

The primary obligation and ultimate responsibility of oral health care providers is not only to restore function, but also to relieve pain. Currently available analgesic agents include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclo-oxygenase-2 (COX-2) inhibitors, acetaminophen and opioid agonists combined with aspirin, acetaminophen or ibuprofen.

Opioid agonists can relieve practically all forms of pain, including visceral pain, but their use is associated with numerous disconcerting side effects such as nausea, vomiting, ileus, urinary retention, sedation, sleep disturbances and respiratory depression.1,2 The efficacy and safety of NSAIDs have been reviewed extensively.3 Potential adverse effects of NSAIDs include peptic ulcer disease, gastrointestinal (GI) bleeding, GI perforation, impaired renal function and inhibition of platelet function.

COX-2 inhibitors have been promoted widely as better alternatives to both opioids and NSAIDs, mainly as a consequence of their putatively lower risk of gastropathy and platelet-related adverse events.1,2,4–8 However, some researchers have expressed skepticism and caution regarding their overall clinical value and rapid acceptance by clinicians and patients alike.9–11 Recently published reports have demonstrated a significantly increased incidence of adverse cardiovascular events occurring in patients being treated with COX-2 inhibitors.12–15

The purpose of this report is to briefly review the value of COX-2 inhibitors in the treatment of acute odontogenic pain.


   PHYSIOLOGY OF COX ISOENZYMES
TOP
 ABSTRACT
 PHYSIOLOGY OF COX ISOENZYMES
ANALGESIC EFFICACY OF COX-2...
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Prostaglandins are ubiquitous endogenous substances known to influence pain perception, modulate inflammation, and affect vascular tone and permeability. COX is known to catalyze the rate-limiting step of prostaglandin biosynthesis. COX (that is, prostaglandin H synthase or prostaglandin endoperoxide synthase) is a fatty-acid oxygenase of the myeloperoxidase superfamily.16 It acts to oxygenate arachidonic acid to form prostaglandin G2; as a peroxidase, it then acts to reduce prostaglandin G2 to form prostaglandin H2. Prostaglandin H2 is further catalyzed by cell-specific synthases to form the five principle prostaglandins (thromboxane A2, prostaglandin D2, F2{alpha}, E2 and I2 [prostacyclin]) (FigureGo).16–18 At least two COX isoforms (COX-1, COX-2) and a splice variant of COX-1 (COX-3, or more appropriately COX-1b or COX-1v) are known to catalyze the rate-limiting step of prostaglandin synthesis.16,18,18–23


Figure 1
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  		Figure. As a consequence of diverse stimuli (for example, tissue trauma), phospholipase A2 acts to free arachidonic acid from membrane phospholipids. Cyclo-oxygenase (COX) acts to oxygenate and then reduce the arachidonic acid to form prostaglandin H2. Prostaglandin H2 is further catalyzed by cell-specific synthases to form the five principle prostaglandins. The predominant target tissues of the five principle prostaglandins are listed. Sources: Chandrasekharan and Simmons16; FitzGerald and Patrono17; and Linton and Fazio.18

 
COX-1 expression. COX-1 is believed to be expressed constitutively in virtually all healthy tissues, including platelets and kidneys, and it exerts several homeostatic or "housekeeping" mechanisms throughout the body.18,20,24,25 For example, COX-1–induced prostaglandins protect the gastric mucosa by enhancing gastric blood flow, increasing mucous and bicarbonate secretion, and inhibiting acid output.8 COX-1–induced thromboxane A2 biosynthesis promotes platelet aggregation. COX-1 inhibitors interfere with thromboxane A2–induced platelet aggregation.

COX-2 expression. COX-2 is expressed primarily in the brain, kidneys, female reproductive system and bone, and it can be induced by inflammatory cytokines in other tissues, such as endothelial cells.4,6,20,24 COX-2 is not found in platelets, but COX-2 in endothelial cells induces prostacyclin synthesis, which prevents platelet aggregation and promotes vasodilation.26 COX-2 inhibitors block endothelial prostacyclin synthesis, which leads to platelet aggregation and vasoconstriction.17,27,28

Acetaminophen, which appears to inhibit the splice variant of COX-1, is a relatively weak inhibitor of peripheral prostaglandin biosynthesis, but it appears to be highly effective in the central nervous system.21 Aspirin and other NSAIDs block, to varying degrees, all COX isoforms and variants. COX-2 inhibitors selectively block COX-2. COX inhibitors alter sensitivity (that is, increase the pain threshold) to noxious stimuli, but they all reach a ceiling dose for their maximum analgesic effect.


   ANALGESIC EFFICACY OF COX-2 INHIBITORS
TOP
 ABSTRACT
 PHYSIOLOGY OF COX ISOENZYMES
 ANALGESIC EFFICACY OF COX-2...
DISCUSSION
 CONCLUSION
 REFERENCES
 
Several studies addressing the efficacy of COX-2 inhibitors for the treatment of acute dental pain have been published recently and are summarized in the tableGo (page 484).1,2,5,29–42 All of the studies used the widely established third molar surgical extraction model to induce postsurgical inflammation-based pain.43 All were randomized, double-blinded and placebo-controlled. However, numerous vagaries in overall study design (such as patient demographics, operator skill, timing of medication therapy, dosing, pain assessment instruments, assessment endpoints) make direct comparisons of any two studies difficult.


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  		TABLE Studies of the efficacy of COX-2* inhibitors for the treatment of acute dental pain.

 
Ibuprofen represents the gold standard against which new analgesic agents are evaluated.

Thirteen studies used single-dosing protocols, thus favoring the test drug with the longest half-life (often the COX-2 inhibitor). Six studies compared the efficacy of a COX-2 inhibitor with that of an opioid/acetaminophen combination1,32,40–42; three studies compared the efficacy of different COX-2 inhibitors against each other2,5,39; three studies evaluated the efficacy of COX-2 inhibitors that have yet to be approved for use by the U.S. Food and Drug Administration38–40; and nine studies compared the efficacy of a COX-2 inhibitor with that of an NSAID, usually ibuprofen.29–31,33–38

In all instances, the tested medications performed better than the placebo. The use of opioid/acetaminophen analgesics was associated with an increased incidence of adverse effects such as nausea, vomiting and dizziness. However, no study reported major adverse events related to bleeding rates or cardiac outcomes. This is not surprising, given the fact that patients with an established cardiovascular risk were disqualified from participation and those who did participate received few doses of the drug. None of the studies established that any of the COX-2 inhibitors was clearly better than ibuprofen for the treatment of surgically induced dental pain. However, in single-dosing scenarios, the tested COX-2 inhibitor often demonstrated a longer duration of action compared with ibuprofen, an expected finding given ibuprofen’s short half-life associated with the dosages administered.


   DISCUSSION
TOP
 ABSTRACT
 PHYSIOLOGY OF COX ISOENZYMES
 ANALGESIC EFFICACY OF COX-2...
 DISCUSSION
CONCLUSION
 REFERENCES
 
Analgesic efficacy. Ibuprofen is the prototypical NSAID and represents the gold standard against which new analgesic agents are evaluated.3,38 Unless there is a specific contraindication to their use, NSAIDs are considered the drugs of choice for treating acute dental pain in ambulatory patients who generally experience a higher incidence of adverse effects after ingesting an opioid analgesic.3,44,45 The aforementioned studies that addressed the efficacy of COX-2 inhibitors for the treatment of surgically induced dental pain failed to show any clear therapeutic advantage over ibuprofen.

Convenience and cost. Patients with acute dental pain often require analgesic therapy for a short time, usually two to four days.6,9 Typically, clinicians prescribe ibuprofen (400 milligrams) to be taken every six hours. This dosage regimen is predicated on the drug’s relatively short half-life. In contrast, the COX-2 inhibitors tend to have longer half-lives and, thus, the dosing schedule is less frequent. The relevance of this variation in dosing frequency over the relatively short period that analgesics are needed has not been evaluated thoroughly in clinical trials. While cost is an important factor in long-term dosing regimens and COX-2 inhibitors are several times more expensive than most NSAIDs, cost probably is not a major issue when prescribing analgesics for the treatment of acute odontogenic pain.6

Safety. As we search for better agents to treat odontogenic pain, we must not forget that our first responsibility is to do no harm. Premarketing clinical trials (phase I, II and III) generally include only 3,000 to 4,000 subjects. Adverse drug events (ADEs) that occur at a low frequency easily can be missed. In addition, premarketing clinical trials are of relatively short duration (weeks or months). Therefore, ADEs that develop with long-term use or those that involve a long latency period also may escape detection. Study groups often exclude children, women and the elderly and are seldom representative of the population exposed to the drug after FDA approval. Consequently, premarketing clinical trials detect only the most common ADEs. Those occurring more frequently than one in 1,000 subjects will be observed and listed subsequently in the product’s official labeling at the time of FDA approval. Therefore, the absence of evidence of harm is not evidence of safety.

Both nonselective NSAIDs and COX-2 inhibitors can induce nausea, vomiting, headache and dizziness. However, in neither case do the adverse effects occur at the rate observed with an opioid analgesic. In general, all COX inhibitors may suppress renal function and lead to a decrease in the effectiveness of angiotensin-converting enzyme inhibitors, angiotensin II antagonists and thiazide diuretics in controlling hypertension.6,44,45 However, a clinically relevant impact on hypertensive therapy usually does not become evident until after seven to eight days of treatment.45 The serum levels of such drugs as lithium, theophyline and methotrexate may be increased, leading to increased toxicity.46

Premarketing clinical trials detect only the most common adverse drug events.

After long-term use, nonselective NSAIDs increase the risk of developing peptic ulcer disease, GI bleeding and renal toxicity.44 The primary purported safety advantages of COX-2 inhibitors over nonselective NSAIDs relate to their theoretical lack of associated gastropathy.6,8,9,25,44 Nonselective NSAID–induced gastropathy is the single most frequently cited ADE (21 percent) in the United States and may underlie up to 35 percent of peptic ulcers reported worldwide.25

The risk of developing gastropathy depends on pre-existing risk factors, such as older age (> 60 years), a history of peptic ulcer disease or GI bleeding, a history of cardiovascular disease and concomitant use of prednisone.25 With long-term NSAID use, high-risk patients develop GI complications at a rate of 5 percent per year, while those with no pre-existing risk factors develop GI complications at a rate of 0.4 percent per year.17 However, when nonselective NSAIDs are prescribed for a short duration, the risk of developing serious gastropathy is estimated to be about 0.25 percent after one month, essentially the same as the risk attributed to rofecoxib.9

It is well-established that nonselective NSAIDs impair platelet function by blocking thromboxane A2 biosynthesis.16–18,20,24,25 However, thromboxane A2 is only one of many bioactive agents associated with platelet activation. Adenosine diphosphate also promotes platelet activation, while endothelium-derived prostacyclin and nitric oxide inhibit platelet function.28 Nonselective NSAIDs also block the synthesis of prostacyclin, but the net effect of these events is a relatively weak inhibition of platelet function in the great majority of patients.28

Coexisting conditions such as the presence of an underlying coagulopathy, alcohol use and concurrent anticoagulant therapy, however, may contribute to significant bleeding in patients receiving treatment with nonselective NSAIDs. COX-2 inhibitors do not block the formation of thromboxane A2.28,34 However, they do decrease the production of the platelet inhibitor prostacyclin.10,11,27 As noted above, prostacyclin also induces vasodilation and this action, along with its antithrombotic effect, likely protects against the development of hypertension and atherosclerosis.27 Mukherjee and colleagues10 and Topol11 postulated that the unaltered thromboxane formation combined with the reduced prostacyclin production induced by COX-2 inhibitors increases the patient’s risk of experiencing an adverse thromboembolic event.

Four recently published studies appear to confirm that such a risk exists.12–15 In a study investigating the use of rofecoxib as a chemopreventive agent for colorectal adenomas, Bresalier and colleagues12 determined that patients receiving rofecoxib treatment were at double the risk of experiencing an adverse cardiac event compared with control subjects. The increased risk became apparent after 18 months of therapy. In another study, Graham and colleagues13 compared the occurrence of adverse cardiac events in patients who received rofecoxib or celecoxib therapy during a three-year period. The authors determined that for patients who received standard or high-dose (> 25 mg/day) rofecoxib therapy, the risk of experiencing an adverse cardiac event increased 1.4-fold or 3.58-fold, respectively, compared with the risk in patients who received celecoxib therapy.

In another study evaluating the use of celecoxib for prevention of colorectal adenoma during a three-year period, the authors15 noted a dose-related tripling of the risk of developing cardiovascular events in patients receiving the drug therapy compared with that in control subjects. Finally, in a study evaluating the use of a 10-day regimen of parecoxib and valdecoxib; placebo and valdecoxib; or placebo alone to treat the postoperative pain associated with coronary artery bypass surgery, Nussmeier and colleagues14 noted that patients receiving either drug experienced a significant increase in cardiovascular events compared with control subjects.

It appears that because COX-2 is the chief source of prostacylcin, COX-2 inhibitors may increase cardiovascular risk by promoting platelet aggregation and vasoconstriction, which increase the risk of thrombosis and artherogenesis, and which, in turn, lead to myocardial infarction, sudden cardiac death and stroke.


   CONCLUSION
TOP
 ABSTRACT
 PHYSIOLOGY OF COX ISOENZYMES
 ANALGESIC EFFICACY OF COX-2...
 DISCUSSION
 CONCLUSION
REFERENCES
 
The successful treatment of acute odontogenic pain remains a challenge for the dental practitioner. Our analysis of the available data indicates that when compared with nonselective NSAIDs, COX-2 inhibitors are no more effective in relieving surgically induced dental pain, are more expensive, and contribute to increased cardiovascular and cerebrovascular morbidity and mortality in susceptible patients. In the rare event that a COX-2 inhibitor may be appropriate, the patient must be informed of the potential risks and the drug should be used for the shortest possible time.

Such compelling clinical scenarios may occur when treating patients with a history of intolerance to opioid analgesics or when treating patients with hypocoagulopathies in whom it may be prudent to reduce the antithrombotic product prostacyclin without changing the production of the prothrombotic product thromboxane A2. However, it is important to point out that concomitant low-dose aspirin therapy appears to greatly reduce the GI-protective effects of long-term COX-2 inhibitor therapy.47–49

As oral health care providers search for new therapeutic agents for patients with odontogenic pain, they must consider efficacy, convenience, cost and safety, as well as remember that the absence of evidence of harm is not evidence of safety.


   FOOTNOTES
 

Dr. Huber is an assistant professor and head, Division of Oral Medicine, Department of Dental Diagnostic Science, The University of Texas Health Science Center at San Antonio Dental School, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900, e-mail "Huberm{at}uthscsa.edu". Address reprint requests to Dr. Huber.


Dr. Terezhalmy is an endowed professor in clinical dentistry, The University of Texas Health Science Center at San Antonio Dental School.


   REFERENCES
TOP
 ABSTRACT
 PHYSIOLOGY OF COX ISOENZYMES
 ANALGESIC EFFICACY OF COX-2...
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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