What You Should Know About COX-2 Inhibitors

Are COX-2 inhibitors good alternatives to nonsteroidal antiinflammatory drugs (NSAIDs)? Yes, traditional NSAIDs inhibit both COX enzymes but they have well-documented gastrointestinal side effects. NSAIDs can cause severe electrolyte disturbances and renal complications such as hyponatremia, hyperkalemia, edema, hypertension, acute and chronic tubulointerstitial nephritis, papillary necrosis and glomerular lesions. Patients with prostaglandin-depleted disease states (cirrhosis, congestive heart failure, chronic renal failure, volume depletion, and nephrosis) who use NSAIDs often develop acute renal insufficiency.1
There are 100,000 hospitalizations per year and 16,000 deaths per year in the U.S. alone due to NSAID complications.2 The development of COX-2 inhibitors has reduced the GI toxicity, however recent studies have revealed potential renal and cardiac complications with COX-2 inhibitors.

Understanding The Dynamics Of NSAIDs And COX-2 Inhibitors
In order to use these medications appropriately, it is essential to have a clear understanding of how they work and a strong awareness of possible side effects.
NSAIDs work by inhibiting COX, the rate-limiting enzyme in the metabolic conversion of arachidonic acid into prostanoids. COX-1 enzymes are found in most tissues and are important in hemostasis and in protecting gastric mucosa. COX-2 enzymes are induced in inflammatory states and tumorigenesis and can be found in neural and renal tissues.

The COX-2 protein is located in the macula densa along the cortical thick ascending loop of Henle and medullary interstitial cells. Cyclooxygenase stimulates the conversion of arachidonic acid into prostanoids. During the inflammatory process, COX-2 can be induced by a variety of stimuli, including endotoxins, cytokines, interleukin-1 and tumor necrosis factor-alpha.3 The most important prostanoids in the kidney are prostacyclin (PGI2) and prostaglandin (PGE2).
Prostaglandins contribute to pain and inflammation. They are potent vasodilators, producing painful edema and sensitize pain receptors to histamine thus lowering the threshold for pain response. PGE2, produced by COX-2, inhibits salt and water reabsorption by the ascending limb and collecting duct. PGE2 is necessary for rejection of NaCl reabsorption. Blockage of PGE2 production by NSAIDs can inhibit salt excretion, leading to peripheral edema, weight gain and increased blood pressure.4 COX-2 inhibitors are not without renal side effects (see “Renal Side Effects of COX-2 Inhibitors” below).4 Increased circulatory volume causes greater tubular flow and secretion of potassium. In healthy individuals, renal prostaglandins do not play a major role in sodium and water homeostasis.5

PGI2 increases potassium secretion. Its inhibition can result in hyperkalemia, particularly when there is underlying renal insufficiency. Hyperkalemia is relatively uncommon and is not prominent with COX-2 inhibitors. Patients receiving potassium supplementation, potassium sparing diuretics or ACE inhibitors have the greatest risk of having an increased potassium level.5 Keep in mind that PGI2 is also a potent vasodilator and helps maintain renal perfusion. Inhibition of PGI2 results in acute renal failure, which usually starts within the first days of therapy and the risk factors include sepsis, shock, SLE, hypereninemia and hyperaldosteronemia.5
Edema and salt and water retention are the most common side effects associated with NSAIDs, affecting 2 to 5 percent of patients who take them.4 The edema and sodium retention are mild and result in weight gain of 1 to 2 kg that occur mostly within the first week of therapy.5 Some risk factors that may predispose patients to this complication are diabetes mellitus, renal disease, circulatory compromise and advanced age. It is unclear whether some selective COX-2 inhibitors produce less edema than others at doses of equal potency and duration. All COX-2 inhibitors have the potential to lead to salt and water retention, edema, exacerbation of CHF and increased blood pressure.
Traditional NSAIDs do cause an increase in baseline blood pressure especially when the patient is taking beta-blockers, calcium channel blockers and ACE inhibitors. Studies have shown NSAIDs reduce the antihypertensive efficacy of diuretics.4 The overall incidence of hypertension is low in those who use COX-2 inhibitors.

Patients with reduced GFR and decreased renal perfusion are at the highest risk of reduced renal function. Typically, there is a rise in blood urea nitrogen (BUN) and serum creatinine with NSAIDs. This is due to inhibition of prostaglandin-mediated vasodilation of preglomerular vessels. Acute deterioration of renal function can be reversed in selected populations, usually younger adults. Only a very small percentage of normal individuals will experience a decrease in GFR. Patients with a serum creatinine of 2 mg/dL may benefit from renal function monitoring during a COX-2 inhibitor regimen, especially if prolonged use is necessary.4
Most renal side effects are reversible after treatment has been discontinued. The side effects described above from the coxibs are dose-related and patients should adhere to the prescribed regimen.5
It is recommended that you use COX-2 inhibitors judiciously in high-risk patients (such as those with chronic renal insufficiency, diabetes, CHF).4 At this time, it is unclear whether long-term use of COX-2 inhibitors will cause significant incidence of interstitial nephritis and papillary necrosis.

Addressing Cardiovascular Concerns
Recent studies have demonstrated an increased risk of cardiovascular events associated with COX-2 inhibitors.6,7 Cyclooxygenase-2 catalyzes the conversion of arachidonic acid to eicosanoids that play an important role in maintaining cardiovascular hemostasis. Thromboxane A2, which is primarily synthesized by platelet COX-1, causes irreversible platelet aggregation, vasoconstriction and smooth muscle proliferation, all of which are linked to coronary heart disease (CHD).
In contrast, vascular prostaglandins I2 (PGI2), which appears to be mostly synthesized by COX-2, counteracts most of these effects of thromboxane A2. This essentially will tip the balance in favor of prothrombotic eicosanoids and lead to increased cardiovascular thrombotic events.6 However, there are no suggestions of an increased death rate from vascular disease following the launch of celecoxib or rofecoxib.8 Many researchers urge caution in prescribing these agents to patients at risk for cardiovascular morbidity.

What About The Effect Of COX-2 Inhibitors On Bone Metabolism?
Using COX-2 inhibitors and bone metabolism is a very complicated issue. Both osteoblasts and osteoclasts can be induced to express the COX-2 enzyme. Prostaglandins play a major role in bone formation and resorption. The major effects of PGs are to stimulate osteoclasts and osteoblasts. COX-2 expression in bone is highly regulated by the systemic and local hormones, cytokines and growth factors that control bone remodeling.3 It is very difficult to predict whether patients will have a beneficial or adverse bone effect.
Outcomes will be different in different types of people. People with high bone turnover (inflammatory disorders, postmenopausal or senile osteoporosis) will have the greatest response.9 Consequently, COX-2 could block bone formation and theoretically weaken the bony skeleton. Obviously, further studies are needed to determine the full effect of COX-2 inhibitors on bone metabolism.

Pertinent Pointers On Drug Interactions And Contraindications
It is not uncommon today for many elderly patients to be on multiple pain medications. We have started using increased dosages of COX-2 inhibitors for elderly patients during the postoperative period. For example, we may prescribe celecoxib 200 mg twice a day. The concomitant use of COX-2 inhibitors and opiate can reduce narcotic consumption.2 COX-2 inhibitors are not contraindicated in pre- or post-surgical patients and should not aggravate postoperative bleeding.
However, COX-2 inhibitors have not been extensively studied in patients younger than 18 years and are not recommended for use in children and adolescents.10 Coxibs are also classified as pregnancy C medications. You should not use these drugs for lactating women or in women who are in their third trimester of pregnancy.10
Both celecoxib and rofecoxib are metabolized in the liver, which is important in our poly-pharmacy elderly population. Celecoxib is metabolized and excreted, primarily by the liver, into bile. Rofecoxib is metabolized by liver enzymes and excreted in the urine.
There are several potential drug interactions for celecoxib and rofecoxib. For instance, celecoxib inhibits cytochrome P450 2D6, which may increase the plasma concentration of drugs (beta-blockers, antidepressants, antipsychotics, and antiarrhythmics) metabolized by this system.2, 10 You should also exercise caution when administering celecoxib with inhibitors of 2C9 (fluconazole) as these will tend to increase the plasma concentration of celecoxib. Rofecoxib is not recommended for treating patients who have moderate to severe hepatic insuffiency.10 You should monitor hepatic enzymes if you suspect liver dysfunction.

Be sure to advise patients that both coxibs interact with warfarin. You should closely monitor anticoagulant levels when initiating or increasing antiinflammatory therapy. Both celecoxib and rofecoxib have been shown to cause a slight elevation of prothrombin time in patients who are taking warfarin.10
COX-2 inhibitors do not impair platelet function or delay bleeding time. However, sometimes anemia is seen in patients receiving valdecoxib. Patients who are on long-term therapy should have their hemoglobin and hematocrit checked. Thromboxane, a prostaglandin, is responsible for platelet aggregation. It is synthesized by COX-1 so COX-2 will have no effect of thromboxane synthesis. In fact, the newest coxib, valdecoxib, has been recommended as a safer analgesic option than conventional NSAIDs in patients for whom bleeding complications is a concern.11 However, patients who use aspirin or NSAIDs for prophylaxis thromboembolic events cannot use COX-2 inhibitors as a substitute.2,10 Aspirin has unique properties causing irreversible platelet inhibition that should not be overlooked.

Taking A Closer Look At COX-2 Indications
COX-2 inhibitors do not interact with methotrexate for the rheumatoid patient. In fact, celecoxib, rofecoxib and valdecoxib are all indicated in treating the signs and symptoms of adult rheumatoid arthritis (RA). Besides being used for osteoarthritis (OA) and RA, physicians are using coxibs for other arthritides such as ankylosing spondylitis, gout, pseudogout and bursitis. In fact, when patients have acute gouty attacks, we will occasionally use a double dose of valdecoxib or celecoxib during the first week of treatment when patients can’t tolerate indomethacin or have inflammatory bowel disease.
At our institution, we routinely prescribe celecoxib 200 mg twice a day for the first five postoperative days and then 200 mg once a day. Recently, we have started using valdecoxib for acute pain relief. Rofecoxib is indicated for the management of acute pain at a dosage of 50 mg once a day. Many researchers have disputed the use of NSAIDs in the postoperative period. In a recent study, Simon et. al., found radiographic, histological and mechanical evidence of failed fracture healing in rats treated with COX-2 inhibitors. 12
There have been no conclusive studies on humans studying the results of bone healing and NSAIDs. COX-2 may be required for normal endochondral ossification, but we have found no delay in wound or bone healing or any other complications associated with using COX-2 inhibitors postoperatively. Furthermore, there is no evidence to suggest that COX-2 inhibitors adversely affect the bone surrounding any implants. We routinely prescribe coxibs for patients who have hallux limitus, metatarsal fractures or lateral ankle sprains and after performing metatarsal osteotomies, rearfoot arthrodesis and Charcot joint reconstruction. Prescribing coxibs also helps reduce postsurgical requirements for opioids after performing extensive surgery.

What About Heel Pain And Acute Soft Tissue Injuries?
Antiinflammatory medications are routinely used for plantar fasciitis and other forms of heel pain. Typically, patients are more reluctant to try COX-2 inhibitors than traditional NSAIDs. Therefore, we use celecoxib, rofecoxib and valdecoxib as the initial oral treatment for heel pain. However, this depends on the patient’s prescription coverage. If a patient does not gain substantial relief from any of the COX-2 inhibitors, then we will usually try a conventional NSAID-like piroxicam along with inserts, stretching and injections. Many of our patients have been very satisfied with the coxibs and routinely ask for a COX-2 inhibitor when periodic heel pain reoccurs.
Treating acute soft tissue injuries is one of the widest uses of COX-2 inhibitors. Antiinflammatories can be a great adjunctive to other conservative modalities. We use COX-2 inhibitors in patients with Achilles tendonitis, lateral ankle sprains, posterior tibial tendonitis and peroneal tendonitis. A recent study on rats analyzed the effects of celecoxib and ligament healing.13 The results of this study did not support using COX-2 inhibitors to treat ligament injuries. However, we have not found any problems using coxibs in our patients for soft tissue injuries.

Final Notes
There are many future applications of COX-2 inhibitors still under investigation. Parecoxib, a new parenteral COX-2 inhibitor, is intended for perioperative analgesic and antiinflammatory use.14 This drug appears to be an alternative to Toradol for those patients with renal disease.

An expert panel from the Journal of Rheumatology published its recommendations regarding the clinical use of cycloxygenase-2 inhibitors (see “Recommendations For Using COX-2 Inhibitors” at right).15 If a patient is using a traditional NSAID and has shown clinical efficacy without apparent adverse effects, then the need to switch to a COX-2 inhibitor is a matter of clinical judgment. Keep in mind that serious NSAID-induced gastrointestinal complications can be asymptomatic. You might consider using an effective gastroprotective agent.
There have been no studies examining the safety of COX-2 drugs and conventional NSAIDs along with a gastroprotective agent. If your patient is not currently using a conventional NSAID but requires antiinflammatory or analgesic therapy, then choosing an NSAID or a COX-2 inhibitor is a matter of clinical judgment. The aforementioned risk factors should probably guide you into using a COX-2 inhibitor.
COX-2 inhibitors appear to be an alternative to narcotics and traditional NSAIDs. While podiatrists should be aware of the potential renal and cardiac side effects as well as the potential drug interactions, these drugs can be beneficial in managing postoperative pain, gout and chronic osteoarthitis. With more indications for COX-2 inhibitors, podiatrists may rely less on conventional NSAIDs and narcotics for pain control.

Dr. Rampetsreiter is a second-year resident at Forest Park Hospital in St. Louis under the direction of Allen M. Jacobs, DPM, FACFAS.

References:

References

1. Perazella MA, Eras J. Are Selective COX-2 Inhibitors Nephrotoxic? American J. Kidney Diseases 2000; 35:937-940.

2. Bell GM, Schnitzer TJ. COX-2 Inhibitors and Other Nonsteroidal Anti-Inflammatory Drugs In The Treatment Of Pain In The Elderly. Clin. Geriatric Medicine 2001; 17:489-502.

3. Appel GB. COX-2 Inhibitors and the Kidney. Clin Exp Rheumatology 2001; 19:S37-S40.

4. Buttar NS, Wang KK. The “Aspirin” of the New Millennium: Cyclooxygenase-2 Inhibitors. Mayo Clin Proc 2000; 75: 1027-1038.

5. Harris RC. Cycloxygenase-2 Inhibition and Renal Physiology. Am. J. Cardiology 2002: 89 (suppl):10D-17D.

6. Garcia Rodriguez LA. The Effects of NSAIDS on the Risks of Coronary Heart Disease: Fusion of Clinical Pharmacology and Pharmoepidemiologic Data. Clin Exp Rheumatology 2001; 19 (suppl 25):S41-S44.

7. Mukherjee D, Nissen SE, Topol EJ. Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors. JAMA 2001; 286:954-959.

8. Jackson LM, Hawkey CJ. COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs: Do They Really Offer Any Advantages? Drugs 2000; 59:1207-1216.

9. Raisz LG. Potential Impact of Selective Cyclooxygenase-2 Inhibitors on Bone Metabolism in Health and Disease. Am J Med 2001; 110:43S-45S.

10. Noble SL, King DS, and Olutade JI. Cycloxygenase-2 Enzyme Inhibitors: Place in Therapy. Amer Fam Physician 2000; 61: 3669-3676.

11. Leese PT, Talwalker S, Kent JD, Recker DP. Valdecoxib does not impair platelet function. Am. J Emerg Med 2002; 20:275-281.

12. Simon AM, Manigrasso MB, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner res 2002; 17:963-976.

13. Elder CL, Dahners LE, Weinhold PS. A cyclooxygenase-2 inhibitor impairs ligament healing in the rat. Am J Sports Med 2001; 29:801-805.

14. Ibrahim A, Park S, Feldman J, Karim A, Kharasch ED. Effects of parecoxib, a parenteral COX-2 specific inhibitor, on the pharmokinetics and pharmacodynamics of propofol. Anesthesiology 2002; 96:88-95.

15. Lipsky PE. Recommendations for the Clinical Use of Cyclooxygenase-2 Specific Inhibitors. Am J Med 2001; 110:3S-5S.

Additional References

16. Frishman WH. Effects of Nonsteroidal Anti-Inflammatory Drug Therapy on Blood Pressure and Peripheral Edema. Am J Cardiology 2002; 89(suppl):18D-25D.

17. Katz WA. Cyclooxygenase-2 selective inhibitors in the management of acute and perioperative pain. Cleve Clin J Med 2002; 69 S: SI65-75.

18. Lema MJ. Emerging options with coxib therapy. Cleve Clin J Med 2002; 69 S: SI76-SI84.