COX-2 Drugs – A Pandora’s Box of Adverse Effects
For years, non-specific anti-inflammatory drugs such as aspirin and paracetamol (acetaminophen) were the medications of choice for joint pain. But NSAIDs quickly became COX-2 inhibitors associated with adverse gastrointestinal effects such as peptic ulcers, leaving arthritis patients with a dilemma: manage the arthritis pain and risk serious stomach complications, or manage the ulcer and live with the pain.
Conventional NSAIDs work by decreasing the production of prostaglandins; they do this by inhibiting the enzyme cyclooxygenase (COX). Prostaglandins are responsible for inflammatory changes in the body.
But, despite being ‘demonised’ by modern medicine, prostaglandins also have important parts to play in everyday health. They are, for instance, involved in the normal functioning of blood platelets, the kidneys and lining of the gastrointestinal tract. Because of this, sweeping inhibition of prostaglandin synthesis can produce a variety of unwanted effects in addition to the desired helpful anti-inflammatory effect.
There are two distinct forms of COX enzymes in the body. The one known as COX-1 is released primarily in the gastrointestinal tract, kidneys and platelets. The other, COX-2, is released primarily in response to inflammation.
At least two COX-2 inhibitors, celecoxib (Celebrex, approved in December 1998) and rofecoxib (Vioxx, approved in May 1999) are available in the marketplace. In 2001, a third – valdecoxib (Bextra) – was added to the list. At their launches, the COX-2 inhibitors were considered a major advance in pain management.
But problems began to surface almost immediately. The first was calling these drugs ‘COX-2 inhibitors’, on the basis of a blood assay done in a lab, not in the body, despite the fact that the US Food and Drug Administration (FDA) has never approved the designation of any drug as ‘COX-2 specific’- that is, specifically designed to block only the actions of COX-2.
Currently available NSAIDs block both COX-1 and COX-2 to some degree (see box p 2), and it’s likely that inhibiting COX-1 causes the well-known toxic side-effects of NSAIDs – peptic ulcer, bleeding and perforation, and kidney damage. So, in theory, a drug that selectively blocks COX-2 will have anti-inflammatory effects, but without the toxic side-effects.
But, in reality, the actions of the two enzymes are not so well delineated. COX-1 and COX-2 serve identical functions in the body, and the involvement of the one more than the other depends on the other enzymes present – however specific they may act in the test-tube.
The FDA classes celecoxib, rofecoxib and valdecoxib as traditional NSAIDs. If the FDA approves a drug as a ‘COX-2 inhibitor’, it will probably have to demonstrate that it produces fewer serious gastrointestinal complications, such as bleeding, perforation and obstruction, than ordinary NSAIDs. But given the complex interactions of these and other enzymes in the body, none of the current so-called COX-2 inhibitors has yet been able to prove their specificity for COX-2 to the FDA’s satisfaction.
First, the good news
Human studies have found benefit with COX-2 inhibitors. When celecoxib and rofecoxib were compared with traditional NSAIDs (such as ibuprofen, naproxen and diclofenac) for osteoarthritis (OA) and/or rheumatoid arthritis (RA), results after six weeks showed pain relief that was significantly better than placebo in OA patients and comparable to that with traditional NSAIDs (J Rheumatol, 1999; 26: 2438-47). Similarly, patients with RA had significantly less pain, and joint swelling and tenderness with either rofecoxib or celecoxib than with a placebo (Lancet, 1999; 354: 2106-11; Clin Ther, 1999; 21: 1688-702).
Nevertheless, neither celecoxib nor rofecoxib has been taken for long enough periods of treatment in a large enough population to conclusively prove their safety.
Data from small trials do suggest a small reduction in GI events (JAMA, 1999; 282: 1919-33). Ulcers were far less frequent with celecoxib and rofecoxib in RA and OA patients compared with traditional NSAIDs. In OA, ulcers larger than 3 mm in diameter (which can develop into serious problems) were seen four to seven times less frequently with rofecoxib (depending on the dosage) than with ibuprofen (Gastroenterology, 1999; 117: 776-83).
In RA patients, the incidence of GI ulcers at 12 weeks with celecoxib was four to six times less frequent than with naproxen (Arthritis Rheum, 1998; 41: 1591-1602). However, with non-ulcer GI symptoms such as dyspepsia, rofecoxib and celecoxib have not convincingly proved able to reduce these symptoms compared with traditional NSAIDs.
The same study also found that neither of these COX-2 inhibitors interfered with blood clotting or bleeding time. However, both can slightly slow blood clotting in warfarin (Coumadin)-treated patients. Consequently, caution is now urged if patients taking anticoagulants are treated with selective COX-2 agents.
In the US, where drug companies are allowed to advertise directly to the public, ads on national television and in popular magazines regularly accentuate the positive side of the COX-2 inhibitors. Most reassure the public that these new anti-inflammatory drugs will safely reduce pain without the risks of adverse effects associated with older anti-inflammatories such as aspirin.
Unfortunately, the truth is that postmarketing medical research is rapidly proving that COX-2 inhibitors can be associated with severe and sometimes life-threatening toxic effects.
A price to pay
As with all ‘miracle cures’, the relief brought about by COX-2 inhibitors comes with a price. Much of the hoopla over these drugs has been based on the ‘fact’ that they cause fewer GI problems than conventional NSAIDs.
But, four years to the day after Celebrex was approved, a study suggests that the drug is no more effective in preventing a recurrent bleeding ulcer in arthritis patients than a traditional NSAID plus a proton-pump inhibitor such as Prilosec (N Engl J Med, 2002; 347: 2104-10). A popular treatment for heartburn that can help prevent stomach ulcers, Prilosec is often given to arthritis patients with a history of bleeding ulcer to counteract the high risk of NSAID aggravation of the problem.
In this study, nearly 5 per cent of patients taking Celebrex had recurrent bleeding – a potentially life-threatening condition – compared with 6 per cent of those taking a traditional NSAID plus Prilosec.
To medical news observers, this result was no surprise. In 1999, the findings of controlled clinical trials were already showing problems. In one of over 1000 patients with RA given celecoxib and compared with those given naproxen or a placebo, a similar rate of GI symptoms occurred with celecoxib and naproxen – 26 and 31 per cent, respectively.
The only real difference was with ulcers: naproxen resulted in five times more ulcers than celecoxib. Although the ulcers were usually less than 3 mm in diameter (and thus not clinically important), nevertheless, they can lead to serious ulcer complications such as perforation or bleeding (JAMA, 1999; 282: 1921-8).
In the same year, a review pooled the results of eight similar randomised controlled studies comparing rofecoxib, traditional NSAIDs and placebo in more than 5000 OA patients. The analysis focused on complications of GI ulcers (perforation, pain and bleeding). In a 12-month period, twice as many bleeding peptic ulcers were seen with NSAIDs than with rofecoxib. Rates for dyspepsia were similar in both groups – somewhere around 25 per cent (JAMA, 1999; 282: 1929-33).
An editorial accompanying the review suggested that to prevent one ulcer complication among low-risk patients in one year, some 500 patients would need to be treated with COX-2 inhibitors – at a cost of nearly $400,000 (JAMA, 1999; 282: 1961-3).
Taking heart
In the last couple of years, more disturbing adverse effects have come to light. An analysis by the World Health Organization of the side-effects of COX-2 inhibitors that have emerged since their release onto the marketplace suggests that the risks of kidney and cardiovascular problems (hypertension and cardiac failure) associated with the use of rofecoxib may be significantly greater than those associated with celecoxib or NSAIDs such as diclofenac and ibuprofen (Clin Ther, 2001; 23: 1478-91).
Other study results have only served to strengthen the WHO’s position. Indeed, the bad news has been uncovered almost by accident.
For instance, a recent review of smaller studies pooled the findings from 23,407 patients with data submitted to the US FDA by pharmaceutical companies (JAMA, 2001; 286: 954-9). Among these studies were two major randomised trials that originally investigated the gastrointestinal safety of rofecoxib and celecoxib: the Vioxx Gastrointestinal Outcomes Research Study (VIGOR), which involved 8076 patients, and the Celecoxib Long-term Arthritis Safety Study (CLASS), involving 7968 patients.
In the VIGOR, RA patients taking rofecoxib had a 238 per cent higher risk of having a cardiovascular event such as a heart attack, unstable angina, cardiac thrombus (blood clot), cardiac arrest, sudden or unexplained death, ischaemic stroke (due to narrowed or blocked blood vessels) and transient ischaemic attacks (mini-strokes in the brain) compared with those taking naproxen.
In the CLASS, there were no significant differences in cardiovascular event rates (myocardial infarction, stroke and death) between celecoxib and conventional NSAIDs (ibuprofen and diclofenac).
However, participants in the CLASS were allowed to take aspirin while those in the VIGOR were not – a twist that was significant for the gastrointestinal safety of celecoxib.
Although both studies were able to show an overall twofold reduction in serious GI complications, in the CLASS, this benefit with celecoxib was cancelled out if the patient also took low-dose aspirin. This finding is particularly relevant given the large number of elderly adults who regularly take low-dose aspirin to protect against heart attack.
Taken altogether, the yearly heart attack rates for COX-2 inhibitors, according to the findings in both the VIGOR and CLASS, were significantly higher than usual: 0.74 per cent with rofecoxib and 0.80 per cent with celecoxib compared with 0.52 per cent among those taking a placebo.
Not surprisingly, the results of this meta-analysis caused some outrage among COX-2 enthusiasts. They noted – and correctly – that neither CLASS nor VIGOR had been originally designed to look at cardiovascular events. Furthermore, they claim that the analysis of these data was done on a post-hoc basis – concluding a causal relationship between events solely because they took place one after the other in time.
Similarly, others have questioned the tactic of using ‘historical’ controls – comparing the findings with results from earlier studies in the medical literature.
Nevertheless, these disturbing findings raise a cautionary flag that should not be ignored.
Smaller studies have also thrown up problems with cardiovascular risk. In one study, blood pressure was increased significantly in 17 per cent of patients taking rofecoxib and in 11 per cent of those taking celecoxib (Am J Ther, 2001; 8: 85- 95). Indeed, no study so far has proven that taking COX-2 inhibitors is safe for the heart.
A kidney punch
High blood pressure increases the risk for heart attack and stroke, and also increases the risk of kidney failure. And case reports are now emerging that describe kidney problems in association with taking COX-2 inhibitors. What’s more, these kinds of side-effects are often reported as mere footnotes to studies – as if they are of no major importance at all.
In one report, it was concluded that Celebrex was effective for pain relief. Yet, the data also showed that celecoxib resulted in kidney problems such as hypertension, peripheral oedema and kidney failure in one-quarter of all patients receiving the COX-2 drug (N Engl J Med, 2002; 347: 2104-10).
In a recent case study reported in The Lancet, doctors describe a patient whose kidneys started to fail after taking Vioxx. The patient’s condition improved following discontinuation of the drug, an indication that the drug was the cause of the kidney dysfunction (Lancet, 2001; 357: 1946-7).
In another study comparing the effects of rofecoxib with the conventional NSAID indomethacin during regular long-term use, both drugs hampered the kidney’s ability to filter waste. However, the authors also suggest that the problem is likely to apply to the entire class of medications. This means that people on sodium-restricted diets and diuretic therapy, and those with impaired kidney function, hypertension, congestive heart failure or liver disease should avoid NSAID therapy, including COX-2 inhibitors (Ann Intern Med, 2000; 133: 1-9).
As sodium excretion by the kidneys is at least partly assisted by the COX-2 enzymes, the use of COX-2 inhibitors can slow the elimination of sodium from the body, thereby leading to fluid retention and raising high blood pressure even further (Curr Opin Rheumatol, 1997; 9: 178-82).
The decision to prescribe COX-2 inhibitors should take into account more than just the degree of pain.
According to Dr Joan M. Bathon in a discussion of COX-2 inhibitors in OA (www.hopkins-arthritis.som.jhmi. edu), there have been clinical trials showing that both rofecoxib and celecoxib can cause serious swelling of the feet even in patients who have normal kidney function.
Disturbingly, though, none of the current COX-2 inhibitors has yet been tested for safety in patients with compromised kidney function
Pain as a result of arthritis can be both debilitating and discouraging. Given that medical science has so little to offer sufferers of either rheumatoid arthritis or osteoarthritis in the way of a cure, simply relieving the pain of arthritis has become the major focus of treatment.
There are many alternative approaches that can help not only to reduce pain, but also to improve mobility and quality of life. A look at the ‘bigger picture’ of the problems of arthritic pain needs to be part of the conventional medical thinking if doctors are ever to offer sufferers more than a trade-off of debilitating symptoms.
Sidebar: Which drugs are COX-2 inhibitors?
All NSAIDs, even those not classed specifically as COX-2 inhibitors, can act to inhibit COX-2 in the body (J Rheumatol, 1998; 25: 2298-302; FASEB J, 1998; 12: 1063-73). From the most selective (they specifically inhibit prostacyclin, which stops platelets from clumping) to the least (from left to right, top to bottom), currently available COX-2-inhibiting drugs are:
rofecoxib (Vioxx)
etodolac (Ultradol)
meloxicam (Mobicox)
celecoxib (Celebrex)
diclofenac (Voltaren)
piroxicam (Feldene)
ibuprofen (Motrin)
naproxen (Naprosyn)
acetasalicylic acid (aspirin)
nabumetone (Relafen)
indomethacin (Indocid)
ketoprofen (Orudus, Orafin, Oruvail)
ketorolac (Toradol).
The gastrointestinal toxicity of an NSAID also varies according to dose and the drug, although all are associated with some degree of GI damage (Semin Arthritis Rheum, 1977; 26: 210). From the least GI toxic to the most (from left to right, top to bottom), these are the NSAIDs to watch out for:
ibuprofen (Motrin)
acetasalicylic acid (aspirin)
diclofenac (Voltaren)
naproxen (Naprosyn)
indomethacin (Indocid)
piroxicam (Feldene)
ketoprofen (Orudus, Orafin, Oruvail).
Based on data presented in Therapeutics Letter, January/February 2001, published by Therapeutics Initiative, University of British Columbia, Department of Pharmacology and Therapeutics, Vancouver, BC, Canada V6T 1Z3
Sidebar: Glucosamine for arthritis
Some observers believe that arthritis may be the result of abnormal glucosamine metabolism. In the body, glucosamine works by stopping the breakdown of proteoglycans (a major building block of cartilage) and by rebuilding damaged cartilage.
These days, glucosamine is hailed as a cure for osteoarthritis. Most supplements consist of the compound glucosamine sulphate as the sulphate form appears to strengthen glucosamine’s effect (Pharmatherapeutica, 1981; 2: 504-8).
Several studies suggest that glucosamine sulphate relieves pain better than NSAIDs like ibuprofen (Curr Med Res Opin, 1982; 8: 145-9; Pharmatherapeutica, 1981; 2: 504-8; Curr Med Res Opin, 1980; 7: 104-9). Also, instead of making the condition worse – like NSAIDs do (Am J Med, 1987; 83 [Suppl 5A]: 29-34) – it seems to reverse the disease by stimulating the production of more cartilage.
In one study, 80 patients with osteoarthritis were given either 500 mg of glucosamine sulphate three times a day or a placebo. While symptoms decreased in both groups, those receiving glucosamine had a significantly greater reduction in symptoms compared with placebo – 73 vs 41 per cent. Furthermore, a sample of cartilage from the placebo group, looked at under electron microscopy, showed definite evidence of osteoarthritis whereas samples from the treated patients showed what appeared to be healthy cartilage (Clin Ther, 1980; 3: 260-72).
The effects of glucosamine sulphate improve over time, so if you wish to try it, give it time – at least three months
Sidebar: Is copper a cure-all?
Although official organisations such as the Arthritis Research Foundation pooh-pooh the idea, in one study of 240 patients with rheumatoid arthritis (RA), those wearing copper bracelets showed statistically significant improvement compared with patients given a placebo bracelet (Agents Actions, 1976; 6: 454-9).
The very low incidence of RA in preindustrial Europe has been put down to the use of copper cooking utensils and plates (Rainsford KD, in Sorensen JRJ [ed], Inflammatory Diseases and Copper, Humana Press, 1982). Supplemental copper may, however, be better for some. Its anti-inflammatory effect is due to copper’s ability to create antioxidants (J Int Acad Prev Med, 1980; 7-21).
This is why practitioners of nutritional medicine sometimes advocate replacing conventional medicine’s high-dose aspirin therapy with a copper-salicylate supplement. In a study of more than 1000 RA patients given this copper-salicylate complex, 89 per cent showed better joint mobility, less joint swelling and normal red blood cell levels for an average of three years (Inflammation, 1977; 2: 217-38).
Sidebar: Nutritional help for arthritis sufferers
Although many doctors still don’t believe it, studies show that changing your diet can help alleviate arthritic symptoms (Lancet, 1986; i: 236-8).
* Eliminate allergens although, even if an individual is allergic to a particular food, this may not necessarily be linked to arthritis symptoms (Clin Exp Rheum, 1995; 13: 167-72). Nevertheless, it may be worth looking into common allergens such as dairy, soya, wheat and the nightshade family (potatoes, peppers, tomatoes and tobacco). In a study of 5000 arthritis patients, 70 per cent reported gradual relief after eliminating nightshades from the diet (J Int Acad Prev Med, 1982; Nov: 31-7). You may wish to see a specialist to arrange for food-allergy testing.
* Chemical sensitivity, especially to food additives or gas heating, may also be linked to arthritis symptoms.
* Fasting. Studies at the University of Oslo have found benefits from a short fast followed by dietary changes (Lancet, 1991; 338: 899-902; Scand J Rheumatol, 1995; 24: 85-93). In one two-year study, improvement was noted in patients with rheumatoid arthritis after fasting followed by an individually adjusted vegetarian diet for a year. Follow-up a year later showed that the benefit remained for those who had stuck to the vegetarian diet (Clin Rheumatol, 1994; 13: 475-82).
* Increase B vitamins. Both B5 (pantothenic acid) and B3 (niacinamide) have been shown to be beneficial at doses of 25 mg. They should be taken within a balanced B-complex supplement and should not be taken at night. Niacinamide reduces inflammation and increases joint flexibility, and may help reduce the amount of first-line anti-inflammatories sufferers need to take (Inflam Res, 1996; 45: 330-4). Also, for those taking methotrexate, folic acid supplements can reduce the toxicity of this powerful immunosuppressant drug (Arthritis Rheum, 1990; 33: 9-18).
* Gentle exercises such as yoga can relieve pain and improve joint function in those with osteoarthritis (J Rheumatol, 1994; 21: 2341-3). Likewise, tai chi was more effective than traditional exercise in improving range of motion (Am J Occup Ther, 1987; 41: 90-5).
* Increase healthy oils. Omega-3 fatty acids can reduce morning stiffness (J Rheumatol, 1992; 19: 1531-6) as can a diet high in polyunsaturated fat and low in saturated fat (Ann Rheum Dis, 2003; 62: 208-14; Lancet, 1985; i: 184-7). Blackcurrantseed oil, rich in gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA), can ease inflammation in RA (Br J Rheumatol, 1994; 33: 847-52). So can fish oil, though you need to take several capsules of EFA supplements daily to derive any benefit. Another alternative is green-lipped mussel extract (Allerg Immunol [Paris], 2000; 32: 272-8), which is not only rich in EFAs, but is also reputed to contain the powerful anti-inflammatory eicosatetraenoic acid (ETA).
* Other beneficial nutrients (apart from glucosamine) include selenium with vitamins C and E, recommended by the Institute of Optimum Nutrition. Antioxidants may be important as trials show that diets high in beta-carotene, and vitamins C and E can slow the progression of osteoarthritis (Arthritis Rheum, 1996; 39: 648-56). Other trials have shown that taking 400-600 IU of vitamin E daily may also help (J Am Geriatr Soc, 1978; 25: 328; Z Orthop, 1986; 124: 340-3).
* Check out homoeopathy. Several studies have shown that individually prescribed homoeopathic remedies can help arthritis (BMJ, 1989; 299: 365-6; Scand J Rheumatol, 1991; 20: 204-8); some may enhance the effect of conventional treatments (Br Homeopath J, 1986; 75: 148-57).
This article first appeared in the April 2003 (volume 14 number 1) edition of What Doctors Don’t Tell You
