COX-2 inhibitors show promise, but questions and concerns still linger

The drugs are as effective and safer than NSAIDs, but some physicians worry about higher cost and some unanswered questions
November 1999 Since becoming the first COX-2 specific inhibitor approved in the United States this January, Celebrex [celecoxib; G.D. Searle & Co.] has become one of the most successful drug launches in history, with more than 11 million prescriptions written as of October. Vioxx [rofecoxib; Merck & Co.], a COX-2 inhibitor approved in May, has also proven to be exceedingly popular. These strong performances are clearly due to the fact that the drugs filled an unmet need for an anti-inflammatory medication as potent as existing nonsteroidal anti-inflammatory (NSAID) drugs, but with fewer gastrointestinal (GI) side effects. However, while many orthopedic surgeons have embraced COX-2 inhibitors, it is still unclear what their overall role in the spectrum of care will be. They expand your ability to treat some patients that we couldnt treat because they couldnt tolerate the side effects, said Richard D. Coutts, MD, of the department of orthopedics and rehabilitation at the University of California at San Diego. Other factors such as cost could also play a part in the acceptance of COX-2 inhibitors, Coutts added. Patients with insurance that will not cover the drugs are shocked when they must pay upwards of $90 for a months supply, Coutts said. The daily wholesale cost for Vioxx is $2.02; the daily cost for Celebrex is $2.42. For those patients, it would make more sense to pay much less to get something like Naprosyn [naproxen] ibuprofen over the counter if they can tolerate it, he said. But I think thats going to continuously present a bit of a quandary to the clinician because there will be less-expensive alternatives, albeit perhaps with a slightly higher complication factor, Coutts said. Ultimately, however, I expect that the COX-2 inhibitors will become the predominant non-steroidal utilized, once clinical experience is gained with their effectiveness and cost comes down. Cost is an issue Edward G. McFarland, MD, director of the division of sports medicine and shoulder surgery at Johns Hopkins Hospital in Baltimore, prescribes COX-2 inhibitors for osteoarthritis (OA) of the knee and shoulder, as well as for rotator cuff tendonitis,

patellofemoral pain syndrome and other types of inflammation. McFarland said he uses Celebrex because it was the first COX-2 inhibitor on the market. However, he is sensitive to financial considerations as well. In cases where cost is an issue and all other things are equal, Ill use one of the less-expensive nonsteroidals because the patient, by and large, doesnt want to get hit with a big bill, he said. Joe Minchew, MD, a spine surgeon and assistant professor of orthopedics at the University of North Carolina School of Medicine in Chapel Hill, said he prescribes both Celebrex and Vioxx because he feels that both are relatively equivalent in terms of efficacy. Minchew said the COX-2 inhibitors work well for the pains that his patients experience due to OA of the spine and degenerative disc disease. For those patients many of whom are older and will likely be on medication for a while the better safety profile of the COX-2 inhibitors make sense. Like Coutts and McFarland, though, he is well aware of his patients concerns over cost. Cost really does become an issue, particularly in the older group who are often on Medicare and have fixed incomes, he said. Dispelling myths Minchew said he is also concerned about a few myths that have arisen regarding the drugs. The first myth is that they are better than traditional NSAIDs in terms of efficacy, he said. However, research has shown COX-2 inhibitors and NSAIDs to be relatively equal in that respect. In addition, while COX-2 inhibitors are clearly better than traditional NSAIDs when it comes to GI safety, they are not completely safe. That fact, he said, is borne out by several recently presented studies. One involved 5155 patients who took Celebrex for a period of up to two years and used blinded evaluations by an external independent review committee. Researchers reported an annualized incidence of upper GI side effects of 0.18% for Celebrex compared to the historical range of such complications 1.3% to 1.9% using conventional NSAIDs. A randomized, controlled, double-blind trial compared the ulcerogenic potential of Vioxx over the course of six months with ibuprofen and placebo in nearly 750 OA patients. At 24 weeks, the endoscopic study showed that 4.6% of patients receiving a once-daily, 25-mg dose of Vioxx were found to have ulcers, compared with 30.2% of the individuals taking 800 mg of ibuprofen three times a day.

Minchew is also troubled by what he believes is another myth of COX-2 inhibitors: that COX-1 is completely beneficial and that COX-2 is only destructive. COX-2 inhibitors are so named because they block cyclooxygenase-2, an enzyme that produces prostaglandins that are responsible for the pain and swelling that accompany arthritis. Traditional NSAIDs relieve pain by blocking COX-2, but they also block COX-1, an enzyme that protects the lining of the stomach and duodenum. A 1998 study attributed 16,500 deaths yearly in the United States to stomach perforations, ulcers and bleeds resulting from chronic use of NSAIDs. Minchew said those who view the two enzymes in black-and-white terms are oversimplifying things. There may be times when COX-1 is involved in inflammation and there are times where COX-2 may be involved in healing and blocking that more specifically may not be beneficial, he said. Brisk sales Despite those concerns, physicians have not been shy about prescribing the drugs. Physicians wrote about 150,000 prescriptions for Celebrex in its first four weeks on the market, making it second only to Viagra, which generated 570,000 in prescriptions in its first four weeks. As of August, Celebrex had garnered $103 million in sales, according to IMS Health, a health care information company in Plymouth Meeting, Pa. Vioxx generated $33 million in sales. As of September, Celebrex accounted for 21.7% of the antiarthritic market, while Vioxx sales comprised 8.7%. NSAIDs and other antiarthritic drugs controlled 69.6% of the market segment. While COX-2 inhibitors have clearly won many converts, the unresolved questions will only be answered by the experience and data generated over the coming years. I think these medicines are great and its no doubt they are a significant advance, said McFarland. I think over time were going to figure out which group they work best for and when the expense is worth it.