What are non-steroidal anti-inflammatory agents (NSAID's) and COX-2 inhibitors?
NSAID's and COX-2 inhibitors are medications that can decrease pain and inflammation and which have a long history of use in various kinds of arthritis and other painful conditions. There are two enzymes (body chemicals) that these medications can block: COX-1 and COX-2. COX-2 is the chemical that causes arthritis inflammation. COX-1 protects the stomach from ulcers. Both of these enzymes have many more actions, but the aforementioned are especially important to understanding the excitement that surrounded the introduction of COX-2 inhibitors. While it was believed that COX-2 inhibitors could stop inflammation in the joints without causing ulcers, it was later discovered that COX-2 inhibitors still caused ulcers, though fewer than the older NSAID's, which block both COX-1 and COX-2 (also called non-selective NSAID's). These older, non-selective medications include naproxen (Naprosyn® and Aleve®), diclofenac, (Voltaren®) and ibuprofen (Motrin®). The newer, COX-2 selective agents include rofecoxib (Vioxx®), celecoxib (Celebrex®) and valdecoxib (Bextra®).
Who ends up using these drugs, and for how long? What are the benefits? What are the dangers?
Many people use these drugs relatively briefly after an injury, but those who use NSAID's for the longest time are those with chronic arthritis. Recent studies raise concerns about the safety of COX-2 inhibitors, e.g., the study that led to Vioxx® coming off the market. These studies suggest cardiovascular issues only after long-term use, and in the Vioxx® study, the problem only showed up after 18 months of use. This creates a quandary; the people most likely to have a problem with these drugs are also the ones who need them the most -- that is, people with chronic arthritis. When COX-2 inhibitors first came on the market, it was suggested that they be used for patients at higher risk for ulcer, such as those who had a prior ulcer. Over time, this use extended to people at lower ulcer risk, as 1) physicians believed these drugs might be safer for everyone and 2) several pharmaceutical manufacturers began large direct-to-consumer ad campaigns. New data has raised the question about whether these drugs should again be used in a more select group of people.
Why were Vioxx® and Bextra®, two of the COX-2 inhibitors, removed from the market? What has the FDA said about COX-2 inhibitors?
In a study to discover if Vioxx® reduced the development of polyps in the colon, an increased risk of heart attack and stroke was shown after 18 months in patients taking Vioxx®. A prior study had suggested more hypertension and edema in patients on Vioxx®, but that earlier study was felt by many physicians to actually reflect protection of the heart by naproxen, the drug being compared to Vioxx®. This is still a matter of some debate. The FDA Arthritis Advisory Panel in February of 2005 advised that all three COX-2 inhibitors might remain on the market, but with warnings about cardiovascular risk. On April 7, 2005, however, the FDA revised their earlier decision, deciding that Celebrex® could remain on the market while requesting that the manufacturer voluntarily withdraw Bextra®. The FDA stated that they were concerned about both cardiovascular and skin toxicity with Bextra®, and did not think there was sufficient data about its safety or effectiveness to justify its continued availability. For Celebrex®, the FDA will require a "black box" warning about cardiovascular risk. For Vioxx®, should the manufacturer wish to put it back on the market, a new public hearing would be required.
Are the older, non-selective, non-steroidal anti-inflammatory agents safer than the COX-2 inhibitors?
On April 7, 2005, the FDA recommended that all NSAIDs, including all over-the-counter agents except aspirin, carry the same "black box" warning as Celebrex about cardiovascular risk. One previous study had suggested that naproxen may increase risk of heart attack and stroke, but there is no conclusive evidence to show cardiac risk for this medication. However, all the NSAID's, both selective and non-selective, can cause hypertension and fluid retention, which can lead to cardiac problems. Currently, the number of long-term studies of the older non-selective medications is very limited, and this leads physicians to fear that if used long-term, these medications may not actually turn out to be safer than the COX-2 inhibitors-this was the basis for the FDA's broad "black box" requirement. It is important to note that there are a number of chronic arthritis sufferers who have very limited mobility without an NSAID, and in many of these cases, a decision may be made to use one of these medications. The decision would depend on which drugs had helped them before, their risk of ulcer and cardiovascular disease, and the alternatives to using NSAID's which are discussed in the next section. It is possible that some people may have success on smaller doses of a COX-2 inhibitor such as Celebrex®, since studies to date have only shown cardiovascular problems when studying patients on higher doses.
What are the alternatives to both COX-2 inhibitors and older non-steroidal anti-inflammatory agents?
A number of other choices are available. In people with rheumatoid arthritis (RA), treatment with a medication that alters the course of their disease, such as methotrexate, may allow them to come off an NSAID. For all kinds of arthritis, other ways to seek pain relief include physical and occupational therapy, local injection with steroids or viscosupplementation (fluids somewhat similar to natural joint lubricants which can decrease pain in osteoarthritis), local heat and ice, splinting, acupuncture, biofeedback, and stress reduction. Pain killers such as acetaminophen (e.g. Tylenol®), codeine, tramadol (Ultram®), propoxyphene (Darvon®), and oxycodone (Percocet®) can often be taken on an "as needed" basis. There is also evidence that the supplements glucosamine and chondroitin sulfate may help with osteoarthritis stiffness and pain. In some patients, a surgical procedure -- such as a total joint replacement -- can dramatically reduce their susceptibility to ongoing pain once their post-operative pain resolves.
How may this issue become clearer in the future? What is the best course for someone with chronic pain right now?
To truly answer the key questions about COX-2 inhibitors and non-selective NSAID's and the cardiovascular system, a large, government-sponsored study should be conducted to compare them over a two year period. This is a difficult (and very expensive) study to do, but many support this option. It would also be very helpful to have smaller studies in arthritis patients at high risk of cardiovascular disease -- at lower doses of the medications -- to monitor the safety of their medications over a two-year period. For now, however, it is clear that each person with chronic arthritis pain needs to discuss the pros and cons of the NSAID's and COX-2 inhibitors with their physician, in relation to their particular case. That discussion needs to include how much pain the person has, which alternatives are available, what has worked for them in the past, their risk for ulcer and cardiovascular disease, and their own personal preferences. Only by individualizing these factors can physicians discover the best course of action for each person.
This article originally appeared in the Summer 2005 edition of HealthConnection, Hospital for Special Surgery's patient education newsletter.
