COX-2 / Arthritis News

When they first emerged on the market, cox-2 inhibitors were considered the optimal painkiller for patients seeking relief from the pain and inflammation of arthritis and other joint diseases. Not only were they effective in minimizing disease symptoms, but brand name cox-2 inhibitors like Vioxx, Celebrex, and Bextra were easier on the stomach than many existing non-steroidal anti-inflammatory drugs (NSAIDS).

Once researchers discovered a link between using the drugs and an increased risk of heart attack and stroke, most of them were removed from the market, making the process of prescribing a cox-2 inhibitor for a patient a delicate process of weighing potential benefits versus risks. At the same time, researchers are finding alternative uses for cox-2 inhibitors, including cancer prevention and reducing nerve pain and damage.

How do cox-2 inhibitors work?
The class of drugs known as NSAIDS work by blocking the enzyme cyclooxygenase, When cyclooxygenase is blocked, it lowers the levels of the lipid prostaglandin, an agent known to cause pain and inflammation in patients with conditions like arthritis.

There are two types of cyclooxygenase, and traditional NSAIDS like ibuprofen and naproxen block both of them. Since one of the types, cox-1, also helps protect the stomach, traditional NSAIDS can cause gastrointestinal discomfort, especially for patients with chronic conditions like arthritis who may need to take them for longer periods of time.

The advantage of cox-2 inhibitors over more traditional NSAIDS is that they only block the second type of cyclooxgenase, cox-2. As such, they reduce pain and swelling and are easier on the stomach at the same time.

Cox-2 inhibitors and cardiovascular risk
There has been a significant amount of attention paid to the risk certain cox-2 inhibitors pose for the cardiovascular system. Before evaluating the drugs involved and the relative risk for certain groups of patients, it is important to first understand the mechanism by which these drugs affect the heart.

However, the same prostaglandin that is lowered by these drugs plays a crucial role in the cardiovascular system: protecting it from a different and damaging form of prostaglandin. By lowering the levels of the beneficial prostaglandin, the harmful type of prostaglandin can have an even more negative effect on the heart.

The FDA and Vioxx, Celebrex and Bextra: a breakdown of recent events The first time the potential cardiovascular risk these popular arthritis drugs posed was identified when researchers conducting a clinical trial to test Vioxx's ability to help prevent colon cancer noticed an increase in cardiovascular events in patients taking the drug for 18 months or longer.

In September of 2004, Merck voluntarily withdrew Vioxx (rofecoxib) from the market. Several months later, Pfizer also withdrew its cox-2 inhibitor, Bextra (valdecoxib), when similar reports were made about the increased incidence of heart attack and stroke in patients consuming the drug. Celebrex (celecoxib) wasn't removed from the market during this time because Pfzier, its manufacturer, maintained it didn't pose the same risks as Vioxx and Bextra.

Celebrex
In February of 2005, the Food and Drug Administration (FDA) announced its course of action in response to these safety concerns. The FDA asked Pfizer to include a "black box" warning with Celebrex, its strongest form of warning, to inform patients of an increased risk of cardiovascular events as well as a potentially life-threatening risk of gastrointestinal bleeding.

Despite the strong warning, the FDA agreed that the benefits of Celebrex outweighed the risks of the drug for certain patients seeking relief from pain. "Clearly someone who is leading a poor quality of life [due to pain] and understands the risks is a good candidate [for Celebrex]. I don't think we should take this pill out of the hands of doctors," said Dr. Michael Domanski of the National Institutes of Health.

The March 2006 issue of the American Journal of Medicine offers an update on the appropriateness of Celebrex in treating arthritis and related joint problems. The new large-scale study—called the Successive Celecoxib Efficacy and Safety Study-1 (SUCCESS-1)—confirmed Celebrex's efficiency in relieving symptoms in comparison with traditional NSAIDS, as well as its lower risk of GI events.

Importantly, this recent study found that the rates of cardiovascular events for patients on Celebrex were not significantly different from those patients taking traditional NSAIDS.

The point of SUCCESS-1 wasn't to investigate cardiovascular risk, however. Another study geared specifically towards evaluating cardiovascular risks of Celebrex versus traditional NSAIDs is expected to commence in coming months.

Vioxx
Also in February of 2005, the FDA recommended that Vioxx return to the market, but said much more safety information was needed before this could happen. Experts added that for those patients who had taken the hugely popular Vioxx, any increased risk of heart attack and stroke most likely dissipated once they stopped taking it.

Bextra
The fate of Bextra was then dealt a further blow when its additional risk of a serious and life-threatening skin reaction was recognized. Especially concerning was the fact that this adverse reaction to the drug was unpredictable; it occurred in patients who had a history of a sulfa allergy and those who didn't, and occurred in patients taking both short-term and long-term dosages. According to the FDA, "the overall risk versus benefit profile for the drug is unfavorable," and Pfizer agreed to suspend sales of Bextra pending further discussion.

Related FDA changes and the status of over-the-counter pain relievers In addition the black box warning for Celebrex, the FDA instated many other changes for NSAIDs. For example, manufacturers of all existing NSAIDS were asked to revise their labels to include a boxed warning stating an increased cardiovascular risk and serious GI bleeding. Celebrex and all other prescriptions were also asked to contain a medication guide for patients to help increase awareness of these risks.

Over-the-counter NSAIDS like Aleve and Advil were also asked to include more specific information regarding these increased risks, as well as the increased risk of skin reactions.

The FDA and legal action
The controversy over cardiovascular risk is not without legal ramifications for major pharmaceutical companies. For instance, Merck faces almost 10,000 lawsuits related to Vioxx, though it has won three of the first four cases that have gone to trial since the patients involved did not fall into the high-risk category—those patients taking the drug for 18 months or longer. This distinction is significant since the FDA recently proposed preventing alleged victims from suing pharmaceutical companies at the state level if the drugs have been declared safe.

Since Celebrex is still on the market and its cardiovascular risk is still being investigated, this ruling could have a great impact on its manufacturer, Pfizer.

So who should still avoid cox-2 inhibitors?
There are still certain groups of patients who should avoid cox-2 inhibitors, especially those patients recovering from cardiac surgery who may have once been prescribed the drugs to reduce their pain, as well as people who require a painkiller for long periods of time, as this is known to increase the risks.

Many elderly patients who Warfarin or Coumadin to thin the blood and control the clots that could cause heart attacks or strokes and also take cox-2 inhibitors for osteoarthritis pain face serious complications. A study out of Toronto's Institute of Clinical Evaluative Sciences found that cox-2 inhibitors doubled the risk of stomach bleeding in patients on Warfarin. When possible, study authors urged such patients to treat their arthritis pain with exercise and rub-on remedies to avoid the risk of bleeding posed by cox-2 inhibitors and over-the-counter NSAIDS alike.

Cox-2 inhibitors and other diseases: off-label uses and updates
Cancer
Both aspirin and cox-2 inhibitors have shown promise in several clinical trials in preventing the polyps that cause colon cancer.

"These agents may very well have a unique set of contributions for patients living with cancer or at risk for cancer. The data strongly support this and justify further investigation," said Dr. Ernie Hawk, director of the National Cancer Institute's Office of Centers, Training, and Resources.

Another trial found that women taking cox-2 inhibitors for at least two years greatly decreased their risk of developing breast cancer. Researchers at Ohio State University looked at women with invasive breast cancer and women in good health. By monitoring which women had also been prescribed cox-2 inhibitors, they could analyze whether taking the drugs increased or decreased the likelihood of developing breast cancer.

For now, this side effect is promising, but it is also worth noting that Celebrex's manufacturer, Pfizer, funded part of the study, the remainder of which was funded by the National Cancer Institute.

Nerve Pain and Damage
Initial clinical studies on rats have shown they may reduce the intense nerve pain and damage caused by diseases like Guillain-Barre´, chronic inflammatory demyelinating polyneuropathy, and peripheral neuropathy. Though more research is needed, it is believed that cox-2 inhibitors block the prostaglandin receptor responsible for neuropathic pain and peripheral nerve damage.

Researchers at Johns Hopkins have also discovered a link between cox-2 inhibitors and preventing brain damage caused by lack of oxygen during a stroke. The prostaglandin blocked by cox-2 inhibitors typically binds to receptors in the brain that cause inflammation and injury after a stroke, so blocking this molecular trigger altogether could greatly reduce the brain damage that often accompanies strokes.

Inflammatory Bowel Disease
In addition, recent studies published in Clinical Gastroenterology and Hepatology found that cox-2 inhibitors are effective in reducing the pain in patients with dormant inflammatory bowel disease and, unlike previously thought, do not increase the likelihood of relapses in patients experiencing remission. What this means for patients with conditions like ulcerative colitis and Chrohn's disease can take a drug like Celebrex for a short period of time without worrying the drug will cause their GI symptoms to flare. Further research is needed in terms of the effects of cox-2 inhibitors on patients with in an acute flare of inflammatory bowel disease.

The Future of Cox-2 Inhibitors
Arthritis medications like Vioxx, Bextra, and Celebrex have had a tumultuous few years since they burst onto the drug scene as the go-to choice for pain relief. For many patients, particularly those in good cardiovascular health who do not need to long-term courses, Celebrex is still considered a safe painkiller that reduces the gastric complications often associated with traditional NSAIDS. In the face of their more limited use, scientists are exploring new ways to use cox-2 inhibitors, and their use in cancer prevention and nerve damage are just some of the options on the horizon.