What's the Word on NSAIDs?

NSAIDs (pronounced "en-seds") are probably the most widely used class of drugs in the country.  More than 30 billion over-the-counter capsules, pills, and tablets are sold in the U.S. each year, and another 70 million prescriptions are filled for NSAIDs. Indicated for mild-to-moderate pain accompanied by inflammation, NSAIDs are inexpensive, nonaddictive, and nonsedating. We take them for headaches, neck and back pain, sports injuries, and menstrual cramps—as well as for muscle aches, sprains, and strains. At least half the prescriptions written for NSAIDs are for joint pain and inflammation, also known as arthritis.

The NSAID Line-up

Acetylsalicylic acid, aka aspirin, was the very first NSAID, originally isolated from willow bark. That was more than 120 years ago. Since that time, dozens of other products have joined aspirin on America's pharmacy shelves. Here are some that are available as over-the-counter preparations:

• Ibuprofen (Motrin^®, Advil^®)
• Naproxen sodium (Aleve^®)
• Ketoprofen (Orudis^®)

Prescription-only NSAIDs include the following:

• Naproxen (Anaprox^®, Naprosyn^®, Naprelan^®)
• Ketorolac (Toradol^®, Acular^®)
• Diclofenac sodium (Voltaren^®) 
• Piroxicam (Feldene^®)
• Sulindac (Clinoril^®)
• Indomethacin (Indocin^®) 
• Nabumetone (Relafen^®) 
• Oxaprozin (Daypro^®)
• Etodolac (Lodine^®) 
• Flurbiprofen (Ansaid^®)
• Diclofenac potassium (Cataflam^®)

A newer category of NSAIDs are the COX-2 inhibitors, which include:

• Celecoxib (Celebrex^®)
• Valdecoxib (Bextra^®)
• Rofecoxib (Vioxx^®)

IMPORTANT: Be aware that the COX-2 inhibitors have been associated with an increased risk of cardiovascular and thrombotic (clotting) events. Rofecoxib (VIOXX) has been pulled off the market for this reason. Even though COX-2 inhibitors may not specifically trigger IBD, it's important to discuss their associated risks, benefits, and side effects with your doctor before taking them.

How NSAIDs Work

As their name implies, NSAIDs work by checking inflammation, which is the immune system's way of responding to injury. Inflammation commonly manifests itself as pain and swelling.
   
Unlike steroids, which quiet inflammation by suppressing the immune system, nonsteroidals (that is, NSAIDs) have a different mode of action. They act by stopping an enzyme—a protein that stimulates changes in the body—from performing its function.  The enzyme in question is cyclooxygenase, otherwise known as COX, which has two forms. The first, COX-1, aids the kidneys; it also guards the stomach lining against digestive chemicals and acids. The second, COX-2, is an enzyme that makes prostaglandins, hormone-like substances that protect the digestive tract but also intensify inflammation, pain, and fever.
 
NSAIDs manage to relieve inflammation and pain by blocking the activity of both COX-1 and COX-2. But in doing so, they also may cause stomach upset and, occasionally, ulcers in both the stomach and duodenum (the first part of the small intestine) as well as bleeding.
 
To counter those effects, another category of NSAIDs was developed. These are the COX-2 inhibitors, which block the action of the COX-2 enzyme that plays a key role in pain and inflammation. Because the COX-1 enzyme isn't its target, this class of drugs does not provoke the undesirable gastrointestinal symptoms as often as traditional NSAIDs do.

The IBD-NSAID Connection

So now we've found out that NSAIDs are pretty much today's wonder drugs when it comes to easing everyday aches and pains. And we've also learned a bit about the mode of action by which NSAIDs accomplish their effect. However, it's that very mechanism that concerns some gastroenterologists when it comes to their patients with Crohn's disease or ulcerative colitis—collectively known as inflammatory bowel disease (IBD).
 
In healthy people, the intestinal environment maintains a healthy balance, with anti-inflammatory proteins keeping pro-inflammatory molecules in check. In people with IBD, however, the immune system can't calm the inflammatory response occurring in the gut. The result is damage to the intestinal lining, which also causes ulcers and increases the flow of intestinal contents, leading to diarrhea and bleeding.

In addition to causing chronic inflammation of the digestive tract, this inappropriate immune response also accounts for the presence of disease beyond the intestine, as inflammatory cells are found in the joints, among other parts of the body. In fact, arthritis is the most common "extraintestinal" complication of IBD, affecting approximately 25% of people with Crohn's disease or ulcerative colitis. It's certainly the leading reason that they take NSAIDs.

Losing the Prostaglandin Protection

However, although NSAIDs block prostaglandins—and thereby reduce the fever, pain, and swelling that prostaglandins cause—that's not necessarily a good thing for the gastrointestinal (GI) tract. It seems that prostaglandins play a useful role there, where they have a protective effect on the mucosa (the lining of the gut). They can quell the effects of cytokines (proteins released by the immune system) that produce inflammation.  In short, that means that although NSAIDs can ease joint pain (for example), they also may cause damage to the mucosa in healthy people or reactivate the symptoms of disease in IBD patients.
    
This potential danger has created some controversy among GI specialists. While some experts see a clear-cut link between NSAID use and flares of disease in people with IBD, others are less convinced.

A Different View

Among the "less convinced" is Uma Mahadevan, M.D., Clinical Assistant Professor of Medicine and Director of Clinical Research at the University of California San Francisco Center for Colitis and Crohn's Disease. She has her own idea about why this issue has become controversial.

"It's because the data are so mixed," explains Dr. Mahadevan. "The initial studies looked at people who came into the hospital with a disease flare and observed that a higher percentage of them had recently taken NSAIDs.

"But if you really examine the data, over-the-counter NSAID use is not well accounted for in all patients. It may be that the people presenting with flares started having arthritis aches and pains related to their disease recurrence so they took NSAIDs to relieve the symptoms. In other words, their disease flare had already begun, and the NSAIDs were used to treat the symptoms rather than trigger them. More recent data from a larger population did not find any increased risk of flare with these medications."

Individualizing Treatment

Cause and effect issues—like the chicken and the egg question—are often difficult to sort out. The question is further complicated by the fact that, as Dr. Mahadevan notes, half the studies say one thing and half say another.
    
One group of U.S. and Danish researchers, headed by principal investigator William J. Sandborn, M.D., recently conducted a controlled trial of the COX-2 inhibitor, celecoxib (Celebrex®), in patients with ulcerative colitis in remission. Comparing patients taking Celebrex versus placebo (inactive substance), they found celecoxib to be as safe as placebo in colitis patients requiring NSAID therapy. They further observed no increase in disease flares in either group.

And in the meantime?  "I think you really have to approach this on a person-by-person basis," observes Dr. Mahadevan.  "If people can tolerate NSAIDs, then it's all right for them to take this class of drugs. That's probably the best answer. For the most part, when they're in remission and the mucosa is quiet, individuals are more likely to tolerate NSAIDs; that's the safest time to take these drugs. When disease is active, inhibiting pathways of prostaglandin and other mediators of inflammation may have more of a detrimental effect than when people are in remission and everything's quiet."
   
If her patients ask if they can take an NSAID, Dr. Mahadevan offers this recommendation.  "I tell them they should take it in limited doses when they're in remission. If they begin to experience increased symptoms of their disease, then they should stop the drug immediately."

The Bottom Line

Talk to your doctor about NSAIDs and then make the decision together, Dr. Mahadevan advises. "Clearly, NSAIDs should be used with caution. Make sure to take them with food. Use them only as needed and watch for any signs of active disease. Do stop NSAIDs if signs develop. Most of the studies (or at least the retrospective COX-2 studies) suggest that if you stop taking them as soon as the symptoms of flare start, the effects may potentially be reversed without any other intervention."

A good substitute for NSAIDs is acetaminophen (Tylenol). "You could also try the COX-2 inhibitors, which tend to be easier on the GI tract than nonsteroidals," says Dr. Mahadevan, "but do so only with the approval of your IBD physician." 

NINA TOBIER

Date Posted: October 27, 2005