Features May 2007 Issue

When Your Drugs Stop Working

The effects of that once-wondrous painkiller can wear off with time. Here’s why, and what you can do when your body builds resistance.

You’ve found a drug that reduces your pain and inflammation but, after a while, the medication doesn’t seem to work for you any longer and your symptoms start to return. The situation is frustrating but not unusual. Whether you have rheumatoid arthritis or osteoarthritis, drug resistance is a potential problem, albeit one that’s easily addressed.

"If drug resistance occurs, you’ll need to take some action to get around it. With osteoarthritis, you want to maintain your comfort level, but if you have rheumatoid arthritis, you also need to

maintain control of the disease in order to prevent joint damage," says John Clough, M.D., staff physician in Cleveland Clinic’s department of rheumatic and immunologic disease. "Before you do anything, call your doctor. He or she can help you manage the problem."

Why drugs quit working

You may have noticed that the activity of your arthritis seems greater at times. When that happens, drugs that previously controlled your symptoms can become less effective. Increased activity of the disease is the most common reason that drugs don’t work as well.

Compared with rheumatoid arthritis—an autoimmune disease that causes joint inflammation—osteoarthritis, which results from the breakdown of joint cartilage, does not involve as much waxing and waning in disease activity. However, if a joint becomes inflamed as a result of injury or overuse, or because the cartilage is wearing down to the point where it can’t bear weight, your medication may no longer be able to do its job.

Another cause of drug ineffectiveness is tachyphylaxis, a decreasing response to a drug. "Drugs decline in activity because the body loses sensitivity to them, but the mechanisms responsible for this phenomenon are not well understood," says Dr. Clough. "Tachyphylaxis may occur, particularly, with some nonsteroidal anti-inflammatory drugs [NSAIDs]."

The cause of drug resistance depends, partially, on your disease. If you suffer from rheumatoid arthritis, you’re likely taking a disease-modifying antirheumatic drug (DMARD) to slow disease progression. Although DMARDs work well at first, they often lose effectiveness after a year or two, when cells recognize the drugs as foreign substances and deactivate them.

Infliximab, a commonly used DMARD, leads to drug-resistance problems in a somewhat different way. Infliximab works by binding to TNFa (tumor necrosis factor alpha), a substance that triggers inflammation, and preventing it from signaling receptors for TNFa on the surface of cells. Your body, however, can make antibodies that fight against infliximab, which acts as an antigen, interfering with its action.

Overcoming resistance

When symptoms of rheumatoid arthritis or osteoarthritis worsen, the dose of the drug you’re taking may need to be increased, providing you’re not at the maximum dose already. Or you may need a different drug.

If you have rheumatoid arthritis, a third option is the addition of one or more drugs. "Adding another drug can give you a better level of control," says Dr. Clough. "You could be prescribed as many as five or six different drugs, each working by a different mechanism of action. A combination of drugs may produce more power than is safe to deliver with just one drug. If your disease becomes less active, you may be able to discontinue taking some of the drugs."

Another technique is alternating prescribed NSAIDs, used in both rheumatoid and osteoarthritis, to overcome tachyphylaxis. "You can cycle drugs in groups of two or three, using each for a month and then going back to the first drug," says Dr. Clough "The drug looks new to the body even though you may have used it before."

"Drug resistance is usually something you can deal with," he adds. "But there’s no ‘one size fits all,’ so treatment should be individualized."