Inflammation not the main suspect in the case of osteoarthritis

Research now points finger at chronic joint degeneration

In the search for the best treatment for patients with osteoarthritis (OA), evidence is mounting against a different enemy — shifting the blame away from inflammation. The change in focus is bringing dramatic changes to how caregivers think about the disease and how it should be treated.

With ongoing research suggesting chronic joint degeneration, not inflammation, is responsible for causing the disease and its associated pain, researchers argue the primary treatment goal should be to fight the pain and not the inflammation.

The new interest in pain relief is leading experts to take another look at the basic first-line treatment, such as exercise and lifestyle changes. There is also concern over some serious mortality and morbidity issues that can come with treating patients with first-generation nonsteroidal anti-inflammatory drugs (NSAIDs). With the return to the basics comes renewed interest in the simple analgesics that do not reduce inflammation.

Relieving the inflammation still is important, however, and the newly available COX-2 inhibitors have provided physicians and patients with a popular new drug treatment without much of the gastrointestinal (GI) side effects associated with other NSAIDs. (See related story, p. 135.)

There is an inflammation component to OA, says Joseph Golbus, MD, head of the division of rheumatology at Evanston Northwestern Healthcare and an associate professor of medicine at Northwestern University Medical School in Evanston, IL. "But inflammation is no longer the primary mechanism."

Golbus says that fundamentally, OA is a mechanical process of the joints. Doctors can treat the inflammation, but it will not prevent the overall progression of the disease. "What you’re really after is pain relief, comfort," he says.

Another argument against treating inflammation is the toll some of the drugs take on the patients. "We’ve realized the toxicity is a bigger issue than we thought in terms of the mortality [from] the ulcers and bleeding, . . . and that’s the turning point. The number of deaths from the anti-inflammatories are far greater than earlier appreciated. If the disease is not life-threatening, and NSAIDs don’t alter the course of the disease, why should we expose patients to the risks? If pain control is really the issue, we ought to rethink [drug regimens]," he says.

Data from epidemiological studies compiled by The American College of Rheumatology (ACR) show that among OA patients over 65, 20% to 30% of all hospitalizations and deaths due to peptic ulcer disease were attributable to NSAID therapy. The same studies show that patients also taking oral corticosteroids and anticoagulants are at higher risk. Overall, the studies found that 30% of all NSAID users will suffer GI side effects, which are likely to begin within three months of therapy. The studies also found that women are more likely to develop GI bleeding than men.

In a related survey of OA patients conducted by the Arthritis Foundation in Atlanta, 58% said they have either changed their medication or stopped taking it because of side effects.

But Golbus says he is not ready to discount the use of NSAIDs and notes that so far, he is a proponent of the new COX-2 inhibitors. The bottom line, he says, is NSAID use is not likely to stop.

Currently, more than a dozen first-generation NSAIDs are on the market, and physicians long have taken a trial-and-error approach to prescribing, based on patient reactions. According to the research firm IMS Health in Westport, CT, sales of anti-arthritics totaled $1.7 billion for 1998, accounting for 70.5 million prescriptions.

"The COX-2s are for real and are probably one of the best-studied drugs in the history of drug development," Golbus says. "That’s why there’s been the push over the last year for the simple analgesics or the selective COX-2 inhibitors."

Of the two cyclooxygenases (or COX enzymes) known to exist, COX-1 protects the stomach lining, while COX-2 causes inflammation. Blocking both enzymes with traditional NSAIDs exposed the stomach to toxicity. The selective COX-2 inhibitors work by blocking only the inflammation response.

Golbus says if patients can get safe relief from inflammation, which the majority of patients still believe is the cause of OA, and can be convinced to maintain analgesic therapy for pain, then new treatment goals can be satisfied.

ACR is revising its 1995 treatment guidelines to emphasize pain relief and to overhaul recommendations on NSAID therapy.

OTC compliance, interactions

Physicians believe the new focus on pain relief and the advent of the COX-2 inhibitors will bring greater patient compliance, especially if side effects decrease during new NSAID regimens. They note, however, the need to improve compliance with analgesic therapy, which traditionally has been erratic.

"Achieving compliance with acetaminophen as first-line pharmacologic therapy is more challenging than it seems," says Stephen Brunton, MD, clinical professor of family medicine at the University of California College of Medicine in Irvine. "Even though acetaminophen is available without a prescription and is less expensive than many other drugs, those factors can be a disincentive because the drugs are not reimbursed by plans, and patients feel like they aren’t getting their money’s worth from a physician when they are told to take what they perceive to be a headache remedy," he says.

Additionally, if the focus on pain relief over anti-inflammation leads to even more reliance on analgesic-only, first-line regimens, patients will need more education on the merits of OTC therapy. "Patients may not understand why they do not need an anti-inflammatory agent when conventional wisdom has labeled OA as an inflammatory condition."

Golbus notes he is concerned that the COX-2 inhibitors already are popular and could replace the first-line analgesic therapy that continues to be a mainstay of treatment guidelines. The allure of a new drug can be so great that patients get wrapped up in it, hoping for a panacea instead of following diet and exercise recommendations.

"Particularly, physicians fall down on the lack of application of the nonpharmacologic therapies, then they are quick to write a prescription," he says. (The Arthritis Foundation, which in May published a national report card on the state of OA therapy, gave physicians an overall grade of C on their use of a comprehensive treatment approach for arthritis. Golbus says the assessment is fair.)

If the COX-2 inhibitors overshadow other regimens, then drug-drug interactions can become a treatment factor. Even the COX-2 drugs, like all NSAIDs, should be used carefully with high-blood-pressure drugs, particularly beta-blockers and ACE inhibitors. "The NSAIDs can cause salt and water retention, which affect high blood pressure and interfere with how the antihypertensives work," says Golbus, who adds that more post-market surveillance needs to occur before the specific interactions between the selective COX-2 inhibitors and antihypertensives are known.

Even acetaminophen therapy has its side effects. The drug is linked to liver toxicity, but mainly in patients using alcohol excessively while taking the analgesic, a factor pharmacists can investigate during patient profiles or in clinics.

Long-term use of acetaminophen also has been associated with renal failure when taken in combination with NSAIDs. Rheumatologists will be watching that combination closely if it becomes more popular than NSAID monotherapy after the new treatment goals and COX-2 inhibitors gain popularity.

Although the American College of Rheum atology is revising its 1995 OA treatment guidelines, much of what is already published will remain. Revisions will focus on strengthening the message of pain relief throughout the stages of treatment. A more substantial change will be adding provisions for the use of COX-2 inhibitors in high-dose second- or third-line therapies for OA of the hip or knee, for example.

The guidelines stress initiating drug-free therapy to gauge any response to exercise, physical therapy, or weight control as needed, before beginning any drug therapy.

For first-line drug therapy, 4,000 mg of aceta-minophen daily is generally recommended. (In specific cases of OA of the knee, aspiration or injections of the intra-articular steroid triamcinolone hexacetonide 40 mg is recommended for consideration prior to the administration of acetaminophen. Also in cases of OA of the knee, the topical analgesics methyl salicylate or capsaicin cream are recommended in combination with acetaminophen.)

In general drug therapy, the lack of response to acetaminophen is followed by the use of low-dose over-the-counter ibuprofen, aspirin, naproxen sodium or non-aceylated salicylates.

The guidelines then move to prescription, or full-dose, NSAIDs. "This is where the guidelines need to be changed the most, as to where the COX-2s will come in," says Golbus. The existing provisions for the combined use of NSAIDs and misoprostol, which is recommended for patients who have risk factors for GI bleeding or ulcers also need to be revised, he says. In general, he says it’s premature to speculate on whether the traditional crop of NSAIDs will be phased out of the guidelines in favor of the COX-2 inhibitors.

Guideline time line

Representatives from the ACR also say it’s too early to reveal much detail about the new guidelines, but they say official interim guidelines or fact sheets concerning the use of COX-2 inhibitors should be published by the end of this year. Post-market surveillance of the COX-2 inhibitors also will be necessary, they add.

Following the use of prescription NSAIDs, current guidelines go on to address different types of elective surgery when drug therapy has failed.

Also this year, the National Institutes of Health is embarking on a comprehensive study of glucosamine therapy, which has not been approved by the Food and Drug Administration for OA.

Glucosamine is an endogenous compound synthesized from glucose believed to work by repairing joints and cartilage through the relief of inflammation and pain. Small studies have alluded to pain relief and increased long-term mobility. Glucosamine is given either orally or by injection into muscle or blood vessel.

Viscosupplementation, the injection of synovial fluid directly into affected joints to replace or boost the viscoelasticity of synovial fluid, is available by the product names Hyalgen and Synvisc, which have been approved by the FDA for OA treatment.

[For additional information, contact the Arthritis Foundation at 1330 W. Peachtree St., Atlanta, GA 30309. Telephone: (404) 872-7100. Web: www. American College of Rheumatology, 60 Executive Park S., Suite 150, Atlanta, GA 30329. Telephone: (404) 633-3777. Web: www.rheumatology. org.]