COX-2s get a boost for treating osteoarthritis pain
By Linda Gundersen
New guidelines urging physicians to use more aggressive drug therapies to treat osteoarthritis pain are raising serious questions about side effects and costs. While acetaminophen remains the drug of choice for patients with mild osteoarthritis pain, experts for years have been advising physicians to use nonsteroidal anti-inflammatory drugs (NSAIDs) more quickly for patients suffering from moderate or severe osteoarthritis pain. Some have even been urging physicians to forgo analgesics altogether and go right to NSAIDs when treating these patients.
Last March, the American Pain Society (APS) complicated the debate by recommending that physicians bypass both acetaminophen and traditional NSAIDs when treating moderate to severe osteoarthritis pain. Instead, the new APS guidelines say that physicians should immediately begin using cyclooxygenase-2 (COX-2) inhibitors.
The rationale behind those guidelines was simple: COX-2 inhibitors are effective, and they don't cause many of the dangerous gastrointestinal (GI) side effects of traditional NSAIDs.
While this new approach to battling osteoarthritis is backed by clinical evidence, it promises to leave some physicians—and their patients—in a quandary. While COX-2 inhibitors are effective, they are also expensive and not always covered by health insurance.
The case for NSAIDs
When it comes to treating osteoarthritis patients with no inflammation and mild pain, most experts still suggest starting with acetaminophen. Guidelines from both the American College of Rheumatology (ACR) and the APS specifically recommend the drug because it is inexpensive, has a good safety profile and works for 15% to 20% of patients.
When treating osteoarthritis patients with moderate to severe pain, however, the issue becomes murkier. For years, the ACR and other authorities had steadfastly recommended using acetaminophen first, even for moderate to severe osteoarthritis pain. But recent evidence has favored NSAIDs. A study of osteoarthritis patients in the July 2001 issue of Arthritis & Rheumatism, for example, found that patients who took NSAIDs felt better than patients who took acetaminophen.
Those findings echo the ACR's 2000 guidelines, in which the group told physicians to consider NSAIDs as first-line therapy for patients suffering moderate to severe osteoarthritis pain. (The ACR guidelines say you can use either nonselective NSAIDs or COX-2 inhibitors. They don't give either drug type priority.)
The ACR's 2000 guidelines pointed out that many patients using acetaminophen will not get sufficient pain relief, even at full doses (1,000 mg, four times a day). (See "Dosing information for analgesics and NSAIDs," below.)
In part, the ACR revised its guidelines to give physicians more flexibility when deciding how to treat osteoarthritis pain. "It's not an either/or situation," explained Roland W. Moskowitz, FACP, a rheumatologist and one of the authors of the ACR guidelines. Physicians can start patients on an NSAID, he explained, and then add—or even switch back to—acetaminophen in two months if patients are doing well. "We're telling physicians to use their judgment."
(The American College of Rheumatology's 2000 guidelines are online.)
The problem of serious side effects
While ACR guidelines give physicians more treatment flexibility, the APS took a much more definitive approach when it released new guidelines in March. The group now urges physicians to bypass nonselective NSAIDs altogether and use COX-2 inhibitors for patients with moderate to severe pain, regardless of their GI history. (The American Pain Society's 2002 guidelines can be ordered through its Web site.)
And if one COX-2 inhibitor doesn't work, the guidelines say, don't give up and switch to traditional NSAIDs. Instead, the guidelines recommend trying all three COX-2 inhibitors on the market—rofecoxib, celecoxib and valdecoxib—before giving patients a traditional NSAID. Only when each of these drugs has been tried and failed should you consider using a nonselective NSAID. For most of their short history, COX-2s have been more or less restricted to use in patients at high risk for GI complications. So why are some experts now giving COX-2s such a blanket endorsement?
The APS based this year's guidelines on a number of studies that highlighted both the safety of COX-2 inhibitors and the risks of traditional NSAID use. While traditional NSAIDs work just as well for pain relief as COX-2s, almost one in 10 people using NSAIDs will develop gastrointestinal problems.
A growing number of studies present an improved safety profile for COX-2s, while numerous other trials confirm the alarming prevalence of NSAID side effects. Evidence shows that up to 30% of all long-term NSAID users will develop at least one ulcer.
Ada K. Jacox, PhD, RN, chair of the APS clinical practice guidelines committee, said that nonselective NSAIDs are responsible for more reported adverse effects than any other class of medication. And Arthur L. Weaver, FACP, director of clinical research at the Arthritis Center of Nebraska, pointed out that 12,000 to 16,000 deaths each year result from upper GI bleeding related to NSAID use.
Even more startling is the fact that roughly 75% to 80% of patients who develop GI bleeding have no previous symptoms. "They just show up in the emergency room having had a major hemorrhage without any warning," Dr. Weaver said.
The ACR's Dr. Moskowitz, who is also professor of medicine at University Hospitals/Case Western Reserve University School of Medicine, said that even though ACR guidelines suggest using either a traditional NSAID or a COX-2, he routinely uses a COX-2.
"Why would you take a drug that causes 10, 20 or 30 erosions in your stomach," he said, "compared to a drug that may cause zero to three?"
The COX-2 conflict
For some physicians, the answer to that question comes down to one word: money.
While COX-2 inhibitors are effective, they are also expensive and not always covered by health insurance.
Put simply, COX-2s are expensive. Rofecoxib, for example, can cost an average of $118 per month. And when health plans and insurers require patients to "fail" two traditional NSAIDs before they will cover COX-2 therapy, the drugs are simply out of reach for many patients.
"That's like saying, 'Don't wear a seatbelt until you've had an accident,' " Dr. Moskowitz said. "Why not use the safer agent if you're going to use an NSAID?"
Gary M. Smith, MD, a general internist in Alexandria, La., said that his practice has many poor and uninsured patients—and that medication costs are always an issue. "You have to consider patients' ability to pay for a drug," he said, "or it doesn't matter how good it is."
In his experience, many patients may not fill the prescription you give them-and they are reluctant to tell you. He recalled one patient at increased risk for GI bleeding who was taking naproxen. "He took the COX-2 prescription I gave him to the pharmacy, found out it was going to cost him $70, said 'No thank you' and kept taking his naproxen—but never mentioned it to me."
The patient landed in the emergency room, where he became obtunded and profoundly hypotensive. "We got him resuscitated and transfused him," Dr. Smith continued. "Fortunately, he responded quickly." An endoscopy revealed signs of hemorrhagic gastritis and the possibility of an ulcer.
What are your options if patients can't take traditional NSAIDs and their insurer won't cover COX-2s? While Dr. Moskowitz said he would not make treatment decisions "on the basis of economics," he will take extra measures if a health plan doesn't approve a COX-2 treatment. He informs the carrier that if the patient develops GI bleeding from traditional NSAIDs, " 'I'm going to lead the charge into court.' " He then finds that coverage often gets approved.
"What they're counting on is that 95% of physicians won't take the time to press the issue," he explained. "If you push it and say 'You are responsible,' they'll be a little freer" about approving COX-2 coverage.
There are other drawbacks to using COX-2 inhibitors. Patients who take aspirin for both osteoarthritis pain and cardiovascular protection will lose that cardiovascular benefit if they switch to a COX-2. And patients who take a COX-2 for pain relief but continue to take low-dose aspirin for cardiovascular protection will lose the stomach protection the COX-2 provides. (Experts point out that small doses of aspirin do not negate the stomach protection.)
If your patient can't use a COX-2 because of cost considerations or other factors, which is the better agent: a traditional NSAID or acetaminophen? ACR and APS guidelines give different recommendations, leaving physicians to figure out an approach of their own.
Experts agree on one thing: Safety issues are still very real when using traditional NSAIDs. The 2001 study in Arthritis & Rheumatism, for example, found the NSAID group reported more side effects, despite the GI protection provided by the drug misoprostol.
"The NSAIDs are going to be more effective, but you're going to be giving someone a drug that clearly has renal and GI risks, and is more expensive," cautioned Thomas J. Schnitzer, MD, PhD, professor and director of clinical research and training at Northwestern University in Chicago.
There are steps you can take to reduce a patient's chance of developing gastrointestinal complications. First, analyze the patient's risk factors to make sure that she is eligible for nonselective NSAIDs. (APS guidelines contain a risk factor analysis tool that can help you quickly determine which patients may or may not be able to use NSAIDs.)
Next, try adding a proton pump inhibitor for GI protection. The problem with that strategy, Dr. Moskowitz pointed out, is that you lose cost savings. The patient's health insurance, however, may cover the dual-drug therapy.
You can also try tracking NSAID-related problems, although even that process may be ineffective. Some experts suggest checking a patient's creatinine and hematocrit within one month of starting NSAID therapy, but problems often occur much sooner. "They may be fine when you do a hematocrit on Friday and then get a big ulcer bleed on Sunday," Dr. Moskowitz said.
One thing you can do: Educate your patients. Most of them are probably aware of the long-term dangers of taking traditional NSAIDs, but they may not know that the GI side effects are typically asymptomatic—and usually immediate. "It's been shown that within days, you put yourself at risk," Dr. Moskowitz said. Most GI incidents, he pointed out, begin to occur within the first month of treatment.
Whichever drug you prescribe—COX-2s or traditional NSAIDs—Dr. Jacox advised physicians to try various drugs within a class if one isn't working. In other words, not all NSAIDs are alike.
"Responsiveness in individual patients to specific NSAIDs varies," Dr. Jacox said. She suggests giving an NSAID a minimum two-week trial; if that doesn't work, try a different one or increase the dosage if possible. "With individual patients, a lot of this is trial and error until you see what works."
Linda Gundersen is a freelance medical writer in Perkasie, Pa.
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.
Acetaminophen. Use acetaminophen in full doses (1,000 mg, four times a day) for one to three weeks. If patients complain that they have tried acetaminophen unsuccessfully, make sure they have used the full dose. Many patients simply give up after taking watered-down dosages.
Some experts prefer to start patients on a lower dose (for mild pain) and tell patients to increase the dose after a week or two if response is insufficient.
Do not exceed the full dose of acetaminophen. The drug can affect prothrombin time, and patients with liver disease or who have a high alcohol intake (more than three drinks a day) should not take acetaminophen.
One other caveat: A recent study suggests that high dosages of acetaminophen increase the risk of gastrointestinal bleeding to a point where the drug begins to resemble a nonsteroidal anti-inflammatory drug (NSAID) in its toxicity.
NSAIDs. Roland W. Moskowitz, FACP, a rheumatologist and one of the authors of the American College of Rheumatology guidelines, suggested using the full recommended dose of any NSAID for osteoarthritis pain. Tell patients to use 500 mg of naproxen twice a day, or 75 mg of diclofenac twice a day.
"Get the patient feeling better," he said. "Then you can cut back on the dose if need be, or get them off of it and go back to acetaminophen.
When prescribing cyclooxygenase-2 (COX-2) inhibitors, Dr. Moskowitz and others also suggested using the full recommended dose. "For celecoxib, that would be 200 mg once or twice a day," he said. "For rofecoxib, 25 mg a day is the most commonly used, although some people use the 12.5 mg dose."
While the news has focused on the change of thinking in pharmacologic treatments of osteoarthritis pain, most experts agree that implementing nonpharmacologic approaches is a critical part of a full treatment regimen.
Arthur L. Weaver, FACP, director of clinical research at the Arthritis Center of Nebraska, put it simply: "As far as first-line therapy goes, it is not analgesics. First-line therapy is nonpharmacologic measures."
Kenneth D. Brandt, FACP, professor of medicine and professor of orthopedic surgery at the Indiana University School of Medicine, concurred. "None of the drugs alone will be very effective in dealing with significant osteoarthritis," he said. "Pills ought to be viewed as adjuncts or as treatment that complements and supplements nonpharmacologic measures."
Weight loss is one measure frequently recommended. But most doctors agree that weight loss is very challenging for patients to achieve, no matter how much physicians stress the pain relief benefits of even modest weight loss, particularly for patients with osteoarthritis of the knee.
"If they've never lost the weight in the past and have tried, will they be able to do it because it's making their arthritis worse? No," said Gary M. Smith, FACP, a practicing internist in Alexandria, La. "In over 20 years, I have yet to see anyone pull it off."
Dr. Brandt, however, said that doctors need to remind patients that, "Osteoarthritis is a disease in which the patient needs to take control." He also urged physicians not to discount other measures, which "may be as effective as pills." They include joint protection, strengthening the periarticular muscles (through quadracep-strengthening exercises, for example), orthotics and thermo-modalities.
Glucosamine is entering the spotlight as a credible osteoarthritis treatment for patients who need pain relief on a daily basis. Dr. Smith, however, warned that glucosamine works only on a cumulative basis. "If patients take medications only intermittently, I don't even mention glucosamine until we get to the point where they have to take something for pain relief every day."
Cost is another factor in glucosamine's favor. Some stores carry 120 capsules of 1,000-mg glucosamine for about $10. Dr. Smith tells his patients to take two a day—and if they have good results, he'll suggest cutting back to one dose daily.
When standard drug treatments fail to relieve pain in patients suffering from osteoarthritis, you have two other options: hyaluronic acid injections and narcotics.
Hyaluronic acid injections (HAIs). Hyaluronic acid injections are injected into the knee to replace synovial fluid. The injections are given once a week for three to five weeks. Patients will often have long-term pain relief, sometimes for up to 12 months. Studies have shown that HAIs are safe and that treatment can be repeated as often as needed, generally every nine months to one year.
The downside is cost: HAIs can run up to $1,000 or more per course. Rheumatologist Roland W. Moskowitz, FACP, one of the authors of the American College of Rheumatology (ACR) guidelines, said that many patients feel that the cost is justified for the 10 to 12 months of pain relief HAIs provide. He added that there is no requirement that only rheumatologists administer the injections, so internists comfortable with minor surgery or joint injections can offer the injections in their office.
Currently, HAIs are only FDA-approved for treatment of osteoarthritis of the knee, but Dr. Moskowitz has successfully used them for osteoarthritis pain in other joints. He cautioned that insurance will probably not cover injection costs for non-FDA approved use.
The FDA and ACR guidelines sanction HAI injections after a trial of acetaminophen and nonpharmacologic therapies has failed. "It can be used even before you give them NSAIDs," Dr. Moskowitz pointed out.
Narcotics. In its March 2002 guidelines, the American Pain Society (APS) suggested moving to narcotics for osteoarthritis pain relief when other medications fail. The guidelines recommend opioids such as oxycodone and morphine.
Gary M. Smith, FACP, a general internist in Alexandria, La., however, cautioned against using narcotics with osteoarthritis patients. Because they already have stiff joints, patients can easily end up with balance problems when you add the fatigue and drowsiness commonly associated with narcotic use. Older patients who regularly take narcotics are at increased risk for falls and injuries.
When prescribing narcotics, Dr. Smith advised paying closer attention to the patient's mental status and level of alertness, and in elderly patients, making sure they have sufficient assistance at home.
Finally, APS guidelines point out that physicians should consider referring patients for surgery sooner rather than later and not wait until the patient is debilitated and can't move.
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