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Number 4 Effective Health Care Comparative Effectiveness and Safety of Analgesics for Osteoarthritis Executive Summary Background Effective Health Care Program Osteoarthritis is a chronic condition involving degeneration of cartilage within The Effective Health Care Program the joints. It is the most common form of was initiated in 2005 to provide valid arthritis and is associated with pain, evidence about the comparative substantial disability, and reduced quality effectiveness of different medical of life. About 6 percent of U.S. adults aged interventions. The object is to help 30 years or older have symptomatic consumers, health care providers, and osteoarthritis of the knee, and 3 percent others in making informed choices have symptomatic osteoarthritis of the hip. among treatment alternatives. Through Osteoarthritis increases with age: the its Comparative Effectiveness Reviews, incidence and prevalence increase two- to the program supports systematic tenfold from age 30 to 65 and continue to appraisals of existing scientific increase after age 65. The total costs for evidence regarding treatments for arthritis, including osteoarthritis, may be high-priority health conditions. It also greater than 2 percent of the gross promotes and generates new scientific domestic product, with more than half of evidence by identifying gaps in these costs related to work loss. existing scientific evidence and supporting new research. The program Common oral medications for puts special emphasis on translating osteoarthritis include nonsteroidal findings into a variety of useful antiinflammatory drugs (NSAIDs) and formats for different stakeholders, acetaminophen. Patients with osteoarthritis including consumers. also use over-the-counter supplements not regulated by the U.S. Food and Drug The full report and this summary are Administration (FDA) as pharmaceuticals, available at www.effectivehealthcare. including glucosamine and chondroitin, as ahrq.gov/reports/final.cfm well as topical agents. Opioid medications are also used for selected patients with efficacy and safety may vary for individual refractory, chronic pain but are not drugs within a class. Nonpharmacologic recommended for first-line treatment of interventions (such as physical therapy, osteoarthritis and therefore not included in weight reduction, and exercise) also help this review. Each class of medication or improve pain and functional status in supplement is associated with a unique patients with osteoarthritis. balance of risks and benefits. In addition, Effective Health Care A challenge in treating osteoarthritis is deciding which Oral agents include: medications will provide the greatest symptom relief • Acetaminophen with the fewest serious adverse effects. NSAIDs decrease pain, inflammation, and fever by blocking • Aspirin cyclo-oxygenase (COX) enzymes. Understanding of the • Celecoxib pharmacology of NSAIDs continues to evolve, but it is • Choline magnesium trisalicylate now thought that most NSAIDs block three different • Chondroitin COX isoenzymes, known as COX-1, COX-2, and COX-3. COX-1 protects the lining of the stomach from • Diclofenac acid. COX-2 is found in joint and muscle, and • Diflunisal mediates effects on pain and inflammation. By blocking • Etodolac COX-2, NSAIDs reduce pain compared to placebo in 1 patients with arthritis, low back pain, minor injuries, • Etoricoxib and soft tissue rheumatism. However, NSAIDs that also • Fenoprofen block the COX-1 enzyme (also called “nonselective • Flurbiprofen NSAIDs”) can cause gastrointestinal bleeding. In the • Glucosamine United States, there are an estimated 16,500 annual deaths due to NSAID-induced gastrointestinal • Ibuprofen complications, a higher death rate than that for cervical • Indomethacin cancer or malignant melanoma. Theoretically, NSAIDs • Ketoprofen that block only the COX-2 enzyme (also called “coxibs,” “COX-2 selective NSAIDs,” or “selective • Ketoprofen ER NSAIDs”) should be safer with regard to • Ketorolac gastrointestinal bleeding, but they also appear to be • Lumiracoxib1 associated with increased rates of serious cardiovascular • Meclofenamate sodium and other adverse effects. Less is known about COX-3, which is found in the cerebral cortex and cardiac tissue • Mefenamic acid and appears to be involved in centrally mediated pain. • Meloxicam For this report, we defined the terms “selective • Nabumetone NSAIDs” or “COX-2 selective NSAIDs” as drugs in • Naproxen the “coxib” class (celecoxib, rofecoxib, valdecoxib, • Oxaprozin etoricoxib, lumiracoxib). We defined “partially selective NSAIDs” as other drugs shown to have partial in vitro • Piroxicam COX-2 selectivity (etodolac, nabumetone, meloxicam). • Rofecoxib1 Aspirin differs from other NSAIDs because it • Salsalate irreversibly inhibits platelet aggregation, and the • Sulindac salicylic acid derivatives (aspirin and salsalate) were considered a separate subgroup. We defined • Tenoxicam1 “nonaspirin, nonselective NSAIDs” or simply • Tiaprofenic acid1 “nonselective NSAIDs” as “all other NSAIDs.” • Tolmetin This report summarizes the available evidence • Valdecoxib1 comparing the benefits and harms of analgesics in the treatment of osteoarthritis. 1 These drugs are currently not approved by the FDA for use in the United States (etoricoxib, lumiracoxib, tenoxicam, tiaprofenic acid) or have been withdrawn from the market (rofecoxib and valdecoxib). 2 Questions addressed in this report are: nabumetone, etodolac) in efficacy for pain 1. What are the comparative benefits and harms of relief or improvement in function. treating osteoarthritis with oral medications or • In one short-term trial, salsalate and aspirin did supplements? How do these benefits and harms not differ significantly in efficacy for pain change with dosage and duration of treatment, and relief or symptom improvement. what is the evidence that alternative dosage • No studies evaluated the comparative efficacy strategies, such as intermittent dosing and drug of salsalate or aspirin vs. a nonaspirin NSAID. holidays, affect the benefits and harms of oral medication use? (Note: The only benefits considered • COX-2 selective NSAID vs. nonselective NSAID under this question are improvements in • COX-2 selective NSAIDs and nonselective osteoarthritis symptoms from long-term use. NSAIDs did not clearly differ in efficacy for Evidence of harms associated with NSAID use pain relief, based on many good-quality, include long-term studies of these drugs for treating published trials. osteoarthritis or rheumatoid arthritis and for cancer prevention.) • COX-2 selective NSAID vs. different COX-2 selective NSAID 2. Do the comparative benefits and harms of oral treatments for osteoarthritis vary for certain • Celecoxib and rofecoxib did not differ demographic and clinical subgroups of patients? significantly in efficacy for pain relief at commonly used and comparable doses, based • Demographic subgroups include age, sex, and on consistent evidence from six good-quality race. trials. • Coexisting diseases include hypertension, • No studies compared efficacy of COX-2s other edema, ischemic heart disease, heart failure; than celecoxib and rofecoxib. peptic ulcer disease; history of previous bleeding due to NSAIDs. Harms: gastrointestinal (GI) and cardiovascular (CV) • Concomitant medication use includes • Rofecoxib vs. nonselective NSAID anticoagulants. • In the only large, long-term trial (VIGOR), 3. What are the comparative effects of coprescribing rofecoxib 50 mg daily caused fewer serious of H2-antagonists, misoprostol, or proton pump ulcer complications than naproxen 1,000 mg inhibitors (PPIs) on the gastrointestinal harms daily in patients with rheumatoid arthritis but associated with NSAID use? also significantly increased the risk of 4. What are the comparative benefits and harms of myocardial infarction. The overall rate of treating osteoarthritis with oral medications as serious adverse events was higher with compared with topical preparations? Topical rofecoxib than with naproxen. preparations include: capsaicin, diclofenac, • There were about 16 fewer symptomatic ibuprofen, ketoprofen, and salicylate. ulcers, including 5.2 fewer serious GI A summary of the findings is shown in Table A. complications, for every 1,000 patients treated with rofecoxib vs. naproxen after a Conclusions median of 9 months of treatment. • There were 3.0 additional myocardial Oral NSAIDS infarctions for every 1,000 patients treated Benefits: improvements in osteoarthritis symptoms with rofecoxib compared to naproxen in • Nonselective NSAID vs. another nonselective VIGOR. NSAID • Rofecoxib was associated with an increased • Many trials found no clear differences between risk of myocardial infarction relative to placebo various nonaspirin, nonselective NSAIDs or in the most comprehensive systematic review partially selective NSAIDs (meloxicam, of randomized controlled trials (RCTs). 3 • About 3.5 additional myocardial diclofenac, ibuprofen, or naproxen in two fair- infarctions occurred for every 1,000 quality meta-analyses of published and patients treated for 1 year with rofecoxib unpublished trials. compared to placebo in the systematic • There have been too few events reported in review. RCTs of patients with chronic conditions to • Rofecoxib was withdrawn from the market in accurately assess CV risk associated with September 2004, primarily because of CV valdecoxib. risks. • Two short-term trials in a high-risk post- • Celecoxib vs. nonselective NSAID or placebo coronary-artery-surgery setting found