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Osteoarthritis: New Insights. Part 2: Treatment Approaches

D. Felson,R. Lawrence,M. Hochberg,T. McAlindon,P. Dieppe,M. Minor,Steven N. Blair,B. Berman,James Fries,M. Weinberger,K. Lorig,Joshua Jacobs,V. Goldberg

Published 2000 in Annals of Internal Medicine

ABSTRACT

There is no known cure for osteoarthritis, and the goal of contemporary management of the patient with osteoarthritis remains control of pain and improvement in function and health-related quality of life with avoidance, if possible, of therapeutic toxicity. Recent studies have demonstrated the potential of treatments ranging from newly approved oral medications to nutriceuticals, patient education interventions, and surgery. Increasingly, appropriate treatment of osteoarthritis combines one or more oral agents with exercise and other biomechanical techniques. This article is part 2 of a two-part summary of a National Institutes of Health (NIH) conference, Stepping Away from OA: Prevention of Onset, Progression, and Disability of Osteoarthritis. The conference brought together experts from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. For research questions and opportunities identified at the conference, see www.nih.gov/niams/reports/oa/oareport.htm(accessed on 25 May 2000). Systemic and Topical Treatments Dr. Marc C. Hochberg (University of Maryland School of Medicine, Baltimore, Maryland), Dr. Timothy McAlindon (Boston University School of Medicine, Boston, Massachusetts), and Dr. David T. Felson (Boston University School of Medicine): Drug therapy for pain management is most effective when combined with nonpharmacologic strategies (1, 2). In 1995, the American College of Rheumatology issued guidelines for the medical management of osteoarthritis of the hip and knee (2, 3). Since then, several systematic reviews of drug therapy for osteoarthritis have been published (4-6). The following recommendations for systemic and topical treatments (except for glucosamine and chondroitin, which were not evaluated) are derived from updated recommendations of the American College of Rheumatology for the treatment of osteoarthritis. Systemic Treatments Nonopioid Analgesics For many patients with osteoarthritis, the relief of mild to moderate joint pain afforded by the simple analgesic acetaminophen is comparable to that achieved with a nonsteroidal anti-inflammatory drug (NSAID) (7, 8). Accordingly, although acetaminophen fails to adequately relieve pain in many patients, it merits a trial as initial therapy on the basis of its overall cost, efficacy, and toxicity profile (9, 10). The daily dose of acetaminophen should not exceed 4 g. Although it is one of the safest analgesics, acetaminophen can be associated with clinically important adverse events, such as prolongation of the half-life of warfarin (11). At therapeutic doses acetaminophen rarely causes hepatic toxicity, but it should be used cautiously in patients with existing liver disease and avoided in patients with chronic alcohol abuse because of known increased risk in these patients (12-14). Even though acetaminophen was reported to be weakly associated with end-stage renal disease, the Scientific Advisory Committee of the National Kidney Foundation recommended it as the drug of choice for analgesia in patients with impaired renal function (15). Tramadol, a centrally acting oral analgesic, is a synthetic opioid agonist that inhibits reuptake of norepinephrine and serotonin. It has been approved by the U.S. Food and Drug Administration for treatment of moderate to severe pain and can be considered for use in patients in whom acetaminophen therapy has failed and who have contraindications to NSAIDs, including the cyclooxygenase-2 (COX-2)specific inhibitors. Although numerous studies have examined use of tramadol to treat general pain, few controlled studies have examined its use in osteoarthritis. The efficacy of tramadol has been found to be comparable to that of ibuprofen in patients with hip and knee osteoarthritis (16), and it is useful as adjunctive therapy in patients with osteoarthritis whose symptoms were inadequately controlled with NSAIDs (17). Daily doses of tramadol have generally been in the range of 200 to 300 mg given in four divided doses. Side effects are common and include nausea, constipation, and drowsiness. Despite the opioid pharmacology of tramadol, a comprehensive surveillance program has failed to demonstrate significant abuse, and tramadol remains an unscheduled agent. Seizures have been reported as a rare side effect, either at doses above the recommended range or at doses within the recommended range in patients with a history of epilepsy and those taking concomitant medications that lower the seizure threshold. NSAIDs For patients who do not obtain adequate symptom relief with nonopioid analgesics, use of NSAIDs should be considered. The choice between a nonselective NSAID and a COX-2specific inhibitor should be made after evaluation of risk factors, particularly for upper gastrointestinal and renal toxicity. Data from epidemiologic studies show that among persons 65 years of age or older, 20% to 30% of all hospitalizations and deaths due to peptic ulcer disease were attributable to therapy with NSAIDs (18-20). Furthermore, the risk for a catastrophic gastrointestinal event in elderly patients taking NSAIDs is dose dependent (18). Risk factors for upper gastrointestinal bleeding in patients treated with NSAIDs include age 65 years or older, history of peptic ulcer disease or previous upper gastrointestinal bleeding, concomitant use of oral corticosteroids or anticoagulants, and possibly smoking and alcohol consumption (21-23). Risk factors for reversible renal failure in patients with intrinsic renal disease who are treated with NSAIDs include age 65 years or older, hypertension or congestive heart failure, and concomitant use of diuretics and angiotensin-converting enzyme inhibitors (24). Additional considerations involved in a practitioner's decision to treat an individual patient with osteoarthritis include existing comorbid conditions and concomitant therapy, as well as the side effects and costs of specific treatments. The options for medical management of the patient with osteoarthritis who is at increased risk for a serious adverse upper gastrointestinal event, such as bleeding, perforation, or obstruction, are use of a COX-2specific inhibitor or a nonselective NSAID with gastroprotective therapy. Two COX-2specific inhibitors, celecoxib and rofecoxib, have been approved by the U.S. Food and Drug Administration for use in patients with osteoarthritis (25, 26). Celecoxib has been found to be more effective than placebo and as effective as naproxen for symptoms in patients with hip or knee osteoarthritis (27-29). Rofecoxib has also been found to be more effective than placebo and is comparable in efficacy to both ibuprofen and diclofenac in patients with hip or knee osteoarthritis (30, 31). Endoscopic studies have shown that celecoxib and rofecoxib are associated with an incidence of gastroduodenal ulcers lower than that of comparator NSAIDs and similar to that of placebo (25). These data suggest an advantageous safety profile compared with nonselective NSAIDs, especially for treatment of high-risk patients (21-23). However, no large long-term studies have been published that were designed to demonstrate differences between COX-2specific inhibitors and nonselective NSAIDs with respect to major gastrointestinal clinical outcomes; such studies are in progress. A further advantage of COX-2specific inhibitors with respect to upper gastrointestinal bleeding is that celecoxib and rofecoxib do not have a clinically significant effect on platelet aggregation or bleeding time. In addition, at doses recommended for treatment of osteoarthritis, these drugs appear to be better tolerated than comparator nonselective NSAIDs, with a lower incidence of dyspepsia and other gastrointestinal side effects. As with nonselective NSAIDs, however, COX-2specific inhibitors can cause renal toxicity. Caution must be exercised, therefore, if these drugs are used in patients with mild to moderate renal insufficiency, and they should not be used in patients with severe renal insufficiency. In addition, celecoxib is contraindicated in patients with a history of allergic reaction to a sulfonamide. The alternative to use of a COX-2specific inhibitor is use of a nonselective NSAID with a gastroprotective agent, an approach endorsed by the American College of Gastroenterology (23). As noted earlier, serious adverse upper gastrointestinal events attributed to NSAIDs in the elderly are dose dependent. Therefore, if nonselective NSAIDs are used, therapy should be begun at low, analgesic doses and increased to full anti-inflammatory doses only if lower doses do not provide adequate relief of symptoms. In a study of 8843 patients with rheumatoid arthritis, misoprostol at a dosage of 200 g four times daily reduced the incidence of serious ulcer complications, including perforation, bleeding, and obstruction, by 51% (32). In a 12-week randomized, double-blind, placebo-controlled endoscopy study, misoprostol at a dosage of 200 g three times per day had comparable efficacy in prevention of both gastric and duodenal ulcers; however, 200 g twice daily conferred significantly less protection against gastric ulcers (33). Side effects, particularly diarrhea and flatulence, may occur with this agent in a dose-dependent manner (33). Alternative approaches to prophylaxis with misoprostol include use of omeprazole or high-dose famotidine, both of which have been shown in carefully conducted endoscopy studies to be effective in treating and preventing NSAID-induced gastropathy (34-37). Histamine-2 blockers in usual doses, however, have not been found to be as effective as misoprostol (36), whereas omeprazole (20 mg/d or 40 mg/d) was as effective as misoprostol (200 g twice daily) in treatment of existing ulcers and was better tolerated and associated with a lower rate of relapse (37). Of note, proton-pump inhibitors have not been approved by the U.S. Food and Dr

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