Update of ACR Guidelines for Osteoarthritis: Role of the Coxibs

S24 Journal of Pain and Symptom Management Vol. 23 No. 4S April 2002 Proceedings from the Symposium The Evolution of Anti-Inflammatory Treatments in Arthritis: Current and Future Perspectives Update of ACR Guidelines for Osteoarthritis: Role of the Coxibs Thomas J. Schnitzer, MD, PhD Office of Clinical Research and Training, Northwestern University Medical School, Evanston, Illinois, USA Abstract The American College of Rheumatology (ACR) recently provided an update to the guidelines published in 1995 on the management of osteoarthritis (OA) of the knee and hip. Members of the Ad Hoc Committee on OA Guidelines followed an evidence-based medicine approach to revise the guidelines by reviewing an extensive literature search of the Cochrane and Medline databases and published abstracts, and discussing evidence with expert rheumatologists. The goal of the guidelines is to provide recommendations to control patients OA pain, improve function and health-related quality of life, and avoid therapeutic toxicity. As in the original guidelines, nonpharmacologic interventions involving patient education and physical measures are recommended following initial diagnosis of OA. The pharmacologic algorithm was updated to include currently available therapeutic agents. Acetaminophen remains firstline therapy because of its cost, efficacy, and safety profiles. Cyclooxygenase-2-selective inhibitors (coxibs) have been included as an alternative to nonselective nonsteroidal antiinflammatory drugs (NSAIDs) in patients at risk for upper gastrointestinal adverse events. Tramadol is an available alternative for patients who have a contraindication to coxibs or nonselective NSAIDs or for those who have not responded to previous oral therapy. Intraarticular injections or topical therapy may be used as monotherapy, or as an adjunct to oral analgesia. Surgical treatment of OA remains a last resort for patients who have failed to respond to nonpharmacologic and pharmacologic treatment approaches, and have progressive limitation in their activities of daily living. Several therapies for the prevention or treatment of OA are currently under investigation, including nutritional supplements, such as glucosamine and chondroitin, disease-modifying OA drugs, and devices, such as acupuncture and electromagnetic therapy. It is anticipated that the guidelines for the management of OA will continue to evolve as new therapies become available. J Pain Symptom Manage 2002; 23:S24 S30. U.S. Cancer Pain Relief Committee, 2002. Key Words American College of Rheumatology, treatment guidelines, osteoarthritis, COX-2 inhibitors Address correspondence to: Thomas J. Schnitzer, MD, PhD, Professor of Medicine, Director, Office of Clinical Research and Training, Northwestern University Medical School, 710 N. Lake Shore Dr., Abbott Hall 5th Flr., Chicago, IL 60611, USA. Accepted for publication: November 19, 2001. Introduction The treatment of osteoarthritis (OA) continues to evolve as knowledge of the underlying pathophysiology of the condition improves, and as new therapeutic modalities are U.S. Cancer Pain Relief Committee, 2002 0885-3924/02/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(02)00372-X

Vol. 23 No. 4S April 2002 ACR Guidelines Update: Role of Coxibs S25 developed and tested in the clinic. In 1995, an ad hoc committee of the American College of Rheumatology (ACR) published guidelines for the treatment of patients with OA of the hip or knee. 1,2 The goals of the treatment of OA of the hip or knee were pain control, limitation of disability, maintenance of joint mobility, and patient education. The guidelines summarized available knowledge and provided an approach to OA management that emphasized the use of safe and effective therapies, particularly highlighting the value and primary position of nonpharmacologic interventions as a base upon which pharmacologic intervention should be built. Because of the chronic nature of OA, safety was a critical factor in distinguishing among various effective pharmacologic therapies. The previous guidelines for OA management recommended that acetaminophen be added to nonpharmacologic modalities in mildly symptomatic patients. A nonsteroidal anti-inflammatory drug (NSAID) was substituted for acetaminophen in patients who had an inadequate response to therapy, unless contraindicated. NSAIDs were not recommended as first-line therapy because of toxicity concerns, primarily involving the gastrointestinal (GI) tract, but also the kidneys and other organs. For example, studies demonstrated that 20% to 30% of hospitalizations and deaths from peptic ulcer disease in patients older than 65 years of age were caused by NSAIDs. 3,4 Patients with severe symptoms who failed to respond to nonpharmacologic and pharmacologic treatment approaches, and had progressive limitation in their activities of daily living, were evaluated for surgical intervention. Intra-articular corticosteroid injections were not routinely recommended, but were reserved for early treatment of patients with OA of the knee who had effusion or local inflammation. Topical analgesics (e.g., capsaicin) were shown to be effective, and joint lavage and arthroscopic debridement were recommended for use only in patients with OA of the knee. Opioid analgesics were reserved for acute exacerbations of pain. The purpose of this article is to review all aspects of the updated guidelines published in 2000 5 for the management of OA of the hip or knee, with emphasis on the role of the cyclooxygenase-2 inhibitors (coxibs). Updating Guidelines for the Treatment of Osteoarthritis Rationale During the past 5 years, much additional literature relating to all aspects of OA has been published. Many of the basic mechanisms involved in OA are being targeted for pharmacologic intervention, providing the first real hope for development of agents that will directly affect the disease process. 6 9 In addition, several new therapies shown to reduce the signs and symptoms of OA (i.e., hyaluronan preparations, tramadol, coxibs) have been approved by the United States Food and Drug Administration (FDA). Furthermore, other studies provided additional support for the benefits of nonpharmacologic interventions. In light of these new data, an updated approach to the management of patients with OA was deemed desirable. Approach Based on these observations, the ACR reconvened some of the members of the original ad hoc committee to review and update the original guidelines for the treatment of OA of the hip or knee. The committee used an evidencebased medicine approach to revise the guidelines by assembling and evaluating existing data from an extensive review of the Cochrane and Medline databases and published meeting abstracts, and by applying clinical judgment and values of expert rheumatologists. 5,10 The goal of the revised guidelines is to provide physicians with an approach for controlling patient pain, improving function and healthrelated quality of life, and avoiding therapeutic toxicity. The committee s philosophy was not to generate fixed rules for practitioners to follow, but rather to generate a range of choices for clinicians, with the most appropriate choice dictated by patient type and preference, and sound clinical judgment. Treatment Approach Nonpharmacologic Treatment As in the original guidelines, nonpharmacologic therapy (Table 1) retains its primacy and position as a base upon which other modalities (Table 2) may be added. 5 Considerable new

S26 Schnitzer Vol. 23 No. 4S April 2002 Table 1 Nonpharmacologic Therapy for Patients with Osteoarthritis (reprinted from Ref. 5, by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.) Patient education Self-management programs (e.g., Arthritis Foundation Self- Management Program) Personalized social support through telephone contact Weight loss (if overweight) Aerobic exercise programs Physical therapy range-of-motion exercises Muscle-strengthening exercises Assistive devices for ambulation Patellar taping Appropriate footwear Lateral-wedge insoles (for genu varum) Bracing Occupational therapy Joint protection and energy conservation Assistive devices for activities of daily living data have bolstered this approach and have confirmed both efficacy and cost-effectiveness when used appropriately. 11 15 However, many, if not most, patients with OA will find that nonpharmacologic interventions alone often do not provide sufficient control of symptoms, and do not allow them to function adequately. Hence, pharmacologic treatment is usually an important and essential next step. Pharmacologic Treatment Acetaminophen has long been considered the drug of first choice in patients with OA who require pharmacologic intervention. The Table 2 Pharmacologic Therapy for Patients with Osteoarthritis (Reprinted from Ref. 5, by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.) Oral Acetaminophin Coxibs Nonselective nonsteroidal anti-inflammatory misoprostol or proton pump inhibitor (in patients at increased risk for upper gastrointestinal adverse events) Nonacetylated salicylate Other pure analgesics Tramadol Opioids Intra-articular Glucocorticoids Hyaluronan Topical Capsaicin Methylsalicylate current guidelines continue to support this position, based on the fact that acetaminophen provides effective relief of pain for many patients with OA, and has been demonstrated to be safe in a wide range of populations. 5,16 However, the guidelines also recognize that several prospective, randomized trials have now convincingly demonstrated that NSAIDs and coxibs provide superior efficacy compared with acetaminophen in patients with OA. 17 19 In addition, surveys have reported that a greater percentage of patients perceive NSAIDs to be more effective and preferable to acetaminophen. 20,21 Some available data suggest that patients with more severe pain respond better to NSAIDs than to acetaminophen, and there is a commonly held belief that patients with inflammatory OA (clinically defined by the presence of detectable effusion) may respond better to an anti-inflammatory drug. 17,22 These latter two groups make up a distinct minority of individuals with OA, but are ones in which consideration of an NSAID or coxib may be warranted as initial pharmacologic therapy. Coxibs may be utilized in at least three different clinical circumstances for pain relief in patients with OA. First, these agents can be used in patients who have had an inadequate response to nonpharmacologic modalities and to maximum doses of acetaminophen. Second, they can be used as initial therapy in the relatively small group of patients with more severe pain who require a greater magnitude of pain relief than commonly obtained with acetaminophen, or in individuals with pain and signs of inflammation (effusion). Finally, coxibs can be utilized as adjunctive therapy for patients who wish to continue acetaminophen, with the hope that there will be a need for lower doses of the coxib because of the underlying analgesic activity of acetaminophen. Although the efficacy of coxibs in the treatment of OA in individuals who have not received adequate pain relief with either NSAIDs or acetaminophen has been demonstrated, no specific studies have tested the other uses, and additional confirmatory data would be helpful. Although NSAIDs could also be utilized in these settings, coxibs are the drug of choice in patients at high risk for developing GI toxicity or bleeding. 23 28 Factors associated with increased risk of GI adverse events (Table 3) have

Vol. 23 No. 4S April 2002 ACR Guidelines Update: Role of Coxibs S27 been repeatedly identified in epidemiologic, as well as prospective, outcome studies. 3,29 31 Additionally, in several studies, fewer patients experienced GI adverse events with coxibs than with traditional NSAIDs. 23 25,27 28 After lack of efficacy, GI side effects are the primary reason individuals discontinue or switch NSAID medications. Thus, fewer GI side effects should result in better compliance, less switching, and a reduced need for GI comedications or GI procedures. The latter two expectations have been documented in the course of clinical efficacy studies, and ultimately can support a pharmacoeconomic basis for the use of coxibs in a wider range of patients than simply those at very high risk of developing GI bleeds. There are special patient populations in whom standard NSAIDs should not be used, and for whom coxibs represent a potential alternative, such as patients on anticoagulation therapy or during the perioperative period. 32 39 However, additional studies are warranted to evaluate coxibs in these situations. Table 3 Risk Factors for NSAID-Induced Upper Gastrointestinal Adverse Events (reprinted from Ref. 5, by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.) Age 65 years Comorbid medical conditions Concomitant use of anticoagulants or oral glucocorticoids History of peptic ulcer disease or upper gastrointestinal bleeding NSAID nonsteroidal anti-inflammatory drug. Alternatives to Coxibs Alternatives to coxibs for the treatment of patients with OA do exist, and the ultimate choice of agent must depend on an overall analysis of benefit, risk, convenience, price, and patient satisfaction. The use of a gastroprotective agent (misoprostol) in combination with an NSAID has been shown to be effective in reducing the rate of serious clinical GI events. 40 42 Proton pump inhibitors or highdose H 2 -receptor antagonists in combination with an NSAID have been shown to be effective in reducing the formation of endoscopic ulceration. 42 45 Although providing greater safety than with an NSAID alone, the addition of a gastroprotective agent means additional pills, additional costs (which are substantial in the case of proton pump inhibitors), and the potential for additional side effects, particularly with misoprostol. However, the use of a traditional NSAID results in platelet inhibition, limiting the use of these combinations in patients with bleeding diatheses, on anticoagulants, or in the perioperative period. Alternatively, for patients with OA who are already taking gastroprotective agents, perhaps for symptomatic relief of gastroesophageal reflux disease, the addition of a traditional NSAID may be both logical and cost-effective. Although coxibs have clearly been shown to reduce GI morbidity compared with NSAIDs, it should be kept in mind that these drugs act in a similar manner at the level of the kidney. 46 48 NSAIDs have been known to demonstrate a dose-dependent effect on blood pressure, and are associated with a small, but measurable, increase in the incidence of edema. 49 54 Similar mechanism-based effects have been reported with the use of rofecoxib and celecoxib. 46,48 Because of the known association between use of NSAIDs and exacerbation of congestive heart failure (CHF), use of NSAIDs or coxibs in patients at high risk for developing CHF, or in those with compromised renal function, should be undertaken with caution. 55,56 Tramadol is an alternative for patients with a contraindication (e.g., impaired renal function) to NSAIDs or coxibs, or those who have not received adequate pain relief with previous oral therapy. 5 Patients who experience severe pain despite treatment with tramadol or those who cannot tolerate the side effects may be candidates for traditional opioid therapy. 57 Topical agents and/or intra-articular injection of involved joints may be used as an adjunct to oral analgesia, as monotherapy in patients with a contraindication to NSAIDs or coxibs, or in patients who have experienced adverse events or a lack of clinical efficacy with oral therapy. 5 As in the original guidelines, surgical treatment of OA is reserved for patients with severe OA who have failed to respond to nonpharmacologic and pharmacologic regimens and have progressive limitations in their activities of daily living. Investigational Treatments As previously mentioned, our understanding of the treatment of OA evolves as knowledge of the underlying pathophysiology of the condition improves and as new therapeutic agents are developed. Many of the basic mechanisms

S28 Schnitzer Vol. 23 No. 4S April 2002 involved in OA are being targeted for pharmacologic intervention, resulting in the development of treatment modalities that directly affect the disease process. 6 9 Several therapies currently under investigation for their role in the prevention or treatment of OA include nutritional supplements, such as glucosamine and chondroitin, disease-modifying OA drugs, and devices, such as acupuncture and electromagnetic therapy (Table 4) Conclusion Coxibs offer an important new alternative to NSAIDs for the treatment of osteoarthritis. In patients in whom acetaminophen and nonpharmacologic interventions do not adequately control pain, coxibs provide a safe and effective therapy that should be considered based on the patient s medical background, tolerance of both serious and nuisance side effects, and availability of this form of therapy. Data from large outcome studies demonstrate that even in patients at low risk of developing serious gastrointestinal events, coxibs cause fewer ulcers than NSAIDs. There is little doubt that rapid acceptance and widespread use of coxibs will lead to fewer serious GI events, and wider use of effective analgesia, not only in patients with OA but in patients with other pain states as well. It is anticipated that the guidelines for the treatment of OA will continue to evolve as new therapies become available. Table 4 Therapies Under Investigation for Use in Patients with Osteoarthritis 5 Pharmacologic agents Nutritional supplements Glucosamine Chondroitin sulfate Antioxidants Disease-modifying osteoarthritis drugs Matrix metalloproteinase inhibitors Growth factors Devices Acupuncture Magnets Pulsed electromagnetic fields Lasers References 1. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, part I: osteoarthritis of the hip. Arthritis Rheum 1995;38:1535 1540. 2. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, part II: osteoarthritis of the knee. Arthritis Rheum 1995;38:1541 1546. 3. Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991;114:257 263. 4. Griffin MR, Ray WA, Schaffner W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988;109: 359 363. 5. Altman RD, Hochberg MC, Moskowitz RW, Schnitzer TJ. Recommendations for the medical management of osteoarthritis of the hip and knee. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000; 43:1905 1915. 6. Amin AR, Abramson SB. The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Curr Opin Rheumatol 1998;10:263 268. 7. Amin AR, Attur MG, Thakker GD, et al. A novel mechanism of action of tetracyclines: effects of nitric oxide synthases. Proc Natl Acad Sci USA 1996; 93:14014 14019. 8. Reginster JY, Deroisy R, Rovati LC, et al. Longterm effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251 256. 9. Smith GN, Yu LP, Brandt KD, Capello WN. Oral administration of doxycycline reduces collagenase and gelatinase activities in extracts of human osteoarthritic cartilage. J Rheumatol 1998;25:532 535. 10. Guyatt GH, Sinclair J, Cook DJ, Glasziou P, for the Evidence-Based Medicine Working Group and the Cochrane Applicability Methods Working Group. Users guides to the medical literature XVI: how to use a treatment recommendation. JAMA 1999;281: 1836 1843. 11. Ettinger WH Jr, Burns R, Messier SP, et al. A randomized trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis: the Fitness Arthritis and Seniors Trial (FAST). JAMA 1997;277:25 31. 12. Hurley MV, Scott DL. Improvements in quadriceps sensorimotor function and disability of patients with knee osteoarthritis following a clinically practicable exercise regime. Br J Rheumatol 1998;37: 1181 1187. 13. Martin K, Nicklas BJ, Bunyard LB, et al. Weight loss and walking improve symptoms of knee osteoarthritis (OA) [abstract]. Arthritis Rheum 1996; 39(suppl):S225.

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