This report was reviewed for medical and scientific accuracy by Naomi Schlesinger, MD, Assistant Professor of Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey; Chief, Rheumatology Section, University of Medicine and Dentistry of New Jersey, University Hospital, Newark, New Jersey; Rheumatologist in Chief, University of Medicine and Dentistry of New Jersey, National Tuberculosis Center, Newark, New Jersey

Editorial

Deborah S. Litman, MD, FACR, Chevy Chase, Maryland

Although nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors have been used to treat the pain associated with osteoarthritis, the American College of Rheumatology (ACR) guidelines published in 1995,¹ and updated in 2000,² recommended acetaminophen (Tylenol) as the first-line pharmacologic agent of choice for the treatment of symptomatic osteoarthritis based on its effectiveness in relieving mild-to-moderate pain, its favorable safety profile, and low cost. The ACR recommendation of acetaminophen as the agent of choice for the pain of osteoarthritis found support in a summary analysis issued by a recognized panel of experts in the treatment of osteoarthritis and convened by the National Institutes of Health (NIH).^3,4

Osteoarthritis is by far the most common form of arthritis and affects approximately 21 million people in the United States alone.⁵ Unlike the case with rheumatoid arthritis, inflammation, if present, is usually mild and localized to the affected joint. Although the etiology of osteoarthritis is not completely understood, it is believed biomechanical stresses affecting the articular cartilage and subchondral bone, biochemical changes in the articular cartilage and synovial membrane, and genetic factors are all associated with its pathogenesis.^6-8 Because of the biomechanical aspects of osteoarthritis, the goals of treatment are designed to reduce pain and improve health-related quality of life, maintain and/or improve joint mobility, and limit functional impairment while avoiding, if possible, adverse effects of therapy. As such, contemporary management of osteoarthritis includes nonpharmacologic modalities combined with or followed by pharmacologic treatment.

Nonpharmacologic treatment options include physical exercise programs to improve aerobic capacity, muscle strength, range of motion and coordination, weight reduction, reduction of joint load through the use of a cane or walker, use of wedged insoles, thermotherapy, and patient education programs. In addition to recommending acetaminophen as the initial pharmacologic agent for the pain of osteoarthritis, both the ACR guidelines and summary analysis emphasize the importance of continuing nonpharmacologic treatment options to supplement the initiation of pharmacologic therapy. Pharmacologic therapy for pain management is most effective when combined with nonpharmacologic strategies.⁹

One of the reasons that acetaminophen is recommended as initial pharmacologic therapy in osteoarthritis is its much more favorable upper gastrointestinal safety profile compared to NSAIDs (eg, ibuprofen, naproxen, indomethacin, diclofenac, and ketoprofen). NSAIDs have been well documented to cause life-threatening toxicities in the form of gastric ulcers, gastrointestinal bleeding, and the resulting complications (eg, perforation, pyloric obstruction).^10-14 Epidemiologic studies show that among persons ≥65 years old, 20% to 30% of all hospitalizations and deaths due to peptic ulcer disease were attributable to therapy with NSAIDs.^15-17

The selective COX-2 inhibitors (celecoxib (Celebrex) and rofecoxib (Vioxx)) were developed as offering a theoretically lower risk of gastrointestinal complications than the nonselective NSAIDs targeting COX-1 and COX-2 because the selective COX-2 inhibitors agents spare the action of COX-1, the enzyme responsible for producing gastroprotective prostaglandins. Recent revelations concerning trial design have called into question the validity of the claim of lower risk of gastrointestinal complications with selective COX-2 inhibitors.^18,19 Specifically, in a study funded by Pharmacia, the Celecoxib Long-term Arthritis Safety Study (CLASS) trial,²⁰ the Food and Drug Administration (FDA) found that celecoxib did not show a safety advantage in upper gastrointestinal events compared to ibuprofen or diclofenac.²¹

In a clinical environment that demands evidence-based medicine, conflicting data presents the clinician with a challenge. In the area of osteoarthritis, guidelines and recommendations have been issued to assist the clinician in that assessment. Additionally, clinical studies continue to be conducted for further evaluation of the pharmacologic treatment options in osteoarthritis. For example, a study by Geba et al²² and funded by Merck, found comparable efficacy and safety between acetaminophen, celecoxib, and rofecoxib 12.5 mg in treating osteoarthritis. The debate surrounding the pharmacologic agent of choice for osteoarthritis will no doubt continue. However, until the preponderance of data suggests otherwise, the guideline recommendations and data summarized in this report provide a significant body of evidence.

Assessing Efficacy of Acetaminophen, Celecoxib and Rofecoxib in Osteoarthritis

To assess the relative therapeutic efficacy of acetaminophen, celecoxib, and rofecoxib in adults with osteoarthritis of the knee, Geba et al evaluated 382 patients (mean age 62.6 years; range, 39-91 years) with osteoarthritis in a multicenter, double-blind, parallel-group study.²² Patients were randomized to receive acetaminophen 4000 mg/day (n = 94), celecoxib 200 mg once daily (n = 97), rofecoxib 12.5 mg once daily (n = 96), or rofecoxib 25 mg once daily (n = 95) for 6 weeks. Patient characteristics and demographics at baseline were comparable between all 4 treatment arms. Inclusion criteria included prior use of NSAID or acetaminophen administration.

Clinical efficacy outcomes were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC²³) and patient global assessment of response to therapy (PGART) administered at Weeks 2, 4, and 6. Safety evaluation was based on physical examination, laboratory testing and reporting of adverse events.

Comparable Efficacy between Acetaminophen, Celecoxib, and Rofecoxib 12.5 mg
After 6 weeks of therapy, there were no statistically significant differences between acetaminophen, celecoxib and rofecoxib 12.5 mg in the WOMAC efficacy measures of pain walking on a flat surface, night pain, rest pain, morning stiffness and WOMAC subscales assessing pain, stiffness and physical function (Table 1). It should be noted that there were statistically significant differences observed with rofecoxib 25 mg compared to acetaminophen, celecoxib, and rofecoxib 12.5 mg. The 25 mg dose is twice the recommended initial dose of rofecoxib (12.5 mg) for treating osteoarthritis.²⁴

At 6 weeks, the percentages of patients who had good or excellent response on PGART measures were 60% in the 25 mg and 56% in the 12.5 mg rofecoxib-treated patients, 46% in celecoxib-treated patients and 39% in the acetaminophen-treated patients. Of note, there was no statistically significant difference in the likelihood of a positive patient response to therapy between acetaminophen- and celecoxib-treated patients. As with the WOMAC scores, a positive response was statistically significantly more likely in patients treated with rofecoxib 25 mg versus celecoxib (P = .03) or acetaminophen (P = .003).

Adverse events were comparable across all treatment arms. Incidences of specific gastrointestinal events were generally low and comparable between treatment arms. There were no reported cases of gastrointestinal bleeding, perforation, or ulceration during the study. Of the patients who discontinued study treatment, 6 acetaminophen-treated patients (of 29, 21%), 4 celecoxib-treated patients (of 17, 24%), 7 rofecoxib 12.5 mg-treated patients (of 17, 41%) and 6 rofecoxib 25 mg-treated patients (of 18, 33%) did so due to adverse events.

With the exception of rofecoxib 25 mg, there were no statistically significant differences in efficacy and safety measures between acetaminophen, celecoxib, and rofecoxib 12.5 mg. However, in interpreting the results of the study, there are several potential limitations. The multiple efficacy endpoints (versus a single primary endpoint) raise potential concerns for interpretation of statistical differences due to multiplicity of analyses. The relatively short duration of the study may have precluded the full manifestation of gastrointestinal and cardiovascular adverse events that have been associated with NSAID and selective COX-2 inhibitor administration.^{15-17, 25-28} This is of clinical relevance where the typical patient with osteoarthritis tends to be older, requires long-term analgesic therapy, and is especially at risk for NSAID-related adverse events.²⁹

The investigators advise that in treating the pain of osteoarthritis, individualized decisions need to be made regarding optimal medical management and modification of treatment based on patient response, published efficacy and safety data, and overall cost considerations.

Where do we Stand with COX-2 Inhibitors and Gastrointestinal Safety? CLASS: A Case in Progress

The objective of the CLASS study²⁰ was to determine whether celecoxib was associated with a lower incidence of significant upper gastrointestinal effects and other adverse effects compared with conventional NSAID therapy. A total of 8059 patients with osteoarthritis and rheumatoid arthritis were randomized to celecoxib 400 mg twice a day (n = 3987), ibuprofen 800 mg 3 times per day (n = 1985), or diclofenac 75 mg twice a day (n = 1996) for 6 months. Concomitant medications that were permitted included aspirin for cardiovascular prophylaxis (≤325 mg/day), oral, intramuscular, and intra-articular glucocorticoids and disease-modifying anti-rheumatic drugs. The primary outcome measures were the incidence of prospectively defined symptomatic upper gastrointestinal and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects reported during the 6-month treatment period.

For all patients, the annualized incidence rates of upper gastrointestinal ulcer complications alone and combined with symptomatic ulcers for celecoxib versus NSAID were 0.76% versus 1.45% (P = .09) and 2.08% versus 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized incidence rates of upper gastrointestinal ulcer complications alone and combined with symptomatic ulcers for celecoxib versus NSAID were 0.44% versus 1.27% (P = .04) and 1.40% versus 2.91% (P = .02). For patients taking aspirin, the annualized incidence rates of upper gastrointestinal ulcer complications alone and combined with symptomatic ulcers for celecoxib versus NSAID were 2.01% versus 2.12% (P = .92) and 4.70% versus 6.00% (P = .49). Investigators concluded that fewer celecoxib-treated patients experienced chronic gastrointestinal blood loss, gastrointestinal intolerance, hepatotoxicity, or renal toxicity compared to ibuprofen- or diclofenac-treated patients.

Shortly after the publication of the 6-month CLASS data, 2 letters published in JAMA drew attention to the fact that complete information from CLASS available at the FDA contradicted these results.^18,19 The 6-month data from CLASS actually referred to the combined analysis of the results of the first 6 months of 2 separate and longer clinical studies. The protocols of these trials differed markedly from the published 6-month data in design, outcomes, duration of follow-up, and analysis.

According to an editorial published in the British Medical Journal,³⁰ 2 issues cause concern. First, the serious irregularities observed in the compilation and publication of the data has yet to be adequately explained. And secondly, the flawed findings in the original publication were widely disseminated and continue to be believed. Subsequent analysis of the data showed a similar incidence in ulcer related complications between celecoxib, ibuprofen, and diclofenac. As a result, the FDA found that celecoxib did not show a safety advantage in upper gastrointestinal events compared to ibuprofen or diclofenac.²¹ The FDA did not approve a labeling change to revise the prescribing information.

Conclusion

These developments create a challenge for the clinician treating patients with osteoarthritis. How to evaluate the efficacy and safety of the multitude of pharmacologic treatment options for osteoarthritis? The guidelines and data summarized in this report support the use of acetaminophen as the pharmacologic treatment of choice based on its effectiveness, favorable tolerability and low cost. For those patients not achieving complete pain relief with acetaminophen, NSAIDs and selective COX-2 inhibitors offer acceptable alternatives; given appropriate patient selection. But, what of gastrointestinal toxicities associated with NSAID and selective COX-2 inhibitor administration? Clearly, future comparative and evaluative studies are warranted. But, such studies must be conducted with an appropriate study design.

References

1. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, II: osteoarthritis of the knee. Arthritis Rheum. 1995; 38:1541-1546.
2. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43:1905-1915.
3. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann Intern Med. 2000;133:635-646.
4. Felson DT, Lawrence RC, Hochberg MC, et al. Osteoarthritis: new insights. Part 2: treatment approaches. Ann Intern Med. 2000;133:726-737.
5. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998;41:778-799.
6. Mow VC, Setton LA, Fuilak F, Ratcliffe A. Mechanical factors in articular cartilage and their role in osteoarthritis. In: Kuettner KE, Recommendations for Hip and Knee OA Management. Goldberg VM, eds. Osteoarthritic disorders. Rosement (IL): American Academy of Orthopaedic Surgeons; 1995:147-172.
7. Poole AR. Imbalances of anabolism and catabolism of cartilage matrix components in osteoarthritis. In: Kuettner KE, Goldberg VM, eds. Osteoarthritic disorders. Rosemont (IL): American Academy of Orthopaedic Surgeons; 1995:247-260.
8. Holderbaum D, Haqqi TM, Moskowitz RW. Genetics and osteoarthritis: exposing the iceberg. Arthritis Rheum. 1999;42:397-405.
9. American Geriatrics Society Panel on Chronic Pain in Older Persons. The management of chronic pain in older persons. J Am Geriatric Soc. 1998;46:635-651.
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24. Vioxx prescribing information [package insert]. Merck & Co. Available at http://www.vioxx.com. Accessed February 12, 2003.
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29. Pincus T, Koch GG, Sokka T, et al. A randomized, double-blind, cross-over clinical trial of diclofenac plus misoprostol vs acetaminophen in patients with osteoarthritis of the hip or knee. Arthritis Rheum. 2001;44:1587-1598.
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Disclosure
Deborah S. Litman, MD, FACR
Consultant-McNeil Consumer and Specialty Pharmaceuticals; Speakers Bureau-McNeil Consumer and Specialty Pharmaceuticals, Merck, Novartis

Naomi Schlesinger, MD
Has no significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Rheumatology Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Rheumatology Express Report™ was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education