Data based on the EULAR recommendations 2003: an evidence-based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT) published in the December 2003 issue of the Annals of the Rheumatic Diseases

This report was reviewed for medical and scientific accuracy by Naomi Schlesinger, MD, Director, Clinical Rheumatology, Assistant Professor of Medicine, Department of Medicine, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary

Michael Doherty, MA, MD, Academic Rheumatology, University of Nottingham, City Hospital, Nottingham, United Kingdom.

According to the recently updated 2003 European League Against Rheumatism (EULAR) treatment recommendations, acetaminophen (Tylenol) continues to be regarded as the initial medication of choice for treatment of pain associated with osteoarthritis of the knee, and if successful, the preferred long-term oral analgesic.¹ This specific recommendation was present also in the 2000 EULAR recommendations² and is in accordance with other osteoarthritis guidelines including the 2000 American College of Rheumatology Subcommittee on Osteoarthritis Guidelines,³ the National Institutes of Health,^4,5 and the 2002 American Geriatrics Society guidelines for management of persistent pain in older persons.⁶ The 2003 EULAR recommendations also highlight the central role of non-pharmacological treatments in the management of knee osteoarthritis (education, aerobic and strengthening exercises, weight loss if overweight or obese, appropriate footwear) and the importance of tailoring the management plan to the individual patient, taking into account factors such as comorbidity, pain severity and patient preference.

Osteoarthritis is the most common form of arthritis in Western populations. Osteoarthritis of the knee alone results in disabling knee symptoms in an estimated 10% of people older than 55 years, a quarter of whom are severely disabled.⁷ Moreover, radiographic evidence of osteoarthritis is present in the majority of people by 65 years of age and in approximately 80% of those older than 75 years.⁸ Further, the annual costs associated with osteoarthritis are considerable. It is therefore imperative that effective evidence-based treatment strategies are identified and implemented to reduce the overall morbidity associated with this disease. Although there is no cure for osteo-arthritis, treatment designed for the individual patient can reduce pain, maintain and/or improve joint mobility, limit functional impairment, and improve quality of life. Treatment recommendations such as those contained in the 2003 EULAR recommendations, provide a basis for the most appropriate treatment strategies. The EULAR recommendations clearly present the evidence for each key clinical statement and differentiate whether the statement is supported by research evidence, expert consensus, or both. Because of the need to individualize management, no simple algorithms are presented but key clinical propositions are addressed.

This Rheumatology Express Report™ provides a detailed review of the 2003 EULAR recommendations for the management of knee osteoarthritis

Evidence-based Approach to the Management of Knee Osteoarthritis

An expert panel with representation from 13 European countries was convened in November 2001 to establish the methodology for updating the database of evidence and recommendations for the treatment of osteo-arthritis of the knee.¹ The objectives of the committee were to describe all the therapeutic modalities used in the treatment of osteoarthritis and review each modality's level of evidence, produce a list of 10 key clinical recommendations for the management of osteoarthritis derived by independent Delphi technique and examine the degree to which the recommendations were supported by research evidence and expert opinion, and specify 10 recommendations for future research in osteoarthritis.

Based on predefined search criteria, an extensive review of the Medline OVID and BIDS Embase databases was conducted which resulted in the selection of 545 publications for review by the expert committee. Searches for previously investigated treatments (from EULAR 2000) were conducted from January 1999 to February 2002. For those treatments not previously investigated, searches were conducted from 1966 to February 2002. The level of evidence was assessed and documented for each treatment. Quality scores were determined for each publication, an effect size comparing the treatment with placebo was calculated where possible, and a toxicity profile was determined for each treatment modality. These publications formed the basis for the expert committee's recommendations. Treatment modalities were classified as non-pharmacological, pharmacological, intra-articular and surgical. All data were assigned a category according to study design, and assessed by the committee. The strength of the recommendations was stratified into categories based on the type of the clinical trial data, and expert committee opinion or clinical experience of respected authorities. Additionally, all treatment modalities were assessed for potential toxicity utilizing the visual analogue scale.

The expert committee identified a total of 33 treatment modalities. Selected treatment modalities are illustrated in Table 1. Of the 33 treatment modalities, 29 were supported by evidence from at least one randomized clinical trial. The exceptions were sex hormones, osteotomy, unicompartmental knee replacement and total knee replacement (surgical trials assessing arthroscopy ±debridement were supported by evidence from randomized clinical trials).

The toxicity profiles of selected treatment modalities are illustrated in Figure 1.

EULAR 2003: Ten Specific Recommendations

1. The optimal management of osteoarthritis of the knee requires a combination of non-pharmacological and pharmacological treatment modalities. Although this statement is intuitive, there is little direct evidence from appropriately designed clinical trials to support it. However, there is an abundance of indirect evidence from randomized clinical trials that individuals receiving analgesics at baseline received additional benefit from non-pharmacological treatments over and above that of the analgesics.

2. The treatment of knee osteoarthritis should be tailored according to knee risk factors (obesity, adverse mechanical factors, physical activity), general risk factors (age, comorbidity, polypharmacy), level of pain intensity and disability, sign of inflammation, location and degree of structural damage. As with the expected relative benefits, potential risks and costs of interventions must be taken into account. Although no research specific to knee osteoarthritis has been done to support a holistic approach to the patient, it is universally accepted.

3. Non-pharmacological treatment of osteoarthritis of the knee should include education, exercise, appliances (sticks, insoles, knee bracing), and weight reduction. Several large randomized controlled trials and meta-analysis have demonstrated the benefits of different educational techniques in reducing pain and increasing coping skills, but with little impact on function in patients with knee osteoarthritis.⁹ Education has been shown to result in fewer visits to the primary care physician, resulting in reduced costs.¹⁰ Although an optimized exercise regimen has not been developed, there is also evidence that joint-specific exercises reduce pain and improve function in patients with knee osteoarthritis,^11,12 in addition to physiotherapy.¹³

Less substantial evidence is available in support of the use of appliances, with the exception of one randomized controlled trial that showed significant improvement in those participants who used a knee brace over those who did not.¹⁴ There is also limited data on the impact of weight loss, however the expert committee concluded that both the use of appliances (weighed insoles^15,16) and weight loss (combined with exercise¹⁷) seem sensible options in patients with knee osteoarthritis.

4. Acetaminophen is the oral analgesic to try first and, if successful, the preferred long-term oral analgesic. This recommendation was based on the results of a randomized controlled trial that showed a significant improvement in pain at rest with acetaminophen compared to placebo,¹⁸ as well as a 4-week randomized controlled trial that showed acetaminophen (4,000 mg/day) was as effective as ibuprofen (2,400 mg/day),¹⁹ even with severe knee pain.²⁰ Moreover, a randomized controlled trial showed that acetaminophen could be used effectively in doses up to 2,600 mg/day for 2 years without significant adverse outcomes.²¹ In the same study, it was shown that the efficacy of acetaminophen was similar to that of naproxen 750 mg/day.

The recommendation of acetaminophen as the initial pharmacological treatment option for the pain of osteoarthritis of the knee is in support of earlier EULAR recommendations,² the American College of Rheumatology Subcommittee on Osteoarthritis Guidelines recommendations for the medical management of osteoarthritis issued in 2000,³ the National Institutes of Health,^4,5 and the American Geriatric Society guidelines for the management of persistent pain in older persons.⁶ Each of the guidelines recommends acetaminophen as initial therapy based primarily on its overall cost, efficacy, and toxicity profile.

5. Topical applications (nonsteroidal anti-inflammatory drugs (NSAIDs), capsaicin) have clinical efficacy and are safe. These agents are well tolerated and accepted by patients. There have been several randomized controlled trials demonstrating efficacy of topical diclofenac,^22,23 topical ketoprofen,²⁴ and topical piroxicam,²⁵ as well as one randomized controlled trial demonstrating the efficacy of capsaicin.²⁶ Large surveillance studies in general practice²⁷ suggest acceptable safety (adverse events <1.5%) with local skin reactions the principal side effect.

6. NSAIDs should be considered in patients unresponsive to acetaminophen. In patients with an increased gastrointestinal risk, non-selective NSAIDs and effective gastroprotective agents, or selective cyclooxygenase (COX)-2 inhibitors should be used. There have been several clinical trials demonstrating the efficacy of NSAIDs and selective COX-2 inhibitors in treating osteoarthritis pain.^28-30 In patients with increased risk of gastrointestinal adverse effects, clinical trial data has shown that gastroprotective agents are effective in reducing gastrointestinal adverse effects.³¹ The use of selective COX-2 inhibitors may have benefit in reducing the risk of gastrointestinal adverse effects associated with the use of NSAIDs.^29,30

7. Opioid analgesics, with or without acetaminophen, are useful alternatives in patients in whom non-selective NSAIDs and selective COX-2 inhibitors are contraindicated, ineffective, and/or poorly tolerated. Although there is little direct evidence to support this claim, it is generally accepted in clinical practice to use an opioid agent when other therapeutic options are limited. However, patients must be counseled on the increased risk of adverse side effects, particularly in the elderly, and potential dependence on these agents. Agents such as tramadol have been shown to allow the reduction of the nap-roxen dose among patients with naproxen-responsive osteoarthritis pain.³²

8. Symptomatic slow-acting drugs for osteoarthritis (SYSADOA) including glucosamine sulfate, chondroitin sulfate, and hyaluronic acid, have symptomatic effects and may modify structure. Randomized controlled trials of glucosamine and chondroitin have demonstrated moderate to large effects on pain and disability compared with placebo, however, these effects may have been exaggerated by publication bias.³³ Hyaluronic acid has been well studied in the treatment of osteoarthritis of the knee. Hyaluronic acid has been shown to significantly reduce osteoarthritis pain with associated functional improvement,³⁴ improve quality of life with reduction of NSAID use,³⁵ and reduce the need for intra-articular corticosteroid injections.³⁶

9. Intra-articular injection of long-acting corticosteroid is indicated for flare of knee pain, especially if accompanied by effusion. Intra-articular corticosteroid injections have been used to relieve pain and inflammation of osteoarthritis for many years. There is evidence to suggest that intra-articular injections of corticosteroid are effective in treating osteoarthritis, but give relatively short-lived benefit.^37,38

10. Joint replacement has to be considered in patients with radiographic evidence of knee osteoarthritis that have refractory pain and disability. The effectiveness of total knee replacement in knee osteoarthritis has a well-established place in those severely incapacitated. A systematic review concluded that total knee replacement was a safe and effective treatment in improving quality of life, as well as reducing pain and improving function in patients with osteoarthritis.³⁹

The final recommendations of the expert committee are illustrated in Table 2.

Conclusion

The optimal management of osteoarthritis of the knee requires a combination of non-pharmacological (eg, exercise, weight loss if overweight or obese, education, insoles) and pharmacological treatment modalities. The updated 2003 EULAR recommendations on the management of osteo-arthritis of the knee continue to support the use of acetaminophen as first-line pharmacological therapy. For those patients who are unresponsive to acetaminophen, topical agents (NSAIDs, capsaicin), oral NSAIDs including selective COX-2 inhibitors (and NSAIDs with gastroprotective agents if indicated) and opioids are appropriate alternative treatment options to consider.

References

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Disclosure
Michael Doherty, MA, MD
No significant relationships to disclose.

Naomi Schlesinger, MD
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.

© 2004 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education