This report was reviewed for medical and scientific accuracy by Leonard H. Sigal, MD, Professor of Medicine and Pediatrics, Chief, Division of Rheumatology & Connective Tissue Research, University of Medicine and Dentistry of New Jersey (UMDNJ), Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

Stephen Brunton, MD, Stamford Hospital/Columbia University, Family Practice Residency Program, Stamford, Connecticut

Osteoarthritis is by far the most common form of arthritis and affects approximately 21 million people in the United States (U.S.) alone.¹ Often referred to as "degenerative joint disease", osteoarthritis is characterized by loss of hyaline articular cartilage with formation of osteophytes, marginal outgrowths (bone spurs), and increased thickness of the bony envelope of the joint.

In the majority of cases, osteoarthritis affects the knee, the hands, and the hip joints but it can also affect the cervical and lumbar regions of the spine, and the first metatarso-phalangeal joint of the foot. The primary clinical symptoms are joint pain, tenderness and/or stiffness, impaired joint function, and development of joint deformity. These are often accompanied with difficulty in walking and climbing, and reduction in the normal activities of living. Osteoarthritis is the most common reason for hip and knee replacement, and represents a significant burden in terms of health costs, lost productivity, and early retirement. It has been estimated that the total costs of arthritis, including osteoarthritis, may exceed 2% of the U.S. gross domestic product.² Although there is no cure for osteoarthritis, treatment designed for the individual patient can reduce pain, maintain and/or improve joint mobility, and limit functional impairment.

Although osteoarthritis is not limited to older persons, it is primarily a disease of aging. In one survey, the incidence and prevalence of disease increased 2- to 10-fold from ages 30 to 65 years and continued to increase with further aging.³ Because the prevalence of osteoarthritis increases with age, the incidence of osteoarthritis is expected to increase dramatically as the cohort of baby boomers advance into old age.

According to Spector et al⁴, genetic factors account for at least 50% of cases of osteoarthritis in the hands and hips and a smaller percentage in the knees. Candidate genetic markers for osteoarthritis include the vitamin D receptor gene, insulin-like growth factor I genes, cartilage oligomeric protein genes, and the human leukocyte antigen (HLA) region. Estrogen deficiency in post-menopausal women may play a role in increasing the risk for osteoarthritis; however, the evidence is conflicting.^5,6 Nutritional factors may also play a role; results from the longitudinal Framingham Knee OA Cohort Study showed that progressive radiographic osteoarthritis and knee pain were negatively correlated with vitamin C intake, whereas results for β-carotene and vitamin E were inconsistent.⁷ Additionally, the risk for progression of osteoarthritis was increased threefold for persons in the middle and lower tertiles of both vitamin D intake and serum level.⁸

Obesity is associated with a high prevalence of knee osteoarthritis and most often precedes the development of joint problems in individuals who are obese.^9,10 In most studies, but not all, the increased risk of osteoarthritis of the knee is higher in overweight women than overweight men.10 The effect of obesity on osteoarthritis is made more disturbing because obesity is reaching epidemic proportions in the U.S. having increased more than 50% in the past 10 to 15 years.¹¹

Other risk factors for osteoarthritis include post-traumatic joint instability¹², peri-articular muscle weakness¹³, sports injuries¹⁴, and occupational factors such as repetitious tasks¹⁵, and heavy physical labor.¹⁶

Whatever the cause of osteoarthritis, it is a condition that will be increasingly encountered by physician assistants in the future. In September 2000, the American College of Rheumatology (ACR) published an update of its 1995 recommendations for medical management of osteoarthritis of the hip and knee¹⁷, followed shortly thereafter by a summary of a National Institutes of Health (NIH) conference on osteoarthritis and its treatment.^18,19 Both of these recommendations state that pharmacologic therapy for osteoarthritis should always be added to nonpharmacologic treatment modalities. Acetaminophen remains the first drug of choice in treating osteoarthritis, primarily because of its effectiveness in relieving mild-to-moderate pain, its favorable safety profile, and inexpensive cost.^17,19,20 For those patients who fail to respond to acetaminophen, other pharmacologic and nonpharmacologic treatments, including nutritional therapies, may be effective.

Nonpharmacologic Modalities in the Treatment of Osteoarthritis

Nonpharmacologic modalities are recognized as a cornerstone in managing osteoarthritis pain and are recommended by all recent and current authoritative guidelines for managing osteoarthritis.¹⁷

Physical exercise programs to improve aerobic capacity, muscle strength, range of motion and coordination have been shown to reduce pain, disability, physician visits, and the need for pain medication in patients with hip or knee osteoarthritis.²¹ The 1995 ACR guidelines on the management of osteoarthritis recommended that overweight patients with osteoarthritis of the hip or knee lose weight to improve symptoms.^22,23 Other strategies recommended by the ACR guidelines include reduction of joint load through the proper use of a cane or walker, use of wedged insoles to correct abnormal biomechanics due to knee deformity^24,25, and patellar taping in cases that involve the patellofemoral compartment of the knee.²⁶ Application of heat to relax muscles and stimulate blood flow, or cold to ease muscle spasms and block pain signals are also appropriate strategies to reduce symptoms.

Finally, education of patients, families, friends, and caregivers is an integral component of osteoarthritis care. Patient education programs have been shown to improve arthritis symptoms 15 to 30% over and above the 20 to 50% improvement with medications and can have an impact up to two years following intervention.²⁷

Pharmacologic Therapy of Osteoarthritis

Pharmacologic therapy with systemic drugs and topical applications, or intra-articular injections should be considered as additions to the nonpharmacologic modalities discussed above, which should be maintained throughout the treatment period. Pharmacologic therapy for pain management is most effective when combined with nonpharmacologic strategies.²⁸

Acetaminophen or Nonsteroidal Anti-inflammatory Drugs?

Acetaminophen (Tylenol, McNeil Consumer and Specialty Pharmaceuticals) has been consistently recommended by all major guidelines as the drug of first choice for osteoarthritis pain. For most patients with osteoarthritis, the relief of mild-to-moderate joint pain with acetaminophen is comparable to that achieved with a nonsteroidal anti-inflammatory drug (NSAID).^29-32 Although acetaminophen lacks anti-inflammatory properties, a study by Bradley et al³³ showed no difference in pain relief between acetaminophen and ibuprofen (Motrin IB, McNeil Consumer and Specialty Pharmaceuticals; Motrin, Pharmacia Corp.) in patients with knee osteoarthritis and clinical signs of inflammation. Subsequent studies have shown mixed results, with some studies showing more benefit with NSAIDs for patients with severe pain.³⁴ Nevertheless, the 2000 ACR guidelines state, "this drug [acetaminophen] merits a trial as initial therapy, based on its overall cost, efficacy, and toxicity profile."^32,35

The daily dose of acetaminophen should not exceed 4 grams.³⁶ Acetaminophen is one of the safest analgesics, but can be associated with clinically important adverse effects if taken in overdose. Even though acetaminophen was suggested to be weakly associated with end-stage renal disease, a subsequent evaluation by the Scientific Advisory Committee of the National Kidney Foundation recommended acetaminophen as the analgesic of choice for patients with impaired renal function.³⁷

Acetaminophen and Alcohol

In 1998, the Food and Drug Administration (FDA) announced that all over-the-counter (OTC) pain relievers/fever reducers must carry a warning on the label directing people who consume 3 or more alcoholic drinks a day to consult with a physician before using these products.³⁸ Acetaminophen was included in this warning due to a series of retrospective case reviews and case reports suggesting that concomitant ingestion of acetaminophen and chronic alcohol consumption may increase the risk liver damage.³⁹ The 2000 ACR guidelines recommended that acetaminophen be avoided in patients with chronic alcohol abuse because of a known increased risk in [this] setting.^40-42 However, recent evidence suggests this advice may be unwarranted.

In a recent randomized clinical trial of 201 patients, no alteration in liver function or evidence of liver injury was found in alcoholic patients who consumed 4 grams of acetaminophen per day.⁴³ Other recent publications, including a systematic review⁴⁴, have put these results into perspective with earlier reports and come to the conclusion that acetaminophen is indeed safe for patients who regularly consume alcohol. However, these patients should be cautioned not to exceed the recommended dose.

For those patients who fail to obtain adequate symptomatic relief with acetaminophen, even with full doses, alternative or additional pharmacologic agents (nonselective NSAID, cyclooxygenase (COX)-2 specific inhibitor) that possess analgesic as well as anti-inflammatory properties should be considered. However, the choice should be made after evaluation of risk factors for serious upper gastrointestinal (GI) and renal toxicity.

One of the reasons that acetaminophen is recommended as initial therapy in osteoarthritis is its much more favorable upper GI safety profile compared to NSAIDs (e.g., ibuprofen, naproxen (Naprosyn, Roche Pharmaceuticals), indomethacin (Indocin, Merck), diclofenac (Voltaren, Novartis Pharmaceutical Corp.), and ketoprofen (Orudis, Wyeth). NSAIDs have been well documented for causing life-threatening toxicities in the form of gastric ulcers, GI bleeding, and their complications (e.g. perforation, pyloric obstruction).^45-49 Remarkably, 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.^50-52 Furthermore, the risk of a catastrophic GI event in elderly patients taking NSAIDs is dose dependent.⁵¹ Risk factors for upper GI bleeding in patients treated with NSAIDs include age (≥ 65 years), history of peptic ulcer disease or previous upper GI bleeding, concomitant use of oral glucocorticosteroids or anticoagulants, presence of comorbid conditions, and possibly, smoking and alcohol consumption.^53-55 Indeed, the alcohol warning on OTC NSAIDs directs consumers who consume 3 or more alcoholic drinks per day to consult with a physician before use because of the risk of stomach bleeding.

Risk factors for reversible renal failure in patients with intrinsic renal disease (usually defined as serum creatinine concentration of ≥ 2.0 mg/dL) who are treated with NSAIDs include age ≥ 65 years, hypertension and/or congestive heart failure, and concomitant use of diuretics and angiotensin-converting enzyme (ACE)-inhibitors.⁵⁶ NSAIDs may also affect the therapeutic actions of many antihypertensive drugs (e.g., diuretics, β-blockers, ACE inhibitors, angiotensin II blockers, alpha1 adrenergic blockers) through mechanisms mediated by prostaglandins.⁵⁷

The COX-2 specific inhibitors, rofecoxib (Vioxx, Merck), celecoxib (Celebrex, Pharmacia Corp.), and valdecoxib (Bextra, Pharmacia Corp.) were developed as theoretically offering a lower risk of GI complications than NSAIDs, because these agents spare the action of COX-1, the enzyme responsible for producing gastroprotective prostaglandins. Indeed, the 8076-patient VIGOR trial showed rofecoxib to be significantly safer than naproxen in terms of clinically meaningful GI toxicity.⁵⁸

Because patients enrolled in the rofecoxib arm of the VIGOR trial experienced a 4-fold increase in the incidence of myocardial infarction (0.4%) versus those patients taking naproxen (0.1%) (Relative Risk, 0.2; 95% Confidence Interval, 0.1-0.7), there is much controversy surrounding the use of COX-2 inhibitors and their possible association with adverse cardiovascular events.⁵⁹

Recent revelations concerning trial design have called into question the validity of the claim of lower risk of GI complications with COX-2 specific inhibitors.^60,61 In one specific case, the FDA has found that celecoxib did not show a safety advantage in upper GI events compared to ibuprofen or diclofenac.⁶² Adding to the controversy is the preliminary finding that COX-2 specific inhibitors may also delay healing in broken bones⁶³ and new evidence questioning the cost-effectiveness of COX-2 specific inhibitors versus less expensive treatments.⁶⁴

Topical Treatments

The use of topical analgesics, such as capsaicin (Zostrix, Genderm) or methylsalicylate (Bengay, Pfizer) may be appropriate either as adjunctive therapy or monotherapy in patients who do not respond to acetaminophen and do not wish to take systemic therapy. Capsaicin induces depletion of substance P, a key neuromodulator of pain transmission. Capsaicin cream should be applied to the affected joint 4 times daily. Patients should be warned about the likelihood of a benign burning sensation upon application and reminded to wash their hands after applying capsaicin, because it is very painful if it touches the eyes or mucous membranes.

Opioids and Other Treatment Options

Opioid analgesics may be appropriate for patients with moderate to severe pain who do not respond to acetaminophen and who have contraindications to NSAIDs or COX-2 inhibitors. Tramadol (Ultram, Ortho-McNeil Pharmaceutical), a centrally acting oral analgesic approved by the FDA for the treatment of moderate to moderately severe pain⁶⁵, has been found to be as effective as ibuprofen for hip and knee osteoarthritis⁶⁶ and has shown efficacy as adjunctive therapy in patients whose symptoms are inadequately controlled by NSAIDs.⁶⁷ Effective daily doses of tramadol range from 200-300 mg, given in 4 divided doses. Side effects include nausea, constipation, and drowsiness.

Patients who do not respond to tramadol or continue to have severe pain may be candidates for potent opioid therapy (e.g., codeine plus acetaminophen).²⁸ Several studies have shown efficacy with this combination, however, tolerability was sacrificed due to adverse effects commonly associated with opioids (e.g. nausea, vomiting, dizziness, constipation).⁶⁸

Intra-articular injections of corticosteroids or hyaluronan formulations have shown to be of value in the treatment of acute knee pain in patients with osteoarthritis and may be particularly beneficial in patients who have signs of local inflammation with a joint effusion. When joints are painful and swollen, aspiration of fluid followed by intra-articular injection of corticosteroid is an effective short-term method of decreasing pain and increasing quadriceps strength.^69,70 Care must be taken not to administer this treatment more than every 3-4 months. Although pain relief is achieved more slowly with hyaluronan (Hyalgan, Sanofi-Synthelabo; Synvisc, Genzyme Biosurgery) injections than with intra-articular corticosteroids, the effect may last considerably longer.⁶⁹ In clinical trials of intra-articular hyaluronan preparations, pain relief was significantly greater than that seen after intra-articular injection of placebo, and comparable with that seen with NSAIDs^69,71,72 while comparable to or greater than that with intra-articular corticosteroids.⁶⁹ Intra-articular hyaluronan therapy may be advantageous in patients in whom nonselective NSAIDs and COX-2 inhibitors are contraindicated. However, limited data are available concerning the effectiveness of multiple courses of intra-articular hyaluronan therapy.⁷³

Alternative Treatments

Nutritional supplements for osteoarthritis have become vogue over the past decade, however, evidence of efficacy is lacking for most of these treatments. One exception is the use of glucosamine and chondroitin sulfate, which have shown efficacy in palliation of joint pain in patients with osteoarthritis of the knee.^74,75 However, the 2000 ACR guidelines stress the need for additional standardized testing and outcome assessments to define the role of these agents. Toward that end, the National Institutes of Health (NIH) is currently funding the 6-month Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), which will test whether glucosamine and chondroitin sulfate used separately or in combination are effective in reducing pain and improving functional ability in 1588 patients with osteoarthritis of the knee.⁷⁶

Summary

Osteoarthritis is a growing problem in the aging U.S. population and will be increasingly encountered by physicians and physician assistants in the future. Clinical practice guidelines stress nonpharmacologic methods as the cornerstone of therapy, which should be supplemented by pharmacologic therapy when necessary. Nonpharmacologic treatments include exercise therapy, weight loss (when appropriate), reduction of load to the affected joint, the application of heat or cold, and patient education. Acetaminophen is the recommended pharmacologic agent for all patients with osteoarthritis, followed by NSAIDs or COX-2 inhibitors, and opioids, if patient pain remains severe. For patients with unsatisfactory response to systemic therapy or who cannot tolerate the pharmacologic agents, intra-articular injection of corticosteroid or hylauronan or topical capsaicin may be viable options.

References

1. 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.
2. Yelin E. The Economics of Osteoarthritis. In: Brandt KD, Doherty M, Lohmander LS, eds. Osteoarthritis. New York: Oxford University Press, 1998:23-30.
3. Oliveria SA, Felson DT, Reed JI, Cirillo PA, Walker AM. Incidence of Symptomatic Hand, Hip, and Knee Osteoarthritis among Patients in a Health Maintenance Organization. Arthritis Rheum 1995;38:1134-1141.
4. Spector TD, Cicuttini F, Baker J, Loughlin J, Hart D. Genetic Influences on Osteoarthritis in Women: A Twin Study. BMJ 1996;312:940-943.
5. Sandmark H, Hogstedt C, Lewold S, Vingard E. Osteoarthritis of the Knee in Men and Women in Association with Overweight, Smoking, and Hormone Therapy. Ann Rheum Dis 1999;58:151-155.
6. Oliveria SA, Felson DT, Klein RA, Reed JI, Walker AM. Estrogen Replacement Therapy and the Development of Osteoarthritis. Epidemiology 1996;7:415-419.
7. McAlindon TE, Jacques P, Zhyang Y, et al. Do Antioxidant Micronutrients Protect Against the Development and Progression of Knee Osteoarthritis? Arthritis Rheum 1996;39:648-656.
8. McAlindon TE, Felson DT, Zhang Y, et al. Relation of Dietary Intake of and Serum Levels of Vitamin D to Progression of Osteoarthritis of the Knee among Participants in the Framingham Study. Ann Intern Med 1996;125:353-359.
9. Maninen P, Riihimaki H, Heliovaara M, Makela P. Overweight, Gender and Knee Osteoarthritis. Int J Obes Rel Metab Disord 1996;20:595-597.
10. Felson DT, Zhang Y, Hannan MT, et al. Risk Factors for Incident Radiographic Knee Osteoarthritis in the Elderly: The Framingham Study. Arthritis Rheum 1997;40:728-733.
11. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and Obesity in the United States: Prevalence and Trends, 1960-1994. Int J Obes Relat Metab Disord 1998;22:39-47.
12. Honkonen SE. Degenerative Arthritis after Tibial Plateau Fractures. J Ortho Trauma 1995;9:273-277.
13. Slemenda C, Brandt KD, Heilman DK, et al. Quadriceps Weakness and Osteoarthritis of the Knee. Ann Intern Med 1997;127:97-104.
14. Buckwalter JA, Lane LE. Athletics and Osteoarthritis. Am J Sports Med 1997;25:873-881.
15. Hadler NM, Gillings DB, Imbus HR, et al. Hand Structure and Function in an Industrial Setting. Arthritis Rheum 1978;21:210-220.
16. Felson DT, Hannan MT, Naimark A, et al. Occupational Physical Demands, Knee Bending, and Knee Osteoarthritis: Results from the Framingham Study. J Rheumatol 1991;18:1587-1592.
17. [no authors listed] Recommendations for the Medical Management of Osteoarthritis of the Hip and Knee: 2000 Update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43(9):1905-1915.
18. 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.
19. Felson DT, Lawrence RC, Hochberg MC, et al. Osteoarthritis: New Insights. Part 2: Treatment Approaches. Ann Intern Med 2000;133:726-737.
20. APS Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis. American Pain Society. Available at: http://www.ampainsoc.org. Accessed June 12, 2002.
21. Van Baar ME, Dekker J, Oostendorp RAB, et al. The Effectiveness of Exercise Therapy in Patients with Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial. J Rheumatol 1998;25:2432-2439.
22. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the Medical Management of Osteoarthritis. Part 1. Osteoarthritis of the Hip. Arthritis Rheum 1995;38:1535-1540.
23. 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.
24. Sasaki T, Yasuda K. Clinical Evaluation of the Treatment of Osteoarthritis Knees Using a Newly Designed Wedged Insole. Clin Orthop 1985;221:181-187.
25. Keating EM, Faris PM, Ritter MA, Kane J. Use of Lateral Heel and Sole Wedges in the Treatment of Medial Osteoarthritis of the Knee. Orthop Rev 1993;22:921-924.
26. Cushnaghan J, McCarthy C, Dieppe P. Taping the Patella Medially: A New Treatment for Osteoarthritis of the Knee Joint. BMJ 1994;308:753-755.
27. The Arthritis Foundation. Available at: http://www.arthritis.org.
28. 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.
29. Towheed TE, Hochberg MC. A Systematic Review of Randomized Controlled Trials of Pharmacological Therapy in Patients with Osteoarthritis of the Knee. Semin Arthritis Rheum 1997;27:755-770.
30. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an Anti-Inflammatory Dose of Ibuprofen, an Analgesic Dose of Ibuprofen, and Acetaminophen in the Treatment of Patients with Osteoarthritis of the Knee. N Engl J Med 1991;325:87-91.
31. Williams HJ, Ward JR, Egger MJ, et al. Comparison of Naproxen and Acetaminophen in a Two-Year Study of Treatment of Osteoarthritis of the Knee. Arthritis Rheum 1993;36:1196-1206.
32. Eccles M, Freemantle N, Mason J, for the North of England Non-Steroidal Anti-Inflammatory Drug Guideline Development Group. North of England Evidence Based Guideline Development Project: Summary Guideline for the Non-Steroidal Anti-Inflammatory Drugs versus Basic Analgesia in Treating the Pain of Degenerative Arthritis. BMJ 1998;317:526-530.
33. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Treatment of Knee Osteoarthritis: Relationship of Clinical Features of Joint Inflammation to the Response to a Nonsteroidal Anti-inflammatory Drug or Pure Analgesic. J Rheumatol 1992;19:1950-1954.
34. Altman RD, IAP Study Group. Ibuprofen, Acetaminophen and Placebo in Osteoarthritis of the Knee: A Six-Day Double Blind Study [abstract]. Arthritis Rheum 1999;42 Suppl 9:S403.
35. Holzer SS, Cuerdon T. Development of an Economic Model Comparing Acetaminophen to NSAIDs in the Treatment of Mild-to-Moderate Osteoarthritis. Am J Managed Care 1996;2 Suppl:515-526. 36. Tylenol Product Information. McNeil Consumer and Specialty Pharmaceuticals. Available at: http://www.tylenol.com. Accessed June 12, 2002.
37. Henrich WL, Agodaoa LE, Barret B, et al. Analgesics and the Kidney: Summary and Recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. Am J Kidney Disease 1996;27:162-165.
38. Over-the-Counter Drug Products Containing Analgesic/Antipyretic Active Ingredients for Internal Use; Required Alcohol Warning. Department of Health and Human Services, Food and Drug Administration. 21 CFR Part 201 [Docket No. 77N-094W]. Federal Register Oct.23, 1998;63(205):56789.
39. Zimmerman HJ, Maddrey WC. Acetaminophen (Paracetamol) Hepatotoxicity with Regular Intake of Alcohol: Analysis of Instances of Therapeutic Misadventure. Hepatol 1995;22:767-773.
40. Schiodt FV, Rochling FA, Casey DL, Lee Wm. Acetaminophen Toxicity in an Urban Country Hospital. N Engl J Med 1997;337:1112-1117.
41. Whitcomb DC, Block GD. Association of Acetaminophen Hepatotoxicity with Fasting and Ethanol Use. JAMA 1994;273:1845-1850.
42. Seifert CF, Lucas DS, Vondracek TG, Kastens DJ, McCarty DL, Bui B. Patterns of Acetaminophen Use in Alcoholic Patients. Pharmacotherapy 1993;13:391-395.
43. Kuffner EK, Dart RC, Bogdan GM, et al. Effect of Maximal Doses of Acetaminophen on the Liver of Alcoholic Patients. Arch Intern Med 2001;161:2247-2252.
44. Dart RC, Kuffner EK, Rumack BH. Treatment of Pain or Fever with Paracetamol (Acetaminophen) in the Alcoholic Patient: A Systematic Review. Am J Therapeutics 2000;7:123-134.
45. Garcia Rodriguez LA, Jick H. Risk of Upper Gastrointestinal Bleeding and Perforation Associated with Individual Nonsteroidal Anti-Inflammatory Drugs. Lancet 1994;343(8900):769-772.
46. Langman MJ, Weil J, Wainwright P, et al. Risks of Bleeding Peptic Ulcer Associated with Individual Nonsteroidal Anti-Inflammatory Drugs. Lancet 1994;343(8905):1075-1078.
47. Lanza LL, Walker AM, Bortnichak EA, Dreyer NA. Peptic Ulcer and Gastrointestinal Hemorrhage Associated with Nonsteroidal Anti-Inflammatory Drug Use in Patients Younger than 65 Years. A Large Health Maintenance Organization Cohort Study. Arch Intern Med 1995;155(13):1371-1377.
48. Peura DA, Lanza FL, Gostout CJ, Foutch PG. The American College of Gastroenterology Bleeding Registry: Preliminary Findings. Am J Gastroenterol 1997;92(6):924-928.
49. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal Toxicity of Nonsteroidal Anti-Inflammatory Drugs. N Engl J Med 1999;340(24):1888-1899.
50. Smalley WE, Griffin MR. The Risks and Costs of Upper Gastrointestinal Disease Attributable to NSAIDs. Gastroenterol Clin North Am 1996;25:373-396.
51. 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.
52. 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(63):257-263.
53. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for Serious Gastrointestinal Complications Related to Use of Nonsteroidal Anti-Inflammatory Drugs: A Meta-Analysis. Ann Intern Med 1991;115(10):787-796.
54. Simon LS, Hatoum HT, Bittman RM, Archbault WT, Polisson RP. Risk Factors for Serious Nonsteroidal-Induced Gastrointestinal Complications: Regression Analysis of the MUCOSA Trial. Fam Med 1996;28:204-210.
55. Lanza FL, and the Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A Guideline for the Treatment and Prevention of NSAID-Induced Ulcers. Am J Gastroenterol 1998;93:2037-2046.
56. Garell S, Matarese RA. Renal Effects of Prostaglandins and Clinical Adverse Effects of Nonsteroidal Anti-Inflammatory Agents. Medicine (Baltimore) 1984;63:165-181.
57. Whelton A. Renal and Related Cardiovascular Effects of Conventional and COX-2-Specific NSAIDs and Non-NSAID Analgesics. Am J Ther 2000;7:63-74.
58. Bombardier C, Laine L, Reicin A, et al. Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520-1528.
59. Mukherjee D, Nissen SE, Topol EJ. Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors. JAMA 2001;286(8):954-959.
60. Berg Hrachovec J, Mora M. Reporting of 6-Month vs. 12-Month Data in a Clinical Trial of Celecoxib. JAMA 2001;286:2398.
61. Wright JM, Perry TL, Bassett KL, Chambers KG. Reporting of 6-Month vs. 12-Month in a Clinical Trial of Celecoxib. JAMA 2001;286:2398-2399.
62. FDA Talk Paper. Labeling Changes for Arthritis Drug Celebrex. U.S. Food and Drug Administration, T02-24, June 7, 2002. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01151.html. Accessed June 12, 2002.
63. Einhorn TA. Do Inhibitors of Cyclooxygenase-2 Impair Bone Healing? J Bone Miner Res 2002;17(6):977.
64. Reuters Medical News. Study Questions Cost-Effectiveness of COX-2 Drugs. Available at: http://www.medscape.com/viewarticle/435966. Accessed June 12, 2002.
65. Ultram Professional Prescribing Information. Ortho-McNeil Pharmaceutical, Inc. Available at: http://www.ultram.com. Accessed June 11, 2002.
66. Dalgin P, and the TPS-OA Study Group. Comparison of Tramadol and Ibuprofen for the Chronic Pain of Osteoarthritis [abstract]. Arthritis Rheum 1997;40 Suppl 9:S86.
67. Roth SH. Efficacy and Safety of Tramadol HCL in Breakthrough Musculoskeletal Pain Attributed to Osteoarthritis. J Rheumatol 1998;25:1358-1363.
68. Kjaersgaard-Andersen P, Nafei A, Skov O, et al. Codeine plus Paracetamol versus Paracetamol in Longer-Term Treatment of Chronic Pain Due to Osteoarthritis of the Hip: A Randomized, Double Blind, Multicenter Study. Pain 1990;32:990-995.
69. Kirwan JR, Rankin E. Intra-Articular Therapy in Osteoarthritis. Baillieres Clin Rheumatol 1997;11:769-794.
70. Creamer P. Intra-Articular Corticosteroid Injections in Osteoarthritis: Do They Work and If So, How? Ann Rheum Dis 1997;56:634-636.
71. Altman RD, Moskowitz RW, and the Hyalgan Study Group. Intra-Articular Sodium Hyaluronate (Hyalgan) in the Treatment of Patients with Osteoarthritis of the Knee: A Randomized Clinical Trial. J Rheumatol 1998;25:2203-2212.
72. Adams ME, Atkinson MH, Lussier AJ, et al. The Role of Viscosupplementation with Hylan G-F 20 (Synvisc) in the Treatment of Osteoarthritis of the Knee: A Canadian Multicenter Trial Comparing Hylan G-F 20 Alone, Hylan G-F 20 with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and NSAIDs Alone. Osteoarthritis Cartilage 1995;3:213-225.
73. Kotz R, Kolarz G. Intra-Articular Hyaluronic Acid: Duration of Effect and Results of Repeated Treatment Cycles. Am J Orthop 1999;29 Suppl 1:5-7.
74. McAlindon TF, LaValley MP, Gulin JP, Felson DT. Glucosamine and Chondroitin for Treatment of Osteoarthritis: A Systematic Quality Assessment and Meta-Analysis. JAMA 2000;283:1469-1475.
75. Deal CL, Moskowitz RW. Nutraceuticals as Therapeutic Agents in Osteoarthritis. Rheum Dis Clin North Am 1999;25:379-395.
76. National Institute of Arthritis and Musculoskeletal and Skin Diseases Press Release. Available at: www.niams.nih.gov/ne/press/2000/gait_qa.htm. Accessed June 11, 2002.

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Disclosure
Leonard H. Sigal, 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(tm) does not include discussion of treatment and indications outside of current approved labeling. This Rheumatology Express Report(tm) was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education