08 may 2009--Osteoarthritis (OA), also known as degenerative joint disease (DJD), is the most common form of arthritis in the United States. 1 Although OA can occur in any synovial joint in the body, it most commonly affects the knees, hips, and hands. OA is the leading cause of disability in elderly persons and affects approximately 14% of all adults aged ≥25 years; >12 million of those affected are aged ≥65 years. Women are more commonly affected than men. 2 OA is associated with remarkable personal, health, and economic costs, including 400,000 hospitalizations and an estimated $8 billion for knee and hip replacements annually. 1 The prevalence of OA is expected to increase in the coming years as risk factors, such as an aging population and obesity, become more prevalent.
The development of OA involves multiple factors that contribute to excessive joint loading, repetitive motion or injury, and inflammation. The most common risk factors in the etiology of OA include advanced age, obesity, past occupation, participation in certain sports, joint trauma, and family history. 1–3
Genetic factors are also thought to play a role in the development of OA, and different genes may be implicated in different types of arthritis. 3 Heberden nodes, bony enlargements of the distal interphalangeal joints of the hand, are 10-fold more prevalent in women than in men, and they occur twice as often in women whose mothers developed these nodes. Genetic factors have been linked to generalized OA, as well as OA of the first metatarsophalangeal joint. This genetic link has been substantiated in twin studies, which have demonstrated a 60% correlation in hip OA and a 70% correlation in spine OA between twins. 4
To date, many intracellular regulators have been identified as potential markers for the expression of OA pathologies. These identified markers include interleukin-1 (IL-1), interleukin-4 (IL-4), and genes that code for asporin, an extracellular matrix protein, and calmodulin, an intracellular regulator. 5
OA has previously been considered a disease resulting from wear and tear of the joints; however, it can be more accurately described as a condition that is a result of various biochemical, biomechanical, inflammatory, and immunologic factors. 5 These factors can cause structural and functional failure of synovial joints with erosion and loss of articular cartilage, meniscal degeneration, and osteophytes. 6 OA can be categorized into 2 major etiologic classes: primary (idiopathic) or secondary. Primary OA is the most common type and can be further classified as localized (involving only 1 or 2 sites) or generalized (affecting ≥3 sites). 3,5 Secondary OA is associated with a known cause such as rheumatoid or other arthritis, trauma, metabolic or endocrine disorders, or congenital factors.
Signs and symptoms of OA may be present for months or years before medical attention is sought; deep, aching, generalized pain is typically what causes patients to initially seek medical attention. Pain is most commonly associated with movement in the beginning stages of disease but also occurs at rest in advanced OA. Other symptoms include joint stiffness that is most pronounced in the morning or after a period of inactivity ("gelling"), lasts <30>
NONPHARMACOLOGIC TREATMENT OPTIONS
The goal of OA treatment is to control symptoms, prevent disease progression, minimize disability, and improve quality of life. Management of OA includes varied techniques and principles, both nonpharmacologic and pharmacologic in nature.
Prevention of OA is the best treatment option. Limiting modifiable risk factors such as obesity, smoking, joint damage, and lack of adequate exercise can have a significant effect on decreasing the risk of OA development. Joint damage can be avoided by limiting exposure to vocational and recreational activities that involve prolonged high-impact and repetitive motion, kneeling, squatting, or heavy lifting. Repetitive recreational activities such as running have not demonstrated the same association with increased development of OA. 4 Once a patient has been diagnosed with OA, appropriate nonpharmacologic methods should be employed as first-line treatments in mild disease or concurrently with pharmacologic management in progressive disease. These techniques include patient education, weight loss, exercise, physical and occupational therapy, assistive devices, acupuncture, ultrasound, and surgery.
Education. Patient education should always be the first step and a continued, integral part of OA treatment. Education should address the disease process, prognosis, and appropriate treatment options, as well as proper resources that the patient can consult for accurate self-management information and programs. The Arthritis Foundation offers such patient-oriented support. 7
Diet and exercise. Obesity remains the most important and modifiable risk factor for the development of OA. In a study of 2,623 patients, Niu et al 8 observed a significant relative risk for developing knee OA in obese (2.4) and very obese (3.2) patients versus those patients with normal body mass index (BMI) ( P <.001). The results, however, did not demonstrate an overall correlation between obesity and the progression of existing OA. A 4-year cohort trial conducted by Wang et al 9 in 39,023 volunteers determined that there was a 3- to 4-fold increased risk of primary joint replacement associated with increased body weight, BMI, fat mass, and percentage fat. Increased waist circumference and waist-to-hip ratio were also associated with an increased risk, suggesting that both biomechanical and metabolic mechanisms associated with adiposity contribute to the risk of joint replacement. 9 Therefore, weight reduction and exercise in combination should be encouraged in all patients with OA, especially in those with OA of the knee and hip. Although each alone is beneficial in disease treatment and prognosis, one 18-month program of a combined regimen of caloric restriction and exercise resulted in a 24% improvement in physical function and a 30.3% reduction in knee pain, a significant improvement compared with the participants who followed only diet restrictions or exercise alone. 10
Physical and occupational therapy. Formal physical and occupational therapy is useful in those patients who are not benefiting from home exercise programs or in those who need further instruction in range of motion, joint protection, or muscle-strengthening principles. In a randomized, controlled trial of 83 patients, Deyle et al 11 determined that improvements in walking distance, function, pain, and stiffness in the group receiving manual therapy of the knee (n=42) were clinically and statistically superior ( P <.05) to the improvements in a control group receiving subtherapeutic ultrasound therapy after 8 weeks and 1 year of treatment. At 1 year, 20% of the control group versus 5% of the treatment group had undergone arthroplasty. Recommendations for exercise regimens should be patient-specific and should include both strengthening and low-impact aerobic exercise such as walking, swimming, or bicycling. Strength training that focuses on the quadriceps, adductor, and abductor muscles has been demonstrated to improve both knee and hip stabilization. All exercise regimens should be initiated by a trained exercise practitioner and continued at home, with intensity and duration increasing slowly as tolerated. 12,13
Assistive devices. Patients with OA may consider using canes and orthotics to assist with stability. The American College of Rheumatology (ACR) recommends using a cane contralaterally to the affected knee joint to manage OA symptoms. 14,15 Reaction forces in an osteoarthritic hip may be reduced by 50% when a patient uses a cane in the contralateral hand. A randomized, controlled trial assessed the use of orthotics and demonstrated no short-term symptomatic relief within a 6-week period, whereas 2 additional randomized, controlled trials determined that knee braces and therapeutic taping of the knee were effective interventions for the management of OA. 16–18 A 6-month, prospective, parallel-group, randomized clinical trial in 119 patients concluded that the use of knee braces (neoprene sleeves and unloader braces) in the management of OA of the knee results in a significant improvement in quality of life ( P =.001) and function ( P ≤.001) specific to OA. 17 Unloader braces appear more effective than neoprene sleeves in relieving symptoms. 17 A 3-week trial of therapeutic knee taping demonstrated a significant reduction in knee pain (21 of 29 patients) when compared with both a control-tape group (14/29) and a no-tape group (3/29); this reduction in pain was maintained for 3 weeks after treatment cessation. 18
Alternative. Acupuncture may provide some pain relief when administered alone or in combination with diclofenac. 19 Acupuncture alone has been associated with improved function; however, it cannot be determined to what extent this improvement is caused by a placebo effect. 20 In randomized, placebo-controlled studies, therapeutic ultrasound has not been demonstrated to be more effective than placebo after 3 months, whether continuous therapeutic ultrasound, galvanic current, or shortwave diathermy was used. 21Surgery. Surgery should be reserved as a last-resort effort to manage OA symptoms in patients whose disease is refractory to less-invasive management methods. Surgical interventions include total joint arthroplasty and joint lavage and debridement. There is no evidence demonstrating that lavage or debridement is more effective in relieving pain or improving function than nonsurgical treatment. 22 Arthroplasty has significantly reduced knee and hip pain and increased functionality in patients who were severely incapacitated before surgery. 14 Studies comparing surgical and nonsurgical management techniques are lacking. 14 If surgery is determined to be the treatment of choice, joint replacement should not be delayed to preserve optimal restorative function. 23 Prosthesis rejection and infection are among the complications that can occur.
PHARMACOLOGIC TREATMENT OPTIONS
Pharmacologic treatment options are listed in the table on p 146-47. 24,25
Acetaminophen and NSAIDs. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are effective for mild-to-moderate pain associated with OA. 26 Data suggest that NSAIDs are more effective than acetaminophen; however, based on the side- effect profile of NSAIDs, acetaminophen is preferred as first-line therapy.
A systematic review involving 5,986 patients confirmed that acetaminophen is effective for the treatment of OA. 26 This study demonstrated that the number needed to treat (NNT) ranges from 4 (for pain response) to 16 (for overall pain reduction). Acetaminophen was more effective than placebo in 5 of 7 trials; the meta-analysis of these data confirmed that acetaminophen is significantly more effective than placebo for reduction of overall pain and pain on motion. This systematic review also confirmed that NSAIDs were superior to acetaminophen for OA in 10 trials. Acetaminophen should be avoided in patients with hepatic impairment.
NSAIDs have consistently demonstrated efficacy for pain relief in OA; however, a meta-analysis of 23 trials that included 10,845 patients demonstrated that NSAIDs are only slightly more effective than placebo for short-term pain relief in OA of the knee. 27–29 All NSAIDs, including cyclooxygenase-2 (COX-2) selective agents, are equally effective for pain relief in OA; choice of agent should be based on patient comorbidities, cost, and side-effect profile. 29,30 Gastrointestinal (GI) and cardiovascular (CV) risks limit routine use of NSAIDs in many patients (see table); a large meta-analysis recommended limiting use of NSAIDs because of the potential for serious adverse effects. 29 Caution is recommended when NSAIDs are administered to patients with CV risk factors; COX-2 selective agents are known to cause CV events, but nonselective agents (such as diclofenac and indomethacin) have also been implicated in increasing the risk of CV complications. 31 Nonacetylated salicylates may be considered for patients with mild renal insufficiency.
COX-2 selective NSAIDs may be beneficial in patients at high risk for peptic ulcer disease or GI bleeding; however, the GI protective benefits of COX-2 selective agents may be negated if the patient is also taking aspirin (even in low doses). 32 Patients who do not respond to selective COX-2 NSAIDs, are on concomitant aspirin therapy, or are at increased CV risk may be candidates for treatment with a nonselective NSAID plus a proton-pump inhibitor (PPI) or misoprostol for added GI protection. 33,34 Misoprostol protects against gastric and duodenal NSAID-induced ulcers. Misoprostol is contraindicated in pregnant woman because of its abortive effects and should be used with caution in women in their child-bearing years who are not using an effective contraceptive. Misoprostol is available alone or in combination with diclofenac. Adverse effects such as abdominal cramps and diarrhea may limit its use. 34 Prophylaxis therapy with a PPI in combination with an NSAID has been demonstrated to be superior to histamine (H 2 ) receptor antagonists combined with an NSAID in preventing GI ulcers and erosions, although the combination of PPI and NSAID is not FDA approved. 33 The decision of which therapy a patient is prescribed should take into consideration the cost, compliance issues, and past response to other therapies.
Topical analgesics. Topical NSAIDs and capsaicin may offer alternatives for patients unable to tolerate systemic agents and may also offer adjunctive therapy for those exhibiting partial response to conventional therapy. The long-term efficacy of topical NSAIDs has been debated; however, a meta-analysis of 4 trials that examined the efficacy of topical NSAIDs in trials lasting >4 weeks demonstrated that diclofenac and eltenac are effective for long-term pain relief in knee OA. 35,36 Topical capsaicin works by depleting the neuropeptide substance P and must be used for at least 3 to 4 weeks to achieve maximal benefit; a meta-analysis of 3 trials confirmed that topical capsaicin is more effective than placebo for pain relief in OA. 37 Capsaicin is commonly associated with a transient local burning sensation. Despite this effect, 1 study reported dropout rates as low as 2%. 38 Given its unique mechanism of action, topical capsaicin may also be useful as an adjunct to an oral analgesic.
Although not formally indicated for OA, lidocaine 5% patches may also offer a topical alternative for some patients. 39 One trial suggests that these patches may be as effective as COX-2 selective NSAIDs; however, these data are limited as the trial ended early because of safety concerns with COX-2 agents. 40
Glucosamine and chondroitin. The efficacy of glucosamine and chondroitin remains controversial. Glucosamine, which is naturally produced in the body, is an aminomonosaccharide that acts as a substrate for glycosaminoglycans, proteoglycans, and hyaluronic acid to form articular cartilage. Chondroitin also serves as a building block for joint cartilage. 41 The large-scale Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT; N=1,583) failed to demonstrate a significant reduction in overall pain after 24 weeks in patients treated with glucosamine only, chondroitin only, or the combination of glucosamine plus chondroitin; however, a subgroup of patients with moderate-to-severe pain did experience significant pain reduction with the combination of glucosamine and chondroitin. 42 An ancillary study of GAIT lasting 2 years evaluated joint space width in 572 patients; the combination of glucosamine and chondroitin failed to demonstrate a reduction in joint width loss. 43 A systematic review of 20 studies involving 2,570 patients demonstrated conflicting results based on glucosamine formulation. 44 Another meta-analysis of 15 trials concluded that there is likely evidence of some degree of efficacy for these agents. 45 Based on the benign side-effect profile of both agents and their potential for efficacy, a trial of glucosamine and chondroitin might be warranted in patients with mild-to-moderate knee OA.
Narcotic analgesics. According to the American Academy of Rheumatology, opioid analgesics such as codeine and oxycodone are not considered a first-line treatment option and should be considered only if traditional methods of pain management (eg, acetaminophen, NSAIDs, or tramadol) have been ineffective for OA or are intolerable; even then, only low-dose opioids should be used, especially in elderly patients. 46,47 The use of strong opioids for long-term pain relief in patients without cancer is a controversial topic; the risks of dependence, addiction, and hyperalgesia are the primary concerns. 46,47 Investigators conducted a meta-analysis of 18 placebo-controlled trials in 4,856 patients treated with weak or strong opioids. 48 Opioids significantly reduced the intensity of pain but had only moderate effects on physical function. Efficacy was assessed by measuring changes in pain intensity or an increase in physical function. The pooled effect size of all opioids for pain intensity was –0.79 (95% CI, –0.98 to –0.59). The pooled effect size of all opioids for physical function was –0.31 (95% CI, –0.39 to –0.24). Safety was measured by the number of treatments that had to be discontinued because of adverse effects. The most common adverse effects were nausea, constipation, dizziness, somnolence, and vomiting. The average rate of discontinuance was higher among patients treated with strong opioids (31%) than among those treated with weak opioids (19%). The number needed to harm among patients treated with strong or weak opioids versus those treated with placebo was 4 and 9, respectively. The high incidence of adverse effects should be considered before opioids are used as a treatment option in patients with OA.
The fentanyl patch provides continuous medication for 24 hours, but this agent should not be used in opioid-naïve patients. According to Langford et al, 49 patients with hip or knee OA experienced a reduction in pain and improved functionality with the fentanyl patch compared with placebo during a 6-week trial. 49 Although adverse effects with this agent are similar to those observed with other opioids, with fewer reports of constipation, the patch is thought to be more tolerable. For optimal results, opioids should be used in conjunction with nonpharmacologic therapies and considered for short-term use only.
Tramadol. Tramadol is an atypical opioid with a dual mechanism of action; it acts centrally on the mu-opioid receptors and inhibits the reuptake of norepinephrine and serotonin. 50 Unlike NSAIDs, tramadol has not been associated with GI bleeds. Eleven trials have compared tramadol or tramadol/acetaminophen with placebo or active controls for the treatment of OA. 51 Patients taking tramadol or tramadol/acetaminophen experienced less pain and increased functionality but reported twice as many adverse effects (see table). The effectiveness of tramadol is still questionable; lack of anti-inflammatory properties and the development of tolerance to tramadol may limit this agent's effectiveness. 51 Tramadol is contraindicated in patients with opioid hypersensitivity and in patients with acute alcohol intoxication.
Intra-articular glucocorticoids. For patients experiencing an acute local inflammation with a buildup of fluid in the joint (effusions), intra-articular glucocorticoid injections (triamcinolone acetonide, triamcinolone hexacetonide, betamethasone, and microcrystalline methylprednisolone) are a safe and effective nonsurgical option. 52,53 The efficacy of corticosteroid injections in areas other than the knee is questionable. Studies evaluating the efficacy of corticosteroid injections in OA of the hip have not been conducted, and the procedure is technically difficult to perform, as it requires fluoroscopic guidance. 54 The ACR recommends that, to reduce the risk of infection, these injections be performed by an experienced physician. A cell count, Gram stain, and culture should be performed if infection is suspected; leukocytosis, fever, or rapid onset of an effusion may be indicative of an infection in the joint. 52 The dose of injection depends on the size of the joint being treated; these agents create a rapid response to pain, but long-term pain relief has not been established. 55
Hyaluronate injections. Intra-articular hyaluron (hyaluronic acid) is a polysaccharide found in the extracellular connective tissue that can act as a joint lubricant. When compared with placebo and NSAIDs, hyaluronic acid injections provided only a slight benefit in pain relief. 56 These agents are approved only for OA of the knee, not of the hip. Although the onset of action is slower than that observed with corticosteroids, these injections have the benefit of a longer duration, but they are also more costly. 55 Hyaluronate injections are administered as weekly injections for 3 to 5 weeks; hylan G-F 20 is administered as a single injection.
Disease-modulating agents. Disease-modulating agents are being investigated as alternative agents for OA. These agents are not intended for the treatment of painful symptoms but for the prevention of further damage to the joints or for the slowing of disease progression in joints already affected. Tetracyclines have certain anti-inflammatory properties and are inhibitors of collagenase and gelatinase; in OA, collagenase, gelatinase, and stromelysin levels are increased. 57 Doxycycline may slow the progression of OA. A 30-month trial comparing doxycycline 100 mg twice daily with placebo in 431 obese women demonstrated radiologic evidence of slowed progression of joint space narrowing (by 33%) in doxycycline-treated patients versus placebo-treated patients. 58 Withdrawals were more frequent in the doxycycline group because of adverse effects such as nausea, heartburn, and photosensitivity (23 vs 9).
Diacerein is currently not available in the United States. This agent has anti-inflammatory and analgesic properties when 50 mg is administered orally twice daily. Studies have demonstrated that diacerein is modestly effective compared with placebo and as effective as NSAIDs for pain relief of hip or knee OA. 59 The most common adverse effect is diarrhea, which is typically observed during the first 2 weeks of treatment. 60
Progress is being made in identifying and understanding the possible genetic contributions to the development of OA. This identification of the common alleles responsible for coding regulatory proteins involved in cartilage function may lead to the potential for new drugs that affect these regulatory proteins and thus potentially prevent, treat, or eradicate OA. The investigation into the role of inflammatory markers in OA such as IL-1, prostaglandin E2, tumor necrosis factor (TNF)-alpha, and nitric oxide also may lead to further treatment options for disease eradication. 5
CONCLUSIONS/ RECOMMENDATIONSNonpharmacologic therapy such as patient education, weight loss, and exercise are the cornerstone of OA treatment. Other nonpharmacologic options such as physical and occupational therapy, assistive devices, acupuncture, and ultrasound may be considered for some patients. Because of the chronic nature of OA, long-term pharmacotherapy is often necessary; the safest pharmacologic option for long-term use is acetaminophen. If acetaminophen is not successful or is contraindicated, a short-term trial of the lowest effective dose of a short-acting NSAID such as ibuprofen or naproxen is recommended (see figure). 61 Topical agents such as capsaicin and topical NSAIDs may offer an alternative in patients unable to tolerate systemic agents and may also be used as additive therapy. Though effective, opioids should be reserved for resistant cases and should be considered for short-term use only. The efficacy of intra-articular glucocorticoids, tramadol, and glucosamine with or without chondroitin is questionable; these agents may be tried when other options fail.
Dr Seed is assistant professor, Pharmacy Practice, Massachusetts College of Pharmacy and Health Science, Worcester. Dr Dunican is assistant professor, Pharmacy Practice, Massachusetts College of Pharmacy and Health Science. Dr Lynch is associate professor, Pharmacy Practice, Massachusetts College of Pharmacy and Health Science.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
1. Arthritis types–Osteoarthritis. Centers for Disease Control and Prevention website. http://www.cdc.gov/arthritis/arthritis/osteoarthritis.htm. Accessed April 23, 2009.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26–35.
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. Sun BH, Wu CW, Kalunian KC. New developments in osteoarthritis. Rheum Dis Clin North Am. 2007;33:135–148.
5. Lajeunesse D, Reboul P. Subchondral bone in osteoarthritis: A biologic link with articular cartilage leading to abnormal remodeling. Curr Opin Rheumatol. 2003;15:628–633.
6. Nuki G. Osteoarthritis: A problem of joint failure. Z Rheumatol. 1999;58:142–147.
7. Marks R, Allegrante JP, Lorig K. A review and synthesis of research evidence for self-efficacy-enhancing interventions for reducing chronic disability: Implications for health education practice (part I). Health Promot Pract. 2005;6:37–43.
8. Niu J, Zhang YQ, Torner J, et al. Is obesity a risk factor for progressive radiographic knee osteoarthritis? Arthritis Rheum. 2009;61:329–335.
9. Wang Y, Simpson JA, Wluka AE, et al. Relationship between body adiposity measures and risk of primary knee and hip replacement for osteoarthritis: A prospective cohort study. Arthritis Res Ther. 2009;11:R31.
10. Messier SP, Loeser RF, Miller GD, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: The Arthritis, Diet, and Activity Promotion trial. Arthritis Rheum. 2004;50:1501–1510.
11. Deyle GD, Henderson NE, Matekel RL, Ryder MG, Garber MB, Allison SC. Effectiveness of manual physical therapy and exercise in osteoarthritis of the knee. A randomized, controlled trial. Ann Intern Med. 2000;132:173–181.
12. Roddy E, Zhang W, Doherty M. Aerobic walking or strengthening exercise for osteoarthritis of the knee? A systematic review. Ann Rheum Dis. 2005;64:544–548.
13. Bennell K, Hinman R. Exercise as a treatment for osteoarthritis. Curr Opin Rheumatol. 2005;17:634–640.
14. Pendleton A, Arden N, Dougados M, et al. EULAR recommendations for the management of knee osteoarthritis: Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2000;59: 936–944.
15. 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;43:1905–1915.
16. Baker K, Goggins J, Xie H, et al. A randomized crossover trial of a wedged insole for treatment of knee osteoarthritis. Arthritis Rheum. 2007;56:1198–1203.
17. Kirkley A, Webster-Bogaert S, Litchfield R, et al. The effect of bracing on varus gonarthrosis. J Bone Joint Surg Am. 1999;81:539–548.
18. Hinman RS, Crossley KM, McConnell J, Bennell KL. Efficacy of knee tape in the management of osteoarthritis of the knee: Blinded randomised controlled trial. BMJ. 2003;327:135.
19. Vas J, Mendez C, Perea-Milla E, al. Acupuncture as a complementary therapy to the pharmacological treatment of osteoarthritis of the knee: Randomised controlled trial. BMJ. 2004;329:1216.
20. Manheimer E, Linde K, Lao L, Bouter LM, Berman BM. Meta-analysis: Acupuncture for osteoarthritis of the knee. Ann Intern Med. 2007;146:868–877.
21. Welch V, Brosseau L, Peterson J, Shea B, Tugwell P, Wells G. Therapeutic ultrasound for osteoarthritis of the knee. Cochrane Database Syst Rev. 2001;(3):CD003132.
22. Moseley JB, O'Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002;347:81–88.
23. Fortin PR, Clarke AE, Joseph L, et al. Outcomes of total hip and knee replacement: Preoperative functional status predicts outcomes at six months after surgery. Arthritis Rheum. 1999;42:1722–1728.
24. Facts & Comparisons. http://factsandcomparisons.com/. Accessed April 28, 2009.
25. Drugstore.com. http://drugstore.com/. Accessed April 28, 2009.
26. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;(1):CD004257.
27. Towheed TE, Hochberg MC. A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the hip. J Rheumatol. 1997;24:349–357.
28. Towheed TE, Hochberg MC. A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee, with an emphasis on trial methodology. Semin Arthritis Rheum. 1997;26:755–770.
29. Bjordal JM, Ljunggren AE, Klovning A, Slordal L. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: Meta-analysis of randomised placebo controlled trials. BMJ. 2004;329:1317.
30. Watson MC, Brookes ST, Kirwan JR, Faulkner A. Non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the knee. Cochrane Database Syst Rev. 2000;(2):CD000142.
31. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006;296:1633–1644.
32. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:1247–1255.
33. Chan FK, Wong VW, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: A double-blind, randomised trial. Lancet. 2007;369:1621–1626.
34. Maetzel A, Ferraz MB, Bombardier C. The cost-effectiveness of misoprostol in preventing serious gastrointestinal events associated with the use of nonsteroidal antiinflammatory drugs. Arthritis Rheum. 1998;41:16–25.
35. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: Meta-analysis of randomised controlled trials. BMJ. 2004;329:324.
36. Biswal S, Medhi B, Pandhi P. Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: Metaanalysis of randomized placebo controlled clinical trials. J Rheumatol. 2006;33:1841–1844.
37. Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin. A meta-analysis. Eur J Clin Pharmacol. 1994;46:517–522.
38. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: A double-blind trial. Clin Ther. 1991;13:383–395.
39. Gammaitoni AR, Galer BS, Onawola R, Jensen MP, Argoff CE. Lidocaine patch 5% and its positive impact on pain qualities in osteoarthritis: Results of a pilot 2-week, open-label study using the Neuropathic Pain Scale. Curr Med Res Opin. 2004;20(suppl 2):S13–S19.
40. Kivitz A, Fairfax M, Sheldon EA, et al. Comparison of the effectiveness and tolerability of lidocaine patch 5% versus celecoxib for osteoarthritis-related knee pain: Post hoc analysis of a 12 week, prospective, randomized, active-controlled, open-label, parallel-group trial in adults. Clin Ther. 2008;30:2366–2377.
41. Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: A comprehensive meta-analysis. Arch Intern Med. 2003;163:1514–1522.
42. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795–808.
43. Sawitzke AD, Shi H, Finco MF, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 2008;58:3183–3191.
44. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2005;(2):CD002946.
45. McAlindon TE, 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.
46. Nuesch E, Rutjes AWS, Husni E, Welch V, Juni P. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2008:(3)CD003115.
47. Goodwin JL, Kraemer JJ, Bajwa ZH. The use of opioids in the treatment of osteoarthritis: When, why, and how? Curr Rheumatol Rep. 2009;11:5–14.
48. Avouac J, Gossec L, Dougados M. Efficacy and safety of opioids for osteoarthritis: A meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2007;15:957–965.
49. Langford R, McKenna F, Ratcliffe S, Vojtassak J, Richarz U. Transdermal fentanyl for improvement of pain and functioning in osteoarthritis: A randomized, placebo-controlled trial. Arthritis Rheum. 2006;54:1829–1837.
50. McClellan K, Scott LJ. Tramadol/paracetamol [erratum in Drugs. 2003;63:1636]. Drugs. 2003;63:1079–1086.
51. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database Syst Rev. 2006;3:CD005522.
52. Schumacher HR, Chen LX. Injectable corticosteroids in treatment of arthritis of the knee. Am J Med. 2005;118:1208–1214.
53. Neustadt DH. Intraarticular steroid therapy. In: Moskowitz RW, Howell DS, Goldberg VM, Mankin H, eds. Osteoarthritis: Diagnosis and Medical/Surgical Management. Philadelphia: WB Saunders Co.; 1992:493.
54. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis. Part I. Osteoarthritis of the hip. American College of Rheumatology. Arthritis Rheum. 1995;38:1535–1540.
55. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;(2):CD005328.
56. Felson DT, Anderson JJ. Hyaluronate sodium injections for osteoarthritis: Hope, hype, and hard truths. Arch Intern Med. 2002;162:245–247.
57. Pelletier JP, Martel-Pelletier J, Howell DS, Ghandur-Mnaymneh L, Enis JE, Woessner JF Jr. Collagenase and collagenolytic activity in human osteoarthritic cartilage. Arthritis Rheum. 1983;26:63–68.
58. Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2005;52:2015–2025.
59. Fidelix TS, Soares BG, Trevisani VF. Diacerein for osteoarthritis. Cochrane Database Sys Rev. 2006;(1):CD005117.
60. Dougados M, Nguyen M, Berdah L, Mazieres B, Vignon E, Lequesne M; ECHODIAH Investigators Study Group. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44:2539–2547.
61. Kwan D, Papoushek C. Osteoarthritis. In: Repchinsky, ed. Patient Self-Care: Helping Patients Make Therapeutic Choices. Ottawa: Canadian Pharmacist Association; 2002:434.