Literature Review of Pharmacological Agents Recommended for Osteoarthritis Management

Annex 6.10.1

Literature Review of pharmacological agents recommended for osteoarthritis management

Intervention / Clinical evidence / Risk/adverse effect / Estimated cost / Comment /
Simple oral analgesia
§  Paracetamol
§  Acetaminophen / §  BMJ clinical evidence review found limited evidence that simple analgesics reduced pain compared with placebo [1]
§  BMJ Clinical review-RCTs found no good evidence that simple analgesics are significantly different from NSAIDS in pain relief 1
§  Review by EULAR reports that paracetamol is as effective as NSAIDS in the management of OA. Furthermore it can be taken safely over the long term [2]
§  A recent metaanalysis comparing NSAIDs to acetaminophen found that patients randomised to NSAIDs had significant improvement in pain compared to acetaminophen [3] / §  Liver damage with overdose
§  Acetaminophen/
paracetamol should be avoided in patients with excessive alcohol consumption or existing liver disease 3
§  A recent study has also raised concerned about the safety of acetaminophen in doses of greater than 2g/day. The study suggests that high dose acetaminophen may results inn an increased risk of gastrointestinal toxicity equivalent to NSAIDs [4] / §  Potential benefit-short term pain relief
§  The gastrointestinal safety of high-dose acetaminophen/paracetamol needs to be evaluated [5]
Oral NSAIDS / §  Systematic reviews found NSAIDS reduce short term pain in OA 1, 2, [6], [7]
§  Oral NSAIDS shown to have equal efficacy compared paracetamol 1, 2, 6, [8]
§  There are no predictors of response to NSAIDS, and no evidence that NSAIDS are more effective in patients with clinical signs of disease than in those with none.6
§  All NSAIDS are thought to have similar pain relieving effects. 2, [9]
§  Insufficient clinical evidence to compare oral versus topical NSAIDS. 1
§  Cochrane review examining the relative efficacy of different NSAIDS used in knee OA concluded that despite the large number of publications in this area, many trials were poorly designed, and there was no evidence to distinguish between the efficacies of equivalent recommended doses of conventional NSAIDs. 2, [10]
§  Cochrane review to determine which NSAIDS is the most effective and which NSAID is the most toxic. Results showed that trails were weakened by both the lack of standardization of case definition of OA and of outcome assessments. No clear recommendations for the choice of specific NSAID therapy in hip OA was offered based on this analysis. 10
§  According to the 2003 EULAR review, the expert committee states that there is evidence that NSAIDs are more efficacious than paracetamol for some patients. The recommendations suggest that given the low-grade inflammatory component of OA, NSAIDs would be the ‘logical drugs in patients unresponsive to paracetamol’. 2 / §  Associated with increased risk of gastrointestinal haemorrhage
§  NSAIDS associated ulcers and ulcer complications are the major iatrogenic disease. 20
§  Potentiation of renal insufficiency, platelet inhibition and prolonged bleeding. [11] / §  ACR and EULAR recommend that NSAIDs should be considered in patients unresponsive to paracetamol. Patients at risk of gastrointestinal toxicity effective gastroprotective agents, or selective COX-2 inhibitors should be used.2, 9
§  Potential benefit-short term relief of pain
§  Potentially harmful in older people and people at risk of renal disease or peptic ulceration
§  There is evidence that adjunctive use of misoprostol; H2 blockers and PPI can reduce the incidence of NSAID induced ulcers. However the cost and prophylactic use of these drugs remains very controversial. 9, [12]
COX-2 selective inhibitors
(coxibs) / §  COX-2 inhibitors have been found to be more effective than placebo in relieving pain in OA. 2
§  This class is just as efficacious as NSAIDs for pain relief but with a reduction of up to 50% in perforation, ulcers and bleeding.Error! Bookmark not defined.
§  Large clinical trials and a recent metaanalysis of rofecoxib shows a significant reduction if gastrointestinal toxicity. The VIGOR trial showed up to a 50% decrease in gastrointestinal adverse effects [13]
§  There are no RCTs comparing cox-2 drugs. 7 / §  Incidence of minor gastrointestinal effects similar to conventional NSAIDS
§  Incidence of renal failure similar to conventional NSIADS
§  Retention of salt and water associated with COX-2 inhibition may lead to edema, congestive heart failure, hypertension and reduction of blood pressure medicines
§  Incidence of myocardial infarction in one trial was fourfold greater among patients treated with COX-2 inhibitor (rofecoxib) than conventional NSAID. 20
§  Concern about loss of antiplatelet activity with COX-2 inhibitor group may contribute to excess cardiovascular complication, especially in the elderly who are at a higher risk of cerebral and vascular thrombosis. 20
§  Concomitant use of low dose aspirin for cardiovascular prophylaxis appears to diminish cox-2 inhibitor gastro-protective effect. / §  Long term safety of drugs unclear
§  Published data on this class of drugs still scarce
§  Potential benefit for patients at risk of gastrointestinal complication
§  Unclear about the comparative COX-2 gastrointestinal effect within this class.
§  Both ACR and EULAR state that patients who at an increased risk of gastrointestinal complications, COX-2 inhibitors or NSAIDs plus a gastroprotective agent may be used. 2, 9
Topical agents / §  Systematic reviews and RCTS found that topical NSAIDs reduced pain compared placebo. 2
§  Topical NSAIDS versus oral NSAIDS- no RCTS comparing the same NSAIDS when given orally versus topically. 12
§  No RCTS comparing topical agents versus other local treatments such as heat or cold packs [14]
§  RCTS found limited evidence that capsaicin improved pain compared to placebo. 1 / §  Local skin irritation (systemic adverse effects similar to placebo). No reports of gastric or renal problems / §  Evidence is poor with most studies since studies are short, mixture of patient groups used, and it is difficult to discern the efficacy of topical routes of administration.
§  Larger well-designed studies required.
§  Topical treatment is an additional option for patients who have inadequate control with oral agents or who require local treatment-further trials are needed in this area.
SYSADOA (Glucosamine sulphate, chondroitin, ASU, Diacerein and hyaluronic acid)
§  Glucosamine
§  Chondroitin Sulphate
§  Glucosamine + Chondroitin (+/-manganese) / Cochrane review of RCTs evaluating the effectiveness and toxicity of glucosamine determined that further research is necessary to confirm the effectiveness and toxicity of glucosamine therapy in OA. Most of the trials reviewed the Rotta preparation only. It is not known whether different glucosamine preparations by different manufacturers are equally effective in the therapy of OA. [15], [16]
§  BMJ clinical evidence reports one systematic review and RCTs provide insufficient clinical evidence on the effects of chrondroitin. 1
§  A metaanalysis of chrondroitin sulphate concluded that this may be effective in OA, but further investigation in larger RCTs for longer time periods are needed to prove its effectiveness as a symptom modifying drug in OA [17]
§  BMJ clinical review found no RCTs of glucosamine plus chondroitin alone. 1
§  EULAR’s review of metaanalysis conclude that glucosamine + chrondroitin demonstrate moderate to large effects on pain in OA compared to OA-however these effects may have exaggerated by publication bias. 2
§  RCTs found limited evidence that Glucosamine + Chondroitin +manganese improved disease severity compared to placebo. 1
§  A systematic and quality assessment and metaanalysis from the Cochrane review concluded that RCTs of glucosamine and chrondroitin preparations for OA demonstrate moderate to large effects. However, quality issues and publication bias suggest that these effects are exaggerated. The authors conclude that some degree of efficacy appears probable for these preparations. These findings are consistent with the expert EULAR committee on OA [18] / §  Review from BMJ state the RCTs did not report any harm. 1 / §  Well-designed RCTs are required to determine the efficacy and toxicity of glucosamine for OA.
The authors recommend ‘further high quality, independent studies to determines the efficacy and utility of these preparations. 18
Intra-articular glucocorticoids / §  Review article and both ACR and EULAR conclude that there is evidence that intra-articular injections of corticosteroids are more effective then placebo-but give relatively short-lived benefit. 2, 6, 8, 9
§  Evidence for predictors of response remains unclear and further studies are needed to address this. 2
§  The BMJ clinical evidence of a systematic review an one RCT found limited evidence that intra-articular corticosteroids reduced pain for 1-4 weeks. 1 / Concerns with post injection flare, long-term joint damage and infection. However this is considered a rare complication. 2
Intra-articular hyaluronic acid / §  In general, studies have shown that Hyaluronic acid treatment have only mild to moderate benefit. [19]
§  Data on the effect of repeated injections, cost benefit, and possible disease modifying effects are lacking. 19, [20]
§  A metaanalysis to compare intra-articular hyaluronic acid to placebo determined that there is a small effect compared to placebo.19
§  EULAR review of 20 studies showed that 18/20 trials showed that hyaluronic acid to be effective than placebo in relieving pain. EULAR states while there is evidence for its use, its delayed onset, cost and logistical issues can offset its use in OA management. 2 / Intra-articular viscosupplements have few side effects. Most common reported adverse effects include: localized reactions, transient local swelling, pain and erythema. 13
Hormone replacement therapy / §  Results of animal studies are conflicting, however there is some evidence that oestrogen may have some harmful effects on cartilage [21] / Limited knowledge on the effects of hormones replacement therapy (HRT) on OA is conflicting. HRT is used in osteoporosis and symptomatic treatment of menopause. It is important to determine the effects of HRT at risk of developing OA. The role of HRT as a possible therapeutic agent in women with OA needs to be identified.

References

6.10.1-1

[1] Scott D, Smith C, Lohmander S Chard J. Musculoskeletal Disorders. Osteoarthritis. Clinical Evidence. The International Source of the Best Available Evidence for Effective Health Care. 2003; 10:1402-1430. BMJ Publishing Group Ltd 2003.

[2] Jordan KM, Arden NK, Doherty M, Bannwarth B, et al. 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). Ann Rheum Dis. 2003; 62:1145-1155.

[3] Hochberg MC. What a difference a year makes, reflections on the ACR recommendations for the medical management of osteoarthritis. Curr Rheumatol Rep. 2001;3 (6)473-478.

[4] Bijlsma JW. Analgesia and the patient with osteoarthritis. Am J Ther. 2002; 9(3):189-197.

[5] Hochberg MC, Dougados M. Pharmacological therapy of osteoarthritis. Best Pract Res Clin Rheumatol. 2001; 15(4):583-593.

[6] Haq I, Murphy E, Darce J. Osteoarthritis. Postgrad Med J 2003; 79:377-383.

[7] Hochberg MC, McAlindon T, Felson DT. Systemic and topical treatments. In Felson DT, conference chair. Osteoarthritis: New insights. Part 2: Treatment approaches. Ann Intern Med. 2000; 133:726-729.

[8] Walker-Bone K, Javaid K, Arden N Cooper Cyprus. Medical Management of OA. BMJ 2000; 321:936-40.

[9] http://www.rheumatology.org/publications/guidelines/oa-mgmt/oa-mgmt.asp?aud=mem. The American College of Rheumatology (ACR). Last accesses February 18, 2004. Altman RD, Hochberg MC, Moskowitz RW, Schnitzer TJ. Recommendations for the medical management of Osteoarthritis of the hip and knee. Arthritis and Rheumatism. 2000; 43(9) 1905-1915.

[10] Towheed T, Shea B, Wells G, Hochberg M. Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the hip (cochrane review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley and Sons, Ltd.

[11] Manek N. Medical Management of Osteoarthritis. Mayo Clin Proc 2001;76:533-539.

[12] Hochberg MC, Dougados M. Pharmacological therapy of osteoarthritis. Best Pract Res Clin Rheumatol. 2001; 15(4):583-593.

[13] Goldberg S, Felt JV, Lonner J. Pharmacologic therapy for osteoarthritis. Am J Orthop. 2002; 31(12) 673-680.

[14] Scott D, Smith C, Lohmander S Chard J. Musculoskeletal Disorders. Osteoarthritis. Clinical Evidence. The International Source of the Best Available Evidence for Effective Health Care. 2003; 10:1402-1430. BMJ Publishing Group Ltd 2003.

[15] Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hochberg MC. Glucosamine therapy for treating osteoarthritis (cochrane review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

[16] Hochberg MC. What a difference a year makes, reflections on the ACR recommendations for the medical management of osteoarthritis. Curr Rheumatol Rep. 2001;3 (6)473-478.

[17] Leeb BF, Schweityer H, Montag K, Smolen JS. A metaanalysis of Chrondroitin sulfate in the treatment of osteoarthritis. Journal of Rheumatology. 2000; 27 (1) 205-211.

[18] McAlindon TE, LaValley MP, Gullin JP, Felson DT. Glucosamine and Chrondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA. 2000; 283(11): 1469-1475.

[19] Lo GH, LaValley M, McAlindon T, Felson D. Intra-articular hyaluronic acid in treatment of knee osteoarthritis. A metaanalysis. JAMA. 2003;290:3115-3121.

[20] Brandt KD Non-surgical Treatment of Osteoarthritis: A Half Century of “Advances”. Ann. Rheum. Dis 2004; 63: 117-122.

[21] Prentice L, Abramson M, Cicuttini F, Wluka A. Hormone replacement therapy for osteoarthritis in peri-menopausal and post-menopausal women (protocol for a cochrane review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiled & Sons, Ltd.