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Managing Arthritis Pharmacological therapies for the treatment of osteoarthritis Geoffrey J McColl
MJA 2001; 175: S108-S111 Summary - Paracetamol - Conventional NSAIDs - Cyclo-oxygenase 2 specific inhibitors (CSIs) - Other treatment options - Conclusion - Competing interests - References - Author's details - Register to be notified of new articles by e-mail - Current contents list - More articles on Rheumatology | |||||||||||||||||
| Summary | ||||||||||||||||||
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Non-pharmacological interventions are the first-line therapy for osteoarthritis. | ||||||||||||||||||
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Osteoarthritis is the most common condition affecting joints and its
prevalence increases with age.1 It is characterised by progressive
abnormalities in the articular cartilage, subchondral bone,
synovial fluid, synovial membrane and periarticular structures, in
particular muscle.1,2 The exact aetiology remains obscure, but
abnormalities in the chondrocyte are probably responsible for the
onset of disease. Environmental risk factors for
osteoarthritis depend on the joint concerned, but include trauma,
nutritional factors (including low dietary intake of vitamins C, D
and E), obesity and specific occupational and other
activities.3 It is
also clear that genetic factors are important in the aetiology of
osteoarthritis.4
Management of osteoarthritis should contemplate both prevention and treatment. Current preventive strategies focus on treating obesity and avoiding joint trauma.3 The future may give us genetic tools to identify individuals at high risk of osteoarthritis, who, in addition to being counselled about environmental factors, could be treated with agents that slow cartilage degradation. However, at present, most therapy is directed towards treating established osteoarthritis. Treatment strategies for established osteoarthritis must acknowledge its diverse pathogenesis, variable symptoms and the diversity of outcomes desired by patients. Traditionally, therefore, the treatment of osteoarthritis is divided into non-pharmacological and pharmacological therapies. The non-pharmacological therapies are discussed by March and Stenmark.5 As these interventions have been shown to be effective, they should generally be instituted before pharmacological therapy. It is also important to note that if non-pharmacological therapies fail as single interventions they may be effective in combination with pharmacological agents. The goals of therapy, either non-pharmacological or pharmacological, are:
These goals must, of course, be achieved with minimal or no toxicity. | ||||||||||||||||||
| Paracetamol | ||||||||||||||||||
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In 2000, the American College of Rheumatology updated its
recommendations for the medical management of osteoarthritis of the
hip and knee.6 The
recommendations continue to emphasise the role of paracetamol as the
initial pharmacological treatment of mild to moderate
osteoarthritis. This contention is certainly supported by a
randomised controlled clinical trial, which found no difference in
the efficacy of paracetamol (4 g daily) and ibuprofen (1.2 g or 2.4 g
daily) in patients with osteoarthritis.7
The role of paracetamol in mild to moderate osteoarthritis has also been promulgated because of its safety, particularly when compared with conventional (non-cyclo-oxygenase-2 selective) non-steroidal anti-inflammatory drugs (NSAIDs). Paracetamol is not, however, entirely safe. The dose of 4 g of paracetamol daily should not be exceeded, as the risk of hepatic toxicity increases with higher doses. The risk of hepatic toxicity is also increased in patients with established liver disease or those who misuse alcohol.8 In addition, paracetamol interacts with warfarin metabolism, particularly when maximal doses are employed.9 Patients with osteoarthritis commonly have other medical conditions, such as heart disease, hypertension, renal impairment and peptic ulcers, which increase the risks of some pharmacological agents, particularly NSAIDs. If a patient's condition fails to respond to paracetamol and non-pharmacological therapies, then rational planning for further therapy must include a risk assessment of his or her comorbidity (Box). First, the risk of gastrointestinal complications should be assessed.10 In patients with one or more gastrointestinal risk factors, a cyclo-oxygenase-2-specific inhibitor (CSI) would be recommended. Second, the risk of renal complications should be assessed.11 In patients with renal risk factors, other non-pharmacological treatment options should be reconsidered before a conventional NSAID or a CSI. If CSIs or NSAIDs are prescribed in patients with renal risk factors, the clinical state should be monitored, in particular the blood pressure and renal function. | ||||||||||||||||||
| Conventional NSAIDs | ||||||||||||||||||
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In those patients with osteoarthritis whose symptoms are not
relieved by non-pharmacological therapy and paracetamol and who
have no gastrointestinal risk factors, it is appropriate to use
conventional NSAIDs, commencing at a low dose and titrating against
efficacy. Virtually all currently available conventional NSAIDs
have been tested in randomised, placebo-controlled trials in
patients with osteoarthritis and rheumatoid arthritis. In these
studies, conventional NSAIDs have been shown to be superior to
placebo, but there has not been evidence suggesting that one agent is
more effective than another.12 There does, however, appear to be a
hierarchy of gastrointestinal risk, with agents such as ibuprofen
and diclofenac being of the lowest risk and piroxicam and ketoprofen
the highest.13
It has been suggested that some patients with osteoarthritis have a more inflammatory phenotype and may benefit more from NSAIDs than paracetamol. The characteristics of patients with "inflammatory" osteoarthritis include joint effusions, nocturnal pain and early morning stiffness. Apart from the study by Bradley and colleagues,7 which showed no difference between patients with "inflammatory" osteoarthritis treated with paracetamol and ibuprofen, there has been no published trial addressing whether the presence or absence of inflammatory features predicts response to either paracetamol or an NSAID. Despite the apparent equivalence of paracetamol and NSAIDs in randomised controlled trials, a recent study surveyed the treatment preferences of 1799 arthritis patients and found that most (63%) preferred NSAIDs to paracetamol.14 In those with gastrointestinal risk factors who are unable to take CSIs, NSAIDs could be prescribed, ideally with an agent to reduce the risk of gastrointestinal bleeding. The prostaglandin analogue misoprostol or the proton-pump inhibitor omeprazole have both been shown to reduce the risk of ulcer complications in patients taking conventional NSAIDs.15,16 Unfortunately, the Pharmaceutical Benefits Scheme in Australia does not currently support the prophylactic co-prescribing of misoprostol or omeprazole. Conventional doses of H2-receptor antagonists have not been found to protect patients from adverse gastrointestinal events.16 | ||||||||||||||||||
| Cyclo-oxygenase 2 specific inhibitors (CSIs) | ||||||||||||||||||
| Cyclooxygenase is the enzyme that converts arachidonic acid to the prostaglandin precursors and has two forms: cyclo-oxygenase-1 and -2 (COX-1 and COX-2). COX-1 is the continuously expressed "housekeeping" enzyme producing prostaglandins involved in protecting the stomach and kidney and activating platelets. In contrast, COX-2 is generally expressed inducibly at sites of inflammation. CSIs, developed in the 1990s, were predicted to have less toxicity but potency equal to conventional NSAIDs. Two, celecoxib and rofecoxib, are currently available in Australia on the Pharmaceutical Benefits Scheme. | ||||||||||||||||||
| Celecoxib | ||||||||||||||||||
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Celecoxib (100 mg twice a day or 200 mg once daily) demonstrated
equivalent efficacy to naproxen (500 mg twice daily) and superiority
to placebo in patients with osteoarthritis of the knee and
hip.17 Adverse
gastrointestinal effects were significantly less frequent in the
celecoxib-treated patients when compared with the
naproxen-treated patients, but modestly increased from the
placebo-treated patients.17 Endoscopic studies,
however, demonstrated the same rate of peptic ulcers in
celecoxib-treated patients as in the placebo-treated patients and
this was significantly lower than in the naproxen-treated
patients.17
Platelet function and bleeding time were not altered by celecoxib,
unlike naproxen, which decreased platelet aggregation and
increased bleeding time.18 In elderly patients,
however, there was no difference between the effects of celecoxib and
naproxen on parameters of renal function.19 In a recent study performed in 810 elderly
patients with osteoarthritis and treated hypertension, celecoxib
200 mg daily induced less systolic blood pressure increase and less
peripheral oedema than rofecoxib 25 mg daily.20
Celecoxib toxicity has been further investigated in a large randomised study (CLASS) comparing the toxicity of celecoxib and diclofenac or ibuprofen in patients with osteoarthritis or rheumatoid arthritis over six months.21 In patients not taking aspirin, ulcer complications (bleeding, perforations or obstructions) were significantly lower in the celecoxib-treated group than the conventional NSAID-treated group. The reduction in the risk of ulcer complications in the celecoxib-treated patients was not seen in the subgroup (20% of the study population) taking aspirin. Hepatic toxicity was also significantly lower in the celecoxib-treated group. Clinically relevant rises in creatinine levels were more frequent in the NSAID-treated group. There was no increase in cardiovascular events in the celecoxib-treated group. | ||||||||||||||||||
| Rofecoxib | ||||||||||||||||||
| Rofecoxib is the second CSI to be made available in Australia. It has also been compared with conventional NSAIDs in the treatment of osteoarthritis of the hip and knee and has demonstrated equipotency to the NSAIDs and superiority to placebo.22 The safety profile would appear similar to celecoxib, with a reduction of gastrointestinal symptoms and ulcers seen on endoscopy.23 A study, similar to CLASS (described above), compared the gastrointestinal toxicity over 12 months in patients with rheumatoid arthritis treated with rofecoxib or naproxen, and found significantly lower ulcer complications in the rofecoxib-treated patients (aspirin co-prescribing was not allowed in this study).24 Unexpectedly, the incidence of myocardial infarction was higher in the rofecoxib-treated than the naproxen-treated patients. Some of this increase may be explained by a failure to prescribe aspirin appropriately in patients with cardiovascular risk factors. It has also been postulated that naproxen may have lowered the incidence of myocardial infarction in the naproxen-treated patients. The corollary to these findings is that those taking CSIs who also have cardiovascular risk factors should be co-prescribed aspirin. | ||||||||||||||||||
| Summary — CSIs in the treatment of osteoarthritis | ||||||||||||||||||
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Both celecoxib and rofecoxib are effective in the treatment of
osteoarthritis of the knee and hip, with significantly reduced
gastrointestinal toxicity, hepatotoxicity and effects on platelet
function. It remains unclear, however, whether CSIs are less likely
to increase blood pressure, worsen heart failure, and cause renal
impairment or peripheral oedema than conventional NSAIDs.
The improved gastrointestinal safety profile alone suggests that CSIs should be used in preference to conventional NSAIDs in patients with the gastrointestinal risk factors described in the Box. Preliminary data suggest that there may be differences between celecoxib and rofecoxib with regard to the induction of peripheral oedema and higher blood pressure in individuals with treated hypertension. Whether other relevant intraclass differences in cardiorenal side effects exist between the CSIs remains to be seen. CSIs (and conventional NSAIDs) should therefore be used with caution in those with renal risk factors. | ||||||||||||||||||
| Other treatment options | ||||||||||||||||||
| Visco-supplementation | ||||||||||||||||||
| Synovial fluid aspirated from a joint affected by osteoarthritis is less viscous and elastic than fluid from a normal joint. This is the result of shortening of the long-chain hyaluronan molecules by catalytic enzymes in the joint. This observation prompted studies in which long-chain hyaluronan molecules were injected into osteoarthritic joints. Hylan G-F 20, which is available in Australia, is one preparation tested in these studies. Hylan G-F 20, when injected into the knee joint weekly for three weeks, decreases weight-bearing and other pain when compared with placebo over 26 weeks.25 Hylan G-F 20 was not, however, significantly different to ongoing use of a conventional NSAID in a second study.26 Adverse events with Hylan G-F 20 include an uncommon but severe reaction in which the injected joint swells and requires aspiration and the exclusion of sepsis. Hylan G-F 20 may have a minor role in the management of patients with knee osteoarthritis in which all other pharmacological therapies have failed or are inappropriate. | ||||||||||||||||||
| Intra-articular injection of corticosteroid | ||||||||||||||||||
| The injection of depot corticosteroid preparations into joints with evidence of local inflammation (eg, a joint effusion) results in up to 6 weeks of decreased pain and increase in function.27 Generally, this technique is not used as monotherapy but combined with other non-pharmacological and pharmacological therapies. The risks of this treatment are low if an appropriate sterile technique is applied.27 | ||||||||||||||||||
| Analgesia | ||||||||||||||||||
| Products containing codeine and paracetamol have been demonstrated to be better than paracetamol alone in the treatment of patients with osteoarthritis of the hip.28 Opioid side effects, however, may limit the escalation of such a therapy. Tramadol, a centrally acting synthetic opioid which also inhibits the reuptake of noradrenaline and serotonin, is also useful in patients with unresponsive moderate to severe osteoarthritis.29 Tramadol is better tolerated and less likely to be addictive than other opioid analgesics. | ||||||||||||||||||
| Glucosamine and chondroitin | ||||||||||||||||||
| A large randomised controlled study of glucosamine in patients with osteoarthritis of the knee confirmed the symptomatic benefit of glucosamine and, in addition, suggested a possible disease-modifying role.30 A large study, funded by the US National Institutes of Health, of glucosamine and chondroitin in patients with osteoarthritis is planned and will help confirm or refute these findings. | ||||||||||||||||||
| Other treatment options | ||||||||||||||||||
| A vast literature exists of small studies, of variable quality, examining the efficacy and toxicity of other interventions in osteoarthritis. Many of these studies demonstrate promising results, and the compounds or procedures are being further evaluated in larger, higher-quality trials. At this point vitamin supplementation, ginger extracts, acupuncture, pulsed electromagnetic field therapy, laser therapy and many others fall into this category and no recommendation can be made about their role in osteoarthritis treatment. | ||||||||||||||||||
| Conclusions | ||||||||||||||||||
| The treatment of osteoarthritis requires a holistic evaluation of the patient's problem and needs and the implementation of appropriate non-pharmacological and pharmacological therapies. Non-pharmacological therapies should be enthusiastically applied well before pharmacological treatment is commenced. Paracetamol remains the treatment of first choice for most patients with osteoarthritis. In those with gastrointestinal risk factors, the CSIs, with their higher gastrointestinal safety compared with conventional NSAIDs, may be applied shortly after. Renal and cardiovascular side effects may occur with either the CSIs or conventional NSAIDs, and patients with renal risk factors should be monitored carefully or an alternative therapy should be considered. Patients who fail to respond to paracetamol, CSIs or NSAIDs may be considered for other therapy, including intra-articular hyaluronan or corticosteroid, tramadol, opioids or perhaps glucosamine. When these measures fail to reduce pain and improve function, a surgical approach will generally be necessary. | ||||||||||||||||||
| Competing interests | ||||||||||||||||||
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Dr McColl is a member of the Pharmacia/Pfizer Celebrex Advisory Board and has received payment for talks from Merck Sharpe and Dohme. | ||||||||||||||||||
| Reference | ||||||||||||||||||
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| Author's details | ||||||||||||||||||
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Centre for Rheumatic Diseases, Royal Melbourne Hospital, Parkville, VIC. Geoffrey J McColl, PhD, FRACP, Senior Lecturer.
Reprints will not be available from the author. ©MJA 2001 | ||||||||||||||||||
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