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Key questions concerning paracetamol and NSAIDs for OA
  1. K D Brandt1
  1. 1Indiana University School of Medicine; and Indiana University Multipurpose Arthritis and Musculoskeletal Diseases Center, 1110 West Michigan Street, Room 545, Indianapolis IN 46217, USA
  1. Correspondence to:
    Professor K D Brandt;
    kbrandt{at}iupui.edu
  1. P Courtney2,
  2. M Doherty2
  1. 2Academic Rheumatology, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, UK

    Abstract

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    • paracetamol
    • non-steroidal anti-inflammatory drugs
    • osteoarthritis

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    The recent leader by Dr Courtney and Professor Doherty provides an excellent evidence based perspective on the treatment of the pain of osteoarthritis (OA) with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) and on the issues related to the appropriate use and positioning of these agents within the therapeutic armamentarium.1

    Clearly, age is a risk factor for NSAID associated serious upper gastrointestinal (GI) adverse events. Because age is also the most powerful risk factor for OA, a disease for which NSAIDs are widely employed as symptomatic treatment, this presents a particular problem for the clinician. It is important to recognise, therefore, that, as pointed out by Courtney and Doherty, a variety of measures can be employed to permit a reduction in NSAID dose or withdrawal of NSAIDs in the elderly.

    Courtney and Doherty raise the possibility that the absence of an antiplatelet effect of coxibs might be disadvantageous and that the antiplatelet effect of non-selective NSAIDs “ . . . .might be advantageous in patients with OA who predominantly are elderly with frequent comorbidity such as obesity and thus often at higher risk of cerebrovascular or ischaemic heart disease.” They note the increased incidence of myocardial infarction (MI) in the rofecoxib treatment arm of the VIGOR trial,2 relative to the naproxen arm. However, the published evidence does not permit the conclusion that any NSAID, other than aspirin, which has been shown to decrease the risk of MI by about 30%, will protect against MI.3,4 With respect to the VIGOR study, if one accepts the proposition promoted by the manufacturer—that is, that rofecoxib treatment did not increase the risk of MI but that naproxen decreased that risk, the effect size of naproxen would have been nearly twice as large as that seen in aspirin prevention trials.

    Despite the contention that treatment with coxibs may increase the risk of thrombotic disease, neither of the two large GI safety studies of coxibs (VIGOR,2 CLASS5) had sufficient statistical power to discern a significant difference in the incidence of MI between treatment groups. Furthermore, the VIGOR trial was conducted exclusively in patients with rheumatoid arthritis, a disease in which the risk of MI is about twice as great as that in OA, and no information was presented to assure that the prevalence of underlying risk factors for MI (for example, obesity, hypercholesterolaemia, diabetes mellitus, smoking) was comparable in the two treatment groups.

    The point is this: in patients with OA who are at risk for MI and are, therefore, candidates for low dose aspirin treatment, there are no data to support the suggestion that any other non-selective NSAID can serve as an alternative to aspirin and hence do “double duty” (aiding both the heart and the joint). There is no basis for the potentially risky recommendation that low dose aspirin prophylaxis is not needed in such patients. It should be recognised, however, that the results of the CLASS study suggest that the gastroprotective effect of celecoxib is mitigated by low dose aspirin use.5 Whether the gastroprotective effect of rofecoxib is similarly abrogated by aspirin use is unknown because patients taking aspirin were excluded from the VIGOR trial.

    Furthermore, the recent study by Catella-Lawson et al suggests that the non-selective NSAID, ibuprofen, may inhibit the antiplatelet effect of aspirin.6 Maximal inhibition of serum thromboxane B2 levels (an index of COX-1 activity in the platelet) and of platelet aggregation produced by a low dose of aspirin were blocked by a single daily dose of ibuprofen (400 mg) given two hours earlier. Similar results were obtained with multiple doses of ibuprofen, 400 mg three times a day, as commonly used in the treatment of OA pain. In contrast, concomitant administration of single doses of rofecoxib, a slow release formulation of diclofenac or paracetamol, 1000 mg, had no effect on aspirin pharmacodynamics. The inhibitory effects of multiple daily doses of ibuprofen were apparent even when subjects received aspirin before their morning dose of ibuprofen. This would suggest that for patients taking low dose aspirin who need an over the counter analgesic for their OA pain, paracetamol might be a better choice than ibuprofen.

    References

    Authors’ reply

    We are grateful to Dr Brandt for expanding on the issue of possible cardioprotection by certain NSAIDs and the interaction between aspirin and coxibs/NSAIDs. We fully concur with the argument that he presents.

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