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COX-2-selective NSAIDs:
New wonder drugs?
1. Introduction
Aspirin and other non-steroidal antiinflammatory drugs (NSAIDs) are one of the most widely used
classes of drugs, with both prescription and over the counter sales of the agents contributing to
total usage. NSAIDs are believed to act through inhibition of prostaglandin (PG) synthesis
secondary to their inhibition of the enzyme cyclooxygenase (COX). This results in suppression of
inflammation, and effective analgesia. Most NSAIDs not only inhibit PGs at sites of inflammation,
but also PGs which serve important functions in other parts of the body, a factor which accounts
for some of the toxicity of these agents. The most frequent complications associated with NSAID
usage are those involving the gastrointestinal tract (GIT). GI bleeding, ulceration and perforation
are a significant cause of morbidity and mortality in patients who are treated with these agents.
A new approach to avoiding NSAID-induced complications became feasible with the discovery
that there are 2 isoforms of COX, COX-1 and COX-2. These enzymes are under distinct
regulatory control mechanisms. COX-1 is constitutively expressed in most tissues, and plays a
major role in normal functioning of the GIT, kidneys and platelets. In contrast, COX-2 is
expressed primarily in response to inflammation, but to some extent in other tissues including
kidneys and brain. Traditional NSAIDs are non-selective and inhibit both COX-1 and COX-2,
providing benefits in inflammation, but at the cost of potential adverse effects. Recently, two
COX-2-selective NSAIDs have been approved by the TGA, celecoxib (Celebrex®) and rofecoxib
(Vioxx®). Celecoxib, the first of these drugs to become available, is one of the best selling new
drugs to be marketed in the USA. It is likely that these agents will be covered by the PBS in the
year 2000. Both drugs are being aggressively marketed by the pharmaceutical industry, however
there is limited clinical experience, and monitoring adverse events in patients is a priority for
clinicians who prescribe these agents.
This document provides a review of the physiology and pharmacology of the COX system, and
published studies and clinical trials which have investigated the COX-2-selective NSAIDs.
Ketorolac Toradol®
Propionic acid derivatives Ibuprofen ACT-3®, Actiprofen®, Brufen®,
Nurofen® Rafen®
Tenoxicam Tilcotil®
* low dose analgesic, antipyretic and antiplatelet preparations of aspirin have been excluded from this list.
Although these data may be used to suggest advantages of one drug over another. their
significance is not clear. For example, the results are based on concentrations of drug in plasma,
which may not reflect the steady state concentration in the synovial fluid. Furthermore, if these
log IC80 ratios of traditional and widely utilised non-selective NSAIDs are compared with the
risk of serious GI toxicity of these agents as determined by a large meta-analysis,26 there is a
correlation, but it is not strong. This suggests that the clinical significance of these data for
predicting adverse GI events is of uncertain importance, and the safety profile of one drug over
another will only be determined by wide use in a clinical setting.
2.7 Rheumatoid arthritis and osteoarthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder characterised by a
deforming polyarthritis and a spectrum of extra-articular manifestations. Therapy with disease-
modifying antirheumatic drugs (DMARDs) is instituted to alter the progress of the disease and
therefore prevent joint deformity and disability. NSAIDs are primarily used in RA for the relief
of pain and inflammation, but do not modify the natural history of RA. Any NSAID may be
used, usually chronically and at the higher end of the dose range. Paracetamol can also be
useful in RA, sometimes allowing use of a reduced dosage of NSAID.27
Osteoarthritis (OA) is a disease affecting the weight-bearing joints and peripheral and axial
articulations. One of the hallmarks of the disease is the progressive degeneration of cartilage
resulting in pain and restricted motion. It is classified as a non-inflammatory arthropathy, but
there may be inflammatory components. Treatment in OA is aimed at pain relief. The first line
treatment is paracetamol in adequate dosage (maximum 4g/day) on an occasional or regular
basis according to symptoms. If this does not control symptoms adequately, a low-dose NSAID
can be added, and dosage increased only if response is unsatisfactory. NSAIDs can also be used
intermittently during flares of OA pain.27
Cytochrome P450 enzymes play a minor role in metabolism of rofecoxib, which is mainly
metabolised in the liver by reduction and then excreted in the urine. There are a number of
drug interactions when rofecoxib is coadministered with other agents. Concomitant
administration of antacids led to a 20% decrease in serum concentrations of rofecoxib.
Concomitant administration of rifampicin decreases rofecoxib plasma concentrations by 50%.
Plasma concentrations of methotrexate are increased by a mean of 23% when administered
with rofecoxib, and plasma concentrations of lithium are also increased by rofecoxib.
Rofecoxib taken with warfarin resulted in a 10% increase in prothrombin time. The mechanism
of these interactions is unknown, but therapy with these agents should be carefully monitored
in patients who are taking rofecoxib. Rofecoxib also may decrease the anti-hypertensive effect
of ACE inhibitors.5, 90, 91
5. Published trials of efficacy and adverse effects with celecoxib and rofecoxib.
This section reviews published efficacy studies and adverse event studies for celecoxib and rofecoxib, and makes recommendations on dosage in RA
and OA. Both celecoxib and rofecoxib were approved for use by TGA when full details of studies comparing the active drug to placebo or other
NSAIDs were available only in abstract form, making critical appraisal and assessment by independent reviewers extremely difficult. The experience
in other countries has been similar (see http://www.ti.ubc.ca/pages/letter31/htm). Several studies have now appeared in the literature, and in this
section, efficacy studies with celecoxib and rofecoxib are reviewed. When the details of phase III studies are available, data from phase 2 studies is
not presented. Some additional data is also presented from the approved product information for both drugs.
Approx. 4200
patients
RA Placebo and 100mg bd Placebo Naproxen Celecoxib doses Celebrex® product
active 200mg bd 500mg bd similar in information. (Some
controlled effectiveness details have not been
clinical trials and published, although
up to 24 comparable to summaries may be
weeks naproxen available in abstract
duration. form)
Approx. 2100
patients
*
Studies in efficacy section - were included again in the Side effects section if the title of the article made a specific reference to side effect profile
†
WOMAC - Western Ontario and McMaster Universities Osteoarthritis Index (Composite of pain, stiffness and functional measures)
¶
VAS -Visual analog scale ‡ACR-20 - American College of Rheumatology responder index (Composite of clinical, laboratory and functional measures)
Additional Study 92
- Four Phase 2 trials: 2 week OA efficacy trial; 4 week RA efficacy trial; 1 week endoscopic study of GI mucosal effects and a 1 week study of effects on platelet function.
5.1.2 Efficacy studies with rofecoxib
Rofecoxib has been approved by the TGA for the treatment of pain associated with OA. Rofecoxib 12.5mg or 25mg given as a daily dose is
significantly superior to placebo for the treatment of the signs of osteoarthritis. To date (Jan 12, 2000) there have been no active controlled trials
published. However, studies published in abstract form report that a daily dose of 12.5mg or 25mg rofecoxib were comparable to ibuprofen 800mg
tds or diclofenac 50mg tds in treatment of OA of the hip and knee.91, 93, 94
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