COX-2-selective NSAIDs: New wonder drugs?
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Document1 1/9/00 4:56 PM Page 1
COX-2-selective NSAIDs:
New wonder drugs?
National Prescribing Service ACN 082 034 393
Level 1/ 31 Buckingham Street, Surry Hills 2010
Phone: 02 9699 4499 l Fax: 02 9699 5155 l email: info@nps.org.auCOX-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.
2. Physiology and pharmacology of the COX
metabolites.
2.1 Biosynthesis of prostaglandins
The eicosanoids are autacoids (locally acting hormones) derived from arachidonic acid. They
comprise prostaglandins (PGs), thromboxanes (TXs) and leukotrienes (LTs). The PGs and TXs are
products of the cyclooxygenase (COX) pathway and are known as prostanoids. The leukotrienes
are byproducts of the 5-lipoxygenase pathway. Arachidonic acid is a component of cell
membranes, which is mainly released from membrane phospholipids by the enzyme phospholipase
A2. Many stimuli can liberate arachidonate, although this differs according to cell type. Examples
are thrombin in platelets, C5a in neutrophils and antigen-antibody reactions in mast cells. Cellular
damage, or influx of calcium into most cells will also activate phospholipases. Liberation of free
arachidonate is the rate determining step in the synthesis of PGs, TXs and LTs.
COX or prostaglandin H2 synthase catalyses the first two steps in the biosynthesis of the PGs from
the substrate arachidonic acid. These are the oxidation and cyclisation of the unesterified
arachidonic acid to the hydroperoxy endoperoxide PGG2, followed by its subsequent reduction to
PGH2.1 PGH2 in turn serves as a substrate for cell specific isomerases which produce a variety of
biologically active products (See Figure 1)Figure 1. Synthesis of the clinically relevant prostaglandins and thromboxanes from arachidonic acid. The half-lives of most PGs in the serum are less than one minute. High concentrations of PG- inactivating enzymes are present in the lung, and 95% of PGE2 and PGF2 are inactivated on first passage. PGI2 (Prostacyclin) is not taken up into the lung, but is hydrolysed nonenzymatically (t1/2 =3 minutes) to the inactive 6-keto-PGF1. TXA2 (Thromboxane A2) has a half-life of 30 seconds, and breaks down nonenzymatically into the stable but inactive TXB2.2 In healthy individuals, PG mediate a range of normal biological functions including gastric protection, renal homeostasis, vascular homeostasis, uterine function, embryo implantation and labour, regulation of the sleep wake cycle, body temperature and inflammation (Table 1). Although most tissues are able to synthesise the intermediate PGH2 from free arachidonic acid, the biologically active PGs synthesised varies in each tissue and depends on the complement of enzymes that are present and their relative abundance. For example, lung and spleen are able to synthesise a whole range of biologically active prostanoids, but the principal enzyme metabolising PGH2 in platelets is thromboxane synthetase, while endothelial cells contain primarily prostacyclin synthase.2, 3 Prostanoid receptors are all G-protein linked, and their stimulation activates distinct cell-signalling pathways.3 Five main prostanoid receptors have been defined and cloned. These have been termed DP-, FP-, EP- TP- and IP-receptors and are the ligands for the natural prostenoids PGD2, PGF2, PGE2, TXA2 and PGI2 respectively. EP-receptors can be divided into four subtypes, EP1 to EP4.4
Table 1. Physiologic Functions of Prostaglandins
(From Kaplan-Machlis et al, 19995).
Physiologic Function Prostaglandin(s) Involved
Relax vascular smooth muscle PGE2, PGF2, PGI2
Promote platelet aggregation TXA2
Inhibit platelet aggregation PGI2
Relax bronchial smooth muscle PGE2, PGI2
Contract bronchial smooth muscle PGF2
Increase renal blood flow PGE2, PGI2
Protect gastric mucosa PGE2, PGI2
Contract uterine smooth muscle PGE2, PGF2
Relax uterine smooth muscle PGI2
Regulation of the sleep/wake cycle PGD2
2.2 Comparisons between COX-1 and COX-2
2.2.1 COX regulation and biology
In 1990 it was reported that stimulation of human monocytes with lipopolysaccharide (LPS)
resulted in a substantial increase in the activity of COX, but did not change the activities of
phospholipase or 5-lipoxygenase.6 It was also observed that dexamethasone could inhibit LPS-
induced increases in COX activity of macrophages, but did not affect basal production of
prostaglandins.7 These results led the investigators to postulate the existence of an ‘inducible’
form of COX which could be upregulated by inflammatory stimuli such as cytokines. This
inducible enzyme (COX-2) was cloned in 1991.
COX-1 is the constitutive form of the enzyme which is expressed in nearly all cell types
throughout the body at a constant level. It’s expression can increase 2- to 4- fold under
stimulatory conditions and it is not appreciably affected by glucocorticoids. In contrast, COX-2
is an immediate early gene product. It’s expression is rapidly upregulated by a variety of
inflammatory stimuli including proinflammatory cytokines (eg. interleukin (IL)-1, IL-2 and
tumour necrosis factor- (TNF-)) bacterial lipopolysaccharide, mitogens and reactive oxygen
intermediates. These stimuli can upregulate COX-2 in macrophages, monocytes, synoviocytes,
chondrocytes, fibroblasts and endothelial cells 10- to 80- fold.8-10 COX-2 is not commonly
found in differentiated cells under normal physiological conditions, but it has been
constitutively found in the kidney,11 vasculature,12 brain,13, 14 ovary, uterus (associated with
embryo implantation), cartilage and bone.15
2.3 Basis of inhibitor selectivity
Differences between COX-1 and COX-2 are summarised in table 2. Although the genes of both
isoforms are different, COX-1 and COX-2 have similar structures and catalytic activities. The
amino acid sequences for the substrate binding and catalytic sites are almost identical, but
COX-2 has valine substituted for isoleucine at positions 434 and 523.16, 17 Valine is smaller than
isoleucine by a methyl group. These substitutions result in a larger and more flexible substrate
channel and a secondary internal pocket off the inhibitor binding site of COX-2 which is not
observed in COX-1. COX-2 selective inhibitors have structures which occupy this additional
pocket (See Figure 2).Figure 2. A single amino acid substitution is responsible for inhibitor selectivity. Larger COX inhibitors cannot occupy the active site of COX-1 since the internal side pocket is not present. (Figure reprinted with permission from Hawkey, C. J. 1999. COX-2 inhibitors. The Lancet. 353: 307-14.18 © The Lancet Ltd.)
Table 2. Summary of the structure, distribution and regulation of
COX-1 and COX-2 (From Brooks, P. 199919).
COX-1 COX-2
cDNA Chromosome 9; 22kB Chromosome 1; 8.3kB
mRNA 2.8kB 4.5kB
Protein 72kDa; 599 amino acids 72kDa; 604 amino acids
Amino acids: 90% between species for both isoforms;
similar Vmax and Km values for arachidonic acid
Differences Glucocorticoids inhibit expression of COX-2, not COX-1;
the active site of COX-2 is larger than that of COX-1
Regulation Predominantly constitutive. Predominantly inducible
Increased 2- to 4-fold (10- to 20-fold).
by inflammatory stimuli Constitutive in certain tissues
Tissue Expression Most tissues, Induced by inflammatory stimuli
but particularly platelets, and mitogens in macrophages/
stomach, kidney monocytes, synoviocyes. chondrocytes,
fibroblasts, endothelial cells. Induced
by hormones in the ovaries and foetal
membranes. Constitutive expression
in the CNS, kidney, testes, tracheal
epithelial cells.
2.4 Non-selective COX inhibitors
NSAIDs are believed to exert their antiinflammatory actions through the inhibition of PG
synthesis by blocking COX.20, 21 The predominant effect of these drugs is in the periphery, but
the antipyretic effects are mediated by inhibition of PG synthesis in the central nervous system.
Aspirin covalently modifies both COX-1 and COX-2 by acetylation of a distinct serine residue
within the active site of the enzyme. This results in an irreversible inhibition of COX activity.
This is an important distinction for aspirin compared to other NSAIDs, since the duration of
activity of aspirin relates to the turnover rate of COX in target tissues.
Traditional NSAIDs are weak organic acids (see Table 3) which serve as reversible inhibitors of
COX activity. Some non-selective NSAIDs such as ibuprofen and mefenamic acid are purely
competitive COX inhibitors. Others including naproxen and indomethacin have a more
complex mechanism of inhibition; they bind very tightly to COX and can be classified as time-
dependent inhibitors.
2.5 COX-2-selective NSAIDs
Two COX-2-selective NSAIDs are currently available to clinicians in Australia. Celecoxib
(Celebrex®, (Searle)) has been approved for use in Australia for the management of pain
associated with osteoarthritis (OA) and rheumatoid arthritis (RA) in adults. Rofecoxib (Vioxx®,
(Merck)) has been approved for the treatment of OA. A third agent, meloxicam (Boehringher
Ingelheim) has been released in Europe, and may be licensed in Australia at some future date.
The indications and recommended dosages for celecoxib and rofecoxib are show in Table 4.
COX-2-selective NSAIDs exhibit time-dependent inhibition of COX-2.Table 3. Chemical classification of NSAIDs available in Australia
Chemical Class Generic Name Proprietary Products Available
Salicylic acid derivatives Aspirin* Ecotrin®
Diflunisal Dolobid
Indole acetic acids Indomethacin Arthrexin®, Hicin®, Indocid®, Indomed®
Sulindac Aclin®, Clinoril®, Saldac®
Heteroaryl acetic acids Diclofenac Diclohexal®, Fenac®, Voltaren®,
Voltaren Rapid®, Dinac®, Diclohexal®,
Arthrotec 50® (Diclofenac
50mg+misoprostil 200microg).
Ketorolac Toradol®
Propionic acid derivatives Ibuprofen ACT-3®, Actiprofen®, Brufen®,
Nurofen® Rafen®
Ketoprofen Orudis®, Orudis SR®, Oruvail SR®
Naproxen/ Anaprox®, Inza®, Naprogesic®,
Crysanal®,
Napoxen sodium Naprosyn®, Naprosyn SR®, Proxen SR®
Tiaprofenic acid Surgam®, Tiafen®
Anthranilic acids (Fenamates) Mefenamic acid Mefic®, Ponstan®
Enolic acids Oxicams Piroxicam Candyl®, Candyl-D®, Feldene®,
Feldene-D®, Moblis®, Moblis-D®
Pirohexal-D®, Pirox®, Rosig®, Rosig-D®
Tenoxicam Tilcotil®
Pyrazolidinediones Phenylbutazone Butazolidin®
* low dose analgesic, antipyretic and antiplatelet preparations of aspirin have been excluded from this list.
Table 4. Specific COX-2-selective NSAIDs available in Australia
Generic Name Proprietary Products Available TGA approved indications and
recommended dosages
Celecoxib Celebrex® Rheumatoid arthritis, 100-200mg twice
daily Osteoarthritis, 200mg once daily or
100mg twice daily. Maximum: 200mg
twice daily
Rofecoxib Vioxx® Osteoarthritis, Initially 12.5mg once daily,
may be increased if necessary to 25mg
once daily2.6 Assessment of COX-2 specificity A number of disparate methods have been used to assess the potency of inhibitors against COX-1 and COX-2. These assays have utilised COX derived from different species and tissues, and as such the results for individual compounds can vary widely.19 At the International Consensus Meeting on the Mode of Action of COX-2 Inhibition, it was proposed that the human whole blood assay (WBA)22 should be adopted as the standard method for assessing differential inhibition of COX isoforms.19 The human whole blood assay has a number of advantages, including the ability to make assessments of inhibitor activity when a drug is taken by a patient before blood collection, or when the inhibitor is added to the blood after sample collection. In the former case, biologically active metabolites can also be assessed. For assessment of COX-1 activity in this assay, blood is allowed to clot for one hour at 37°C in the presence or absence of inhibitor, and then the serum is assayed for TXB2. Since TXB2 is predominantly derived from platelets in this system, and platelets cannot synthesise COX-2 (See Blood Clotting below), serum TXB2 levels reflect platelet COX-1 activity. For assessment of activity against COX-2, blood is collected in heparinised tubes and incubated for 24hrs at 37°C in the presence or absence of inhibitor, together with LPS. LPS results in PGE2 production by circulating monocytes as a consequence of inducing COX-2, so after 24hrs, serum is assayed for PGE2.22 Enzyme inhibitors are usually described according to their efficiency in inhibiting enzyme activity. The most common variable is the IC50 (concentration of inhibitor which results in a 50% reduction in COX activity). A low IC50 indicates a drug is more potent than one with a high IC50. For COX, the results of inhibitor assays are commonly expressed as a ratio of IC50 for COX-2/COX-1. A smaller value therefore implies a greater selectivity of an agent for COX- 2. Recently, a number of modifications have been made to the COX-2 component of the WBA. This modified assay is the William Harvey Human Modified Whole Blood Assay (WHMA).23 The changes were made in an attempt to compensate for the longer incubation times in the COX-2 component of the WBA (24hrs) compared to the COX-1 component (1hr), since it is now obvious that the potency of inhibitors for prostanoid formation is dependent upon the supply of arachidonate both in vivo and in vitro.24, 25 In addition, the investigators who developed this assay expressed their results as the ratio of IC80, since steady state plasma concentrations of many NSAIDs, aspirin and meloxicam produce approximately 80% inhibition of both COX-1 and COX-2 in this assay system 23 (see Figure 3).
Figure 3. Selectivity of COX-2 inhibitors and NSAIDs given as log inhibitory concentration (IC80) ratio. The ‘0 line’ indicates equipotency (i.e. an IC80 ratio of 1). (Figure reprinted with permission, from Brooks, P.M. COX-2 inhibitors. Australian Prescriber 2000. 23:30-2. See http://www.australianprescriber.com ) 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 2.7.1 COX-2 in RA and OA 2.7.1.1 Studies in experimental animals The role of COX-2 has been studied in animal models of inflammatory arthropathies. COX-2 but not COX-1 is induced in the synovial tissues of rats with adjuvant arthritis (a model of rheumatoid arthritis).28 In this model, a COX-2-selective inhibitor (SC-58125) reduced paw oedema and decreased PGE2 concentrations in the paw to baseline levels with an efficacy indistinguishable from indomethacin. 2.7.1.2 Studies in humans COX-2 is also induced in humans with RA and OA. Using immunohistochemistry with a specific antibody directed against COX-2, Crofford et al demonstrated that COX-2 is present in vivo in synovial tissues from patients with RA.29 Siegle et al studied the expression of COX-1 and COX-2 in patients with inflammatory arthropathies (RA, ankylosing spondylitis, or psoriatic arthritis) and in patients with OA. Using both immunohistochemistry with image analysis and reverse transcription polymerase chain reaction (RT-PCR), expression of COX-2 protein and mRNA respectively were significantly higher in inflammatory arthropathies compared to OA.30 The upregulated COX-2 expression in inflammatory arthropathies in this latter study is consistent with a recent study which reported significantly higher concentrations of PGE2 in the synovia of patients with RA compared to those with OA.31 Despite low levels of COX-2 expression in the synovium of patients with OA, cartilage may be a significant source of COX-2 and PGs in these patients. A recent study employing explant cultures of cartilage from OA-affected patients reported upregulation of COX-2 mRNA and protein which coincided with superinduction of PGE2.32 3. Physiological and pathophysiological roles of prostanoids/adverse effects of NSAIDs The main adverse effects of the non-selective NSAIDs involve the GI tract, the kidney and blood clotting. Since PGs mediate a variety of physiological functions, inhibiting their production likely accounts for some of the adverse events associated with NSAID therapy. It is largely the inhibition of COX-1 which is believed to contribute the adverse effect profile of the NSAIDs as a class. However, some effects of individual NSAIDs may be unrelated to COX inhibition. For example, aplastic anaemia has been reported following phenylbutazone treatment, and tiaprofenic acid can cause cystitis. It has been hypothesised that specific COX-2-selective NSAIDs will have a superior adverse effect profile compared to the non-selective inhibitors
(particularly GI side effects), but it is possible that the COX-2-selective NSAIDs will cause unwanted effects independent of their selective actions on COX-2. Drug adverse effects can be classified as being type A or type B reactions. Type A reactions are common reactions which are dose-dependent and in line with the pharmacology of the drug. Type B reactions are idiosyncratic, rare and more likely to be serious. Most clinical trials are powered to detect drug efficacy, not safety. Therefore, although type A reactions will often emerge in the clinical trial process, this is not always the case. For example, it was some years after marketing that the ACE inhibitor cough emerged as one of the most common adverse effects of this class of drug. Since type B reactions are infrequent, they are rarely detected by clinical trials. These reactions emerge as a consequence of vigilant reporting of adverse reactions. This section reviews some of the physiological roles of COX and PGs, in addition to describing some of the adverse effects commonly associated with COX inhibition by non-selective NSAIDs. The adverse effects of the COX-2-selective NSAIDs which have emerged in clinical trials are discussed below in section 5.2. 3.1 Inflammatory and immune responses PGs are released by a large variety of mechanical, thermal, chemical and microbiological insults, and they contribute significantly to the signs and symptoms of inflammation.33 In areas of acute inflammation, PGE2 and PGI2 are generated by local tissues and blood vessels, while mast cells release PGD2. Monocyte-lineage cells (macrophages) can release PGE2 and TXA2. PGs, in particular PGE2 are major mediators of the inflammatory response. PGEs and PGE2 in particular, modulate the oedema and pain which constitute the classical signs of inflammation. PGEs do not directly increase vascular permeability, but can increase plasma exudation induced by other mediators such as C5a.34 PGEs can also increase blood flow to inflamed areas thereby enhancing leukocyte infiltration and contributing to the development of oedema.2 PGE2 also lowers nociceptive thresholds, sensitising peripheral sensory nerve endings and thereby potentiating the effects of nociceptive agents such as bradykinin and histamine. In addition, COX products are thought to act in the spinal cord to facilitate the transimission of pain responses.35 PGE2 is also a pyretic agent and contributes to fever associated with infections.36 Inhibition of the synthesis of PGs is believed to account for the clinical efficacy of the NSAIDs. It is important to remember that the inflammatory process is a defence mechanism to protect the body from noxious stimuli. It is only when the inflammatory response is not appropriately limited and continues unnecessarily that COX-2 activity becomes detrimental. 3.2 The GI tract 3.2.1 PG’s and their role in gastric protection Cytoprotective PGs in the stomach are thought to be synthesised primarily by COX-1 which is widely distributed throughout the GIT. Basal expression of COX-2 mRNA and protein can also be detected in the GI mucosa.37 In the stomach, PGE2 and PGI2 inhibit gastric acid secretion stimulated by feeding, histamine or gastrin. Volume, acidity and pepsin content of secretion are all reduced. Both PGE2 and PGI2 are vasodilators in the GI mucosa, and PGI2 may be directly involved in the regulation of blood flow. Mucous secretion in the stomach and small intestine is increased by PGEs. These effects help to maintain the integrity of the GI mucosa.2 In addition, PGEs and their analogues inhibit gastric damage caused by a variety of ulcerogenic agents and promote healing of duodenal and gastric ulcers.38 3.2.2 Incidence and awareness of adverse GI effects after NSAID therapy The most common adverse events associated with NSAID therapy involve the GI tract.39 There is a major risk of GI disturbances, perforation, ulcers and bleeding associated with NSAID usage which represents a significant socioeconomic burden. The risk of an adverse GI event
increases linearly with age 40, and remains constant over time.41, 42 Other risk factors for GI damage are higher doses of NSAIDs (including the use of two or more NSAIDs), a history of gastroduodenal ulcer or gastrointestinal bleeding, concomitant use of corticosteroids, serious coexisting conditions, and concomitant use of anticoagulants.40 Within a six month period of treatment, between 5 and 15% of patients can be expected to discontinue therapy because of dyspepsia 43, and it has been estimated that approximately 0.4- 2% of patients who take an NSAID for a year are at risk of developing a serious ulcer complication.38, 39 The mortality rate amongst patients who are hospitalised for NSAID-induced upper GI bleeding is approximately 10%. In the USA, the number of deaths per year attributed to NSAID gastropathy is estimated to be 7600 and the number of hospitalisations is 76000/year.39 In the UK, it has been estimated that 12 000 ulcer complications and 1200 deaths/year are attributable to NSAID usage.44 There are no recent figures which document the incidence of serious NSAID-induced GI complications in Australia, although it has been estimated that in 1988 there were approximately 1200 hospital admissions for ulcer complications attributable to NSAID usage, in people aged 65 years and over.45 Surveys in Australia in the late 1980s showed that approximately 20% of the elderly population were taking NSAIDs, and that 43% of community use of NSAIDs was in patients over 60 years of age.45, 46 Since this time there has been a significant reduction in prescription sales of NSAIDs in Australia (Figure 4a) as a consequence of educational and regulatory interventions.45 In 1996 Henry and coworkers published a meta-analysis of clinical trials which highlighted differences in GI risk associated with specific NSAIDs.26 This study reported the lowest pooled risk was associated with diclofenac and ibuprofen at doses of less than 1600mg/day. The highest pooled relative risk was with piroxicam and ketoprofen (See Figure 5). It is important to note that the relative risk for ibuprofen increases at doses greater than 1600mg/day, and for all NSAIDs, the antiinflammatory effects and the incidence of adverse effects are both dose related.47 Figure 4. a) Graph showing the declining number of NSAID prescriptions dispensed from June 89 to June 99. b) Graph showing NSAID usage stratified by GI Risk for the corresponding period.
Figure 4b. Figure 5. Graph showing comparison by meta-analysis of the pooled relative risk (±95% confidence intervals) of serious upper GI complications from exposure to individual NSAIDs compared with exposure to ibuprofen. Risk was not established for diflunisal due to an insufficient number of studies) and tenoxicam or tiaprofenic acid due to unavailability of comparative data.
The National Prescribing Service (NPS) conducted an educational campaign early in 1999 to alert to differences in relative risk associated with NSAIDs. Although statistics for the latter half of 1999 are not yet available, data obtained from the PBS show that in the first half of 1999, prescribing of longer acting (higher risk) agents fell. There has been a corresponding increase in the number of prescriptions of shorter acting (lower risk) agents (Figure 4b). Although prescribers are generally aware of the potential for adverse effects with NSAID therapy, public perceptions and understanding about side effects and drug usage may not always reflect that of health care professionals. For example, a recent survey of 4799 people conducted in the USA reported that 45% of the group took NSAIDs for five or more consecutive days/month, and 40% of these took both OTC and prescribed NSAIDs. Many of the group were unaware or unconcerned about the possibility of adverse GI effects, and incorrectly believed that warning signs would precede a serious GI episode.42 There are currently no data available on OTC consumption of naproxen sodium, ibuprofen, mefenamic acid, topical diclofenac or aspirin in Australia. 3.2.3 Pathogenesis of mucosal injury Gastroduodenal mucosal injury develops when the normal defensive properties of the mucosa are overwhelmed by gastric acid. NSAIDs contribute to mucosal injury by two independent mechanisms: 1) a topical effect related to the physico-chemical properties of NSAIDs themselves 48 and 2) a systemic effect through decreased mucosal PG synthesis.49 The vast majority of NSAIDs are weak organic acids. In the stomach, they remain in unionised form and can freely diffuse across the membrane of mucosal cells. Once inside the neutral cytoplasm, the drug ionises resulting in trapping of hydrogen ions within the cell.50 Systemic inhibition of PG synthesis impairs mucosal repair and microvascular blood flow, and also results in inhibition of hepatocyte growth factor production which may delay healing of mucosal ulcers.51 Indeed, the systemic effects of these agents appear to have the predominant role in ulcer development, even though superficial mucosal injury may be reduced. In support of this, the use of enteric coated aspirin preparations and parenteral or rectal administration of NSAIDs have failed to prevent the development of ulcers.46, 52, 53 3.2.4 Clinical spectrum of injury The spectrum of NSAID-related gastroduodenal injury includes a combination of subepithelial haemorrhages, erosions, and ulcerations that is often referred to as NSAID gastropathy. The distinction between erosions and ulcerations depends on pathological definitions: erosions are defined as lesions confined to the mucosa, and ulcers are defined as lesions that penetrate the muscolaris mucosae into the submucosa. An ulcer can cause haemorrhages when it erodes into the arteries below the mucosa. In practice, an endoscopic definition is used, which is based on a subjective assessment of the size, shape, and depth of the lesion. The likelihood of a lesion being an ulcer increases with lesion size. Erosions are likely to be small and superficial, whereas ulcers tend to be at least 5 mm in diameter with apparent depth.54 Although some studies have defined ulcers as a mucosal break of ≥ 3mm in diameter, Graham in an editorial in Gastroenterology makes the point that ‘a 5mm lesion provides a more acceptable standard for a potentially serious lesion, and results of any study that provide data about 3mm ‘ulcers’ should be viewed with caution.’55 3.2.5 COX-2 in the GI tract Helicobacter pylori infection can also lead to ulcers which are often accompanied by a wide field of non-erosive inflammatory gastritis. H. pylori infection is more common in elderly patients, as is NSAID use.56 The relationships between NSAID use, H. pylori infection and gastric damage are not well understood. NSAID usage does not increase susceptibility to H. pylori infection but whether a mucosa which has been damaged by H. pylori infection is more susceptible to the toxic effects of NSAIDs is unclear. Eradication of H. pylori before starting NSAID therapy reduces the occurrence of gastroduodenal ulcers in patients who have not previously taken NSAIDs.57 However, another study investigating the effects of H. pylori
eradication in patients with current or previous NSAID-induced ulcers or dyspepsia who continued to use NSAIDs found that H. pylori eradication did not alter the outcome in terms of ulcer recurrence or dyspepsia.58 COX-2 is induced by gastric injury, and gastritis caused by H. pylori is associated with COX-2 expression not only in mononuclear cells, but also parietal cells and gastric epithelium.59, 60 Eradication of H. pylori leads to reduced expression of COX-2 in the gastric epithelium, but levels remain elevated and are strongly correlated with the severity of chronic inflammatory cell infiltrate.60 The relationship of COX-2 induction in the gut secondary to H. pylori infection needs further exploration. It was initially hypothesised that COX-2 may play a role in the immune response against H. pylori since COX-2 is expressed around the rim of the ulcer, and in animal studies, COX-2 inhibition retarded ulcer healing.61 Recent studies have highlighted the importance of both COX isoforms in the formation of new capillary blood vessels (angiogenesis).62 Angiogenesis is essential for wound and ulcer healing, and also for the growth and metastasis of solid tumours. This action of COX-2-selective NSAIDs accounts for their activity in the prevention of colon and other cancers.63-67 However it also suggests these agents should be used with caution in patients with active GI ulcers. 3.3 The kidney Adverse renal effects occur in approximately 5% of patients who are taking NSAIDs, and advanced age is a primary risk factor in these individuals. PG’s synthesised by the kidneys affect haemodynamics and sodium and water metabolism. PGI2, PGE2 and PGD2 dilate the glomerular arterioles and enhance renal perfusion.68 PGE2 and PGF2 have diuretic and natriuretic effects since they inhibit sodium reabsorption at the thick ascending limb of the loop of Henle.69 Despite these many actions, PGs modulate but do not maintain normal renal blood flow in healthy individuals. However, PG production becomes important in maintaining blood flow and glomerular filtration in the compromised kidney.70, 71 This is particularly important in patients with congestive heart failure, liver cirrhosis, compromised renal function or when diuretics are administered concomitantly (hypovolaemic subjects).72-74 In individuals with these clinical conditions, renal function is highly dependent upon local production of PGE2 within the kidney to offset the vasoconstrictor effects of high concentrations of angiotensin, vasopressin and catecholamines that result from the activation of pressor reflexes. Inhibition of PG synthesis by NSAIDs in these patients can lead to sodium and water retention and weight gain, and can also precipitate acute renal failure when reduced PG synthesis leads to unopposed vasoconstriction.2, 73 Renin release is also partially controlled by PGI268 and inhibition of PG synthesis by NSAIDs can occasionally affect the renin-angiotensin-aldosterone system leading to a reduction in aldosterone secretion. In patients with renal impairment, especially those treated with agents that increase serum potassium levels (for example, potassium sparing diuretics, potassium supplements, ACE inhibitors and angiotensin II receptor antagonists), this can lead to hyperkalaemia.73, 75 3.3.1 COX-2 expression in the kidney The role of COX-2 in generating PGs in the kidney is complex and still being defined. In the adult human kidney, constitutive expression of COX-2 protein and mRNA is detectable in endothelial and smooth muscle cells of arteries and veins and intraglomerularly in podocytes.11 Studies in the rat have demonstrated that high levels of COX-2 can be induced in the kidney in response to appropriate stimuli. Salt restriction alters the intra-renal distribution of COX-2 and dramatically upregulates its expression in the macula densa and surrounding cortical thick ascending limb.76 There may also be important feedback loops between the renin-angiotensin system and renal expression of COX-2. For example, administration of a selective COX-2 inhibitor blocked increases in renal renin production in response to a low-salt diet or after administration of ACE inhibitors,77, 78 and administration of ACE inhibitors led to increased COX-2 expression in the macula densa of rats on control or low sodium diets.78
In a study assessing the influence of COX inhibition on renal function in young, healthy and salt-depleted males, celecoxib was found to cause Na+ and K+ retention. These are early clinical features of renal dysfunction induced by NSAIDs in hypovolaemic patients. Conversely rofecoxib had minimal effects on renal function in healthy, elderly patients with normal renal function (defined as creatinine clearance > 50mL/min or serum creatinine < 2mg/dL) and a high intake of dietary sodium (200mEq/day). These data support the findings in animals which suggest that COX-2 expression may be important in the physiological response to a low sodium diet. An important role of COX-2 in kidney function and development is suggested by studies utilising COX knockout mice. COX-2 homozygous knockout (-/-) mice show severe renal pathology which progressively deteriorates with age 79, 80, but the kidneys of COX-1 homozygous (-/-) knockouts show only minor abnormalities even at 5 months of age.81 3.4 Blood clotting The endothelial cells which line the circulatory tree serve as a barrier between flowing blood and the vessel wall, and actively elaborate antithrombotic factors such as PGI2 and nitric oxide which maintain fluidity of blood. PGI2 derived from endothelial cells effects relaxation of vascular smooth muscle cells, and also blocks platelet activation when released into the bloodstream. At sites of vascular injury the antithrombotic properties of the endothelium is lost, and the platelets are exposed to thrombotic substances that lead to platelet activation. Activated platelets release ADP and TXA2. ADP leads to the activation of other platelets. TXA2 which is the major product of arachidonate metabolism in platelets is a powerful inducer of platelet aggregation and a potent vasoconstrictor. Platelets do not have nuclei and therefore cannot produce inducible COX, so COX-1 is the only isoform detectable in the these cells. Inhibition of COX-1 is the aim of ‘half an aspirin a day’ prophylaxis against thromboembolic disease, and is achieved by decreased production of TXA2. Within 2 hours of a single dose of aspirin, COX-1 is irreversibly inhibited for the life of the platelet in the circulation (8-10 days). PGI2 production by endothelial cells is also temporarily decreased, but COX-1 in these cells can regenerate within hours, so PGI2 synthesis is reestablished.2, 82 Although PGI2 is a potent vasodilator and inhibitor of platelet activation, its role in the intact organism has remained speculative in the absence of an antagonist of the PGI2 receptor. However, mice deficient in the IP- receptor (the receptor through which PGI2 mediates its effects) suggest an important role for PGI2 in mediating inflammation and preventing thrombosis.83 Furthermore, a recent study by McAdam and coworkers suggests that COX-2 may play a major role in the biosynthesis of both systemic and renal PGI2 under physiological conditions.84 In this study, celecoxib (doses up to 800mg), rofecoxib and ibuprofen (800mg) all suppressed excretion of the metabolite of PGI2. However, only ibuprofen significantly inhibited TXB2 formation ex vivo. This study was conducted in young, healthy volunteers and it remains to be determined whether these effects are sustained during chronic dosing in patients at risk for cardiovascular disease. 3.5 Gestation and parturition Both COX-1 and COX-2 are involved in reproduction. COX-2 is important in rupture of the follicle during ovulation, and implantation of the embyro in the uterine endometrium.15 PGs are expressed in the uterine epithelium, and can lead to contraction of uterine smooth muscle. They are important for inducing uterine contractions during labour, and NSAIDs can therefore increase the duration of gestation and delay premature labour.85 However, they are rarely used for this purpose, since in the foetus, PGs maintain the patency of the ductus arteriosis. NSAIDs can therefore lead to premature duct closure and disruption of fetal circulation.86 The significance of COX in reproduction is supported by studies in knockout mice. COX-2 knockout mice are infertile, and COX-1 knockout mice have few live births when female homozygotes are mated to male homozygotes.79, 81
4. Drug interactions
Celecoxib is metabolised to inactive metabolites via CYP2C9. Drugs known to inhibit this
isoenzyme should be coadministered with caution due to the potential risk of increasing the
plasma concentration of celecoxib.
Although not involved in its metabolism, celecoxib is an inhibitor of CYP2D6, and hence has
the potential to cause an interaction resulting in the elevation of plasma concentrations of any
drugs metabolised via this isoenzyme.
Table5. Drug interactions involving celecoxib 5, 87, 88
Drug involved in interaction Mechanism and result of interaction
Inhibitors of CYP2C9: Elevated plasma concentration of celecoxib. Two fold
amiodarone, cimetidine, increase in celecoxib plasma concentration with
fluoxetine, zafirlukast, coadministration of fluconazole.
fluconazole, fluvastatin,
fluvoxamine, metronidazole
ACE inhibitors, angiotensin II Coadministration of celecoxib may diminish the
receptor antagonists antihypertensive effect of ACE inhibitors, potential to
induce acute renal impairment in patients who are
renally compensated.
Frusemide and thiazides Inhibition of renal prostaglandins by celecoxib may
reduce the natriuretic effect.
Lithium Increased lithium plasma levels by 17%, monitor
closely.
Antacids Coadministration of aluminium and magnesium
containing antacids reduce plasma concentration of
celecoxib due to impaired oral bioavailability.
Warfarin Increased prothrombin time and bleeding events
reported, predominantly in elderly patients on
warfarin and celecoxib, monitor carefully 8 9
Substrates of CYP2D6: beta- Increased plasma concentration of substrates due to
blockers (metoprolol, inhibition of metabolism by celecoxib.
propanolol), certain
antidepressants (amitriptyline,
desipramine, clomipramine,
fluoxetine, paroxetine,
venlafaxine), perhexiline and
antipsychotics (haloperidol,
risperidone, thioridazine)
Codeine and oxycodone Potential for the conversion of codeine to morphine
and oxycodone to oxymorphone via CYP2D6 to be
inhibited by celecoxib, some patients may experience
a decrease in pain relief from codeine and oxycodone
preparations.
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, 915. 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. 5.1. Efficacy studies 5.1.1 Efficacy studies with celecoxib Celecoxib has been approved for use in Australia for the management of pain associated with osteoarthritis (OA) and rheumatoid arthritis (RA) in adults. In OA, celecoxib at doses of 100mg bd and 200mg bd provides significant reduction in pain associated with OA compared with placebo. When compared with naproxen 500mg bd, celecoxib 100mg bd is as efficacious as higher doses. Hence, the recommended dose of celecoxib in OA is 100mg bd with or without food. In RA, celecoxib 100mg bd and 200mg bd provides a significant reduction in pain and inflammation compared to placebo. These doses are equally efficacious and comparable to naproxen 500mg bd or diclofenac SR 75mg bd, although the product information reports that some patients derived additional benefit with 200mg bd.
Table 6. Published efficacy trials with celecoxib
Patients Design/Age Exclusions Dur-ation Main efficacy measures Drug & n Better n Comp-arable n Significant Notes Reference
Dose than to Adverse Effects*
OA, knee Multicentre, Patients with 12 weeks 1. patient and physician’s 50mg bd 203 204 Naproxen 198 Most common 50mg celecoxib Bensen, W. G., et al.
randomised, NSAID or global assessment of OA; 100mg bd 197 placebo 500mg bd events were GIT minimally (1999). Treatment of
double-blind sulphonamide (assessed 2. WOMAC†; 200mg bd 202 placebo symptoms , and effective osteoarthritis with
placebo & sensitivity wks 2,6 3. patient’s assessment of these were compared to celecoxib, a
active excluded & 12) OA pain on a VAS¶ similar amongst higher cyclooxygenase-2
controlled malignancy 4. OA severity index all groups celecoxib doses inhibitor: A randomized
trial active renal GI One patient in or naproxen controlled trial. Mayo
hepatic or naproxen group Clinic Proceedings.
Mean 62-3 yo coagulation had a bleeding Higher doses 74:1095-1105
disorders; ulcer, one were of
oesophageal or patient in comparable Supported in part by
gastroduodenal celecoxib 50mg efficacy to each Searle
ulceration in group had an other and to
previous 30 days ulcer naproxen
OA, knee Identical to Zhao, S. Z., et al. (1999).
previous study Evaluation of the
functional status aspects
of health-related quality
of life of patients with
osteoarthritis treated
with celecoxib.
Pharmacotherapy.
19:1269-1278
RA Multicentre, active renal GI 12 weeks 1. patient and physician’s 100mg bd 240 placebo 231 Naproxen 225 See table 2.1 for all celecoxib Simon, L. S., et al. (1999).
randomised, hepatic or global assessment of 200mg bd 235 * 500mg bd GI adverse events doses were Anti-inflammatory and
double-blind coagulation (assessed arthritis 400mg bd 218 placebo similarly upper gastrointestinal
placebo & disorders; wks 2,6 & 2. patients assessment of placebo No adverse renal efficacious effects of celecoxib in
active malignancy, 12) arthritis pain on a VAS effects. rheumatoid arthritis - A
controlled oesophageal or 3. count of painful/tender randomized controlled
trial gastroduodenal joints * 0-2% incidence trial. JAMA: Journal of
ulceration in 4. count of swollen joints patient of fluid retention the American Medical
Mean 54-5 yo prev. 30 days or 5. duration of morning but not & hypertension Association. 282:1921-
if baseline stiffness physician in all groups 1928
endoscopy 6. functional disability global
showed ulcers or index questionnaire assess- Supported by Searle
> 10 erosions 7. Cp C-reactive protein ment
continued next pageTable 6. Published efficacy trials with celecoxib continued
RA randomised, any concomitant 24 weeks 1. physician and patient 200mg bd 326 Diclofenac 329 See table 2.1 for Celecoxib and Emery, P. et al. (1999).
double-blind rheumatic assessment of arthritis SR GI side effects - diclofenac were Celecoxib versus
parallel condition, active (assessed 2. number of tender or 75mg bd similarly diclofenac in long-term
active- or suspected wks 4, 8, painful joints effective in management of
controlled peptic ulceration 12, 16,20 3. number of swollen managing RA rheumatoid arthritis:
trial or GI bleeding, & 24) joints pain and randomised double-
coagulation 4. patients responding inflammation blind comparison.
Mean 54-55yo defect or any according to ACR-20‡ Lancet. 354: 2106-2111
other disorder 5 functional disability
precluding score with the modified Supported by Searle
NSAID use, health assessment
malignancy, questionnaire
renal or hepatic 6. duration of morning
disorder, stiffness (VAS)
inflammatory 7. Cp C-reactive protein
bowel disease, 8. withdrawals due to
diclofenac treatment failure.
intolerance,
hypersensitivity
to NSAIDs, COX-
2-selective
NSAIDs or
sulphonamide,
any abnormal
clinical or
laboratory values
pretreatment
+others (see
study)
OA, knee Placebo and Signs and symptoms of 100mg bd Placebo Naproxen Celecoxib Celebrex® product
and hip active arthritis, WOMAC, OA 200mg od 500mg bd comparable to information. (Some
controlled flare 200mg bd naproxen. details have not been
clinical trials Total daily dose published, although
up to 12 of 200mg summaries may be
weeks maximally available in abstract
duration. effective. form)
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
Table 7. Published efficacy trials with rofecoxib
Patients Design/Age Exclusions Dur-ation Main efficacy measures Drug & n Better n Comparable n Significant Notes Reference
Dose than to Adverse Effects
OA, Randomised Previous 6 weeks 1) WOMAC 25mg od 73 Placebo 72 1 gastric bleed Both doses of Ehrich, E. W. et al. (1999). Effect
knee placebo gastric/duodenal 2) patient assessment of OA 125mg od 74 in association rofecoxib were of specific COX-2 inhibition in
controlled trial ulceration; history of (assessed pain on a VAS with gastric superior to osteoarthritis of the knee: A 6
GI bleeding; renal 1,2,4 & 6 3) physician and patient and duodenal placebo from week double blind, placebo
Mean 63.5yo impairment, wks) global assessment of ulcers in 1wk (1st controlled pilot study of
diabetes, history of response to Tx rofecoxib assessment) for rofecoxib. Journal of
cardiovascular, 4) physician global 125mg duration of study Rheumatology. 26:2438-2447
hepatic, neurological assessment of disease status treatment
neoplastic or (Likert scale) group 125mg is 5 times
coagulation disorder 5) patient global assessment the maximum
of disease status Dose-related recommended
6) % of patients who peripheral dose for
discontinued due to lack of oedema 2.7% treatment of OA
efficacy and 6.8% in 25
and 125mg
treatment
groups
respectively
RA Phase II other inflammatory 8 weeks 1) swollen joint count 5mg od 158 No clinically 25 and 50mg Schnitzer, T. J. et al. (1999). The
arthropathies, 2) tender joint count 25mg od 171 Placebo 168 significant rofecoxib safety profile, tolerability, and
Randomised, uncontrolled (assessed 3) patient global assessment 50mg/od 161 oedema or significantly effective dose range of
double-blind diabetes, active GI 2,4 & 8 of disease activity on a VAS hypertension. better than rofecoxib in the treatment of
placebo bleeding or weeks) 4) investigator global No serious GI placebo. 5mg rheumatoid arthritis. Clinical
controlled trial ulceration, assessment of disease activity effects not significantly Therapeutics. 21:1688-1702
positive stool guaiac (Likert scale) different to
Mean 54-55yo screen, malignancy, 5) Stanford Health placebo.
recent serious assessment questionnaire
cardiovascular disability index Rofecoxib Groups
disease, hepatic or 6) patient global assessment well matched for
renal impairment, of pain on a VAS age and sex
NSAID or 7) levels of C-reactive protein
paracetamol
sensitivity
OA, Six randomised Signs and symptoms of OA 1.25mg od Placebo Diclofenac Rofecoxib Vioxx® Product Information.
knee or clinical trials of 25mg od 50mg tid comparable to (Full details of studies not
hip rofecoxib Joint space narrowing at one diclofenac or published, although summaries
lasting from 6 year (compared to diclofenac Ibuprofen ibuprofen may be available in abstract
to 86 weeks. only) 800mg tid form)
4035 patients
including
approx. 400 pts
>80yo5.2 Adverse effect studies with celecoxib and rofecoxib The COX-2-selective NSAIDs are new drugs for which there is a limited amount of published comparative safety data. Most clinical trials are powered to detect drug efficacy, not drug safety.. Drug side effects can be classified as being type A or type B reactions. Type A reactions are common reactions which are dose-dependent and in line with the pharmacology of the drug. These effects will often emerge in the clinical trial process, but this is not always the case. For example, it was some years after marketing that the ACE inhibitor cough emerged as one of the most common side effects of this class of drug. In contrast, type B reactions are idiosyncratic, rare and more likely to be serious. Since they are infrequent, these reactions are rarely detected by clinical trials but emerge as a consequence of vigilant reporting of adverse effects. Therefore, and accurate picture of a drug’s adverse effects profile may not appear until several years after a drug is introduced into therapeutics. 5.2.1 Gastrointestinal (GI) complications The most common adverse effects of celecoxib and rofecoxib in clinical trials are dyspepsia, abdominal pain and diarrhoea. When compared to non- selective NSAIDs, the COX-2-selective NSAIDs result in a lower incidence of dyspepsia, but the difference is modest and may not be clinically relevant. The major marketing tactic for the COX-2-selective NSAIDs is their relative safety compared with traditional NSAIDs. To date, no studies have assessed the effect of celecoxib or rofecoxib on PG synthesis in the human gastric mucosa at therapeutic doses. However, in clinical trials there is a statistically significant decrease in the incidence of endoscopically proven ulcers in patients treated with both agents. Several factors complicate the interpretation of published clinical trials. Firstly, most studies have defined an ulcer as a ‘3mm lesion with unequivocal depth’, although one study also used 5mm ulcers as a secondary end-point (see section 3.24). In the majority of patients these ulcers are asymptomatic, and are a surrogate endpoint which may or may not reflect the real risk of developing serious ulcer complications. This has been a contentious issue in the literature, but there is evidence that endoscopic ulcers are predictive of adverse clinical events. Secondly, limited numbers of patients have been treated with either agent so the incidence of potentially uncommon GI side effects may not become evident until the drugs are more widely used in clinical practice. A third difficulty is that although some studies permitted inclusion of patients with a history of GI ulcers or bleeding, no published study has permitted inclusion of patients with active ulcers. Since COX-2 is detectable in the ulcerated mucosa, and animal studies have suggested that COX-2 inhibitors may impair ulcer healing, care must be taken in using these agents in patients who have existing ulcers or erosions. Because of these factors, large scale post-marketing surveillance and vigilant adverse event reporting will be required to determine to what extent these agents significantly decrease the incidence of clinically important ulcers, particularly in patients at high risk for ulcer complications. Peterson and Cryer in an editorial in JAMA make the following point ‘In patients with RA with no risk factors for NSAID-induced ulcers, the risk of developing an ulcer complication related to NSAID use is only 0.4%.38 Assuming that a COX-1-sparing NSAID will prevent complicated ulcers in approximately 50% of patients taking NSAIDs (reducing the risk to 0.2%), 500 low-risk patients would need to be treated with a COX-1-sparing NSAID to prevent each complicated ulcer that might have developed had all of these low-risk patients been taking traditional NSAIDs.’ These figures are based on drug costs in the USA, and do not take into account the costs of endoscopies, concomitant treatment with gastroprotective agents, or hospitalisations for serious GI toxicity. Due to the perceived relative safety of celecoxib with regard to GI complications, it is likely that it will be prescribed for those patients at greatest risk, such as patients with a history of GI erosion or ulceration. The GI complication rate in this group of patients is as yet unknown
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