COX 2-selective NSAIDs:
Biology, promises, and concerns
Brian F. Mandell, MD, PhD*
Education program director,
Department of Rheumatic
and Immunologic Diseases
Abstract
Celecoxib (Celebrex) is the first of a new family of
nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cyclooxygenase 2
(COX 2) while sparing COX 1. Clinical trials indicate that it is approximately as
effective in relieving the pain of osteoarthritis and the pain and inflammation of
rheumatoid arthritis as nonselective NSAIDs, but causes less gastrointestinal ulceration
and bleeding. This paper reviews the pharmacology and possible clinical role of celecoxib
and other COX 2-selective NSAIDs.
Key Points
- COX 2-selective NSAIDs do not inhibit platelet
function, and so may be good choices in patients with thrombocytopenia who require NSAID
therapy.
- COX 2-selective NSAIDs offer a distinct safety
advantage over most nonselective NSAIDs in patients who are at high risk for gastric
complications, but they should not be assumed to be totally without gastric complications.
- The primary question in determining whether a
patient needs a COX 2-selective NSAID is whether he or she needs any NSAID in the first
place—another drug or a nonpharmacologic approach may be more appropriate.
Comprehensive reading and
reference list.
The cyclooxygenase (COX)-2 inhibitors are a new
family of nonsteroidal anti-inflammatory drugs (NSAIDs) designed specifically to limit the
side effects of gastric erosions, ulcerations, and bleeding that occur with other NSAIDs.
One such drug—celecoxib (Celebrex)—is already available, and others are in
development.
In the pages that follow I review the
pharmacology of these new drugs and offer my perspective on their clinical role, which I
would sum up as follows: they do offer a substantial safety advantage, but we should not
assume they will be completely harmless. The first question to ask is not whether your
patient needs a COX 2-selective NSAID, but whether he or she needs any NSAID or if an
analgesic or disease-modifying drug might be more appropriate.
The Problem:
NSAID-Induced Gastropathy
NSAIDs are generally well tolerated, but they
have predictable side effects, including gastropathy, especially in certain groups.
In clinical trials, approximately 20% of patients
who took NSAIDs for even short periods developed gastric erosions that were detectable on
endoscopy. Fewer than 10% of these endoscopic lesions lead to clinically significant
events.1 However, so many people take NSAIDs that even uncommon clinical events
have a significant financial and societal impact. Case-control studies show that persons
admitted to the hospital because of upper gastrointestinal bleeding or complications of
gastric ulcers are more likely to have been taking prescribed or over-the-counter NSAIDs
than are matched controls.2
NSAIDs Inhibit Cyclooxygenase
NSAIDs inhibit cyclooxygenase (COX), a
rate-limiting enzyme in the pathway that synthesizes prostaglandins such as prostaglandin
E, prostacyclin, and thromboxanes.3 Since prostaglandins mediate not only
certain aspects of inflammation but also renal blood flow, hemostasis, and gastric
"cytoprotection," at first it did not seem possible to produce an effective
NSAID that was free of adverse effects.
COX 1, COX 2, and the
COX Hypothesis
In the early 1990s, researchers discovered that
COX exists in two isoforms: COX 1 and COX 2 (reviewed by Smith and DeWitt4). The genes for
the two forms are on separate chromosomes, the two forms are present in various amounts in
different organs, and they serve distinct, although occasionally redundant, biologic
functions.
Platelets contain only COX 1, but many other
tissues express COX 1 in their resting state. In contrast, although specific areas of the
brain and kidney manufacture COX 2 in their resting states, COX 2 is more frequently
expressed in several tissues as part of an activation response to cytokines, growth
factors, or local injury. Glucocorticoids inhibit mRNA synthesis of COX 2 but not COX 1.
Nonselective NSAIDs inhibit the enzyme activity of both isoforms.
These observations led to the "COX
hypothesis," ie, the notions that:
• COX 1 products are responsible for normal
homeostasis ("housekeeping" functions), while COX 2 products are responsible for
modulating dynamic processes such as inflammation;
• Inhibition of COX 1 is primarily
responsible for the organ-specific toxicity of nonselective NSAIDs, and in particular that
gastric injury is solely related to inhibition of COX 1-generated prostaglandin E, since
COX 1 is the predominant form of COX in healthy gastric mucosa, and exogenous
prostaglandin E is capable of protecting against NSAID-induced gastric injury; and
• NSAIDs that selectively inhibit COX 2
would provide effective and safe anti-inflammatory therapy.
Why the COX hypothesis
is oversimplistic
In the intervening years, as more research was
performed in animals and as COX 2-selective NSAIDs were developed, it was recognized that
the initial COX hypothesis was an oversimplification. The roles of COX 1 and COX 2 vary
among animal species, but studies in animals nevertheless expand their possible role in
humans. Among the recent findings:
COX 1 inhibition is not the only factor in
NSAID-induced gastropathy.
In the initial COX hypothesis, it was assumed the
COX 1 was required for gastric protection and COX 1 inhibition by NSAIDs caused gastric
pathology. We now know that although COX 1 inhibition plays a significant, perhaps
preeminent, role in causing NSAID-induced gastropathy, it is not the only factor. Two
lines of evidence support this conclusion.
• Clinical trials and post-marketing studies
suggest that some nonselective NSAIDs (nabumetone, etodolac) are less likely to cause
gastropathy than other nonselective NSAIDs. Gastrointestinal safety is thus likely also
related to drug properties such as potency, enterohepatic circulation, penetration through
cytoprotective barriers, and the concentration of the drug in the gastric mucosa.
• "Knockout" mice that lack the
gene for COX 1 (and therefore do not express COX 1 at all) do not develop spontaneous
gastropathy, but still develop gastric ulcers when given the nonselective NSAID
indomethacin.5
COX 1 may play a role in inflammation and
analgesia
In some animal models of inflammation, COX 1
mediates some of the inflammation.6 The human counterparts to these studies,
however, have not been identified.
COX 2 plays more roles than once thought.
COX 2 serves a greater biologic role than simply
mediating pain and inflammation, as demonstrated in animals that lack the COX 2 gene and
also with the use of COX 2-selective inhibitors in animals. In particular, COX 2 plays a
role in:
• Gastric mucosal healing in
chemical-induced injury7 and in colitis.8 (There are no published
data on surgical wound healing.)
• Bone remodeling (possibly)9
• Gastric adaptive cytoprotection10
• Modulating renal function in some animals
(although this role is not fully defined in humans).
COX 2 may also promote cellular proliferation.
Selective COX 2 inhibitors (like some nonselective NSAIDs) decrease colonic polyposis and
the development of colon adenocarcinoma in animals,11 and I expect they will
have a similar effect in humans, since many nonselective NSAIDs decrease the frequency of
colon cancer in humans.
COX 2-selective NSAIDs maynot be totally without
adverse effects
Clinical trials have demonstrated that COX
1-sparing NSAIDs are less injurious to the gastric mucosa than are nonselective NSAIDs,12
but we should not assume that they are totally without adverse effects, especially in the
presence of coincident gastric injury.
On the other hand, it seems unlikely that COX
2-selective NSAIDs will cause more side effects than nonselective NSAIDs, except perhaps
in situations in which the balance between COX 1 and COX 2 is of paramount importance in
maintaining homeostasis. Such situations have yet to be clinically identified, but in
theory include thrombosis at the site of atherosclerotic or injured endothelium, where
selective COX 2 inhibitors decrease prostacyclin generation, leaving prothrombotic
platelet-derived thromboxane untouched.13 Preliminary unpublished data from
clinical trials of two selective COX 2 inhibitors suggest that there is no dramatically
increased rate of thrombosis.
The animal studies noted above illustrate the
need for long-term clinical studies in high-risk patients to demonstrate the improved
safety of these drugs.
Clinical effects of
COX 2-Selective NSAIDs
What do we know about use of COX 2-selective
NSAIDs in humans—and what do we not know?
Efficacy in chronic pain
Clinical trials have demonstrated that COX
2-selective NSAIDs relieve the discomfort of osteoarthritis of the knee and hip as
effectively as nonselective NSAIDs such as diclofenac, ibuprofen, and naproxen given in
anti-inflammatory doses. Comparable efficacy has also been demonstrated in patients with
rheumatoid arthritis, although published studies with celecoxib were relatively short,
lasting months, not years.12
Of note: most of these studies only included
patients who had clearly responded previously to other NSAIDs. In the general population
the response rate can be expected to be lower, but not necessarily lower than with other
NSAIDs.
Moreover, for the provision of analgesia,
inhibition of COX 2 in the spinal cord may be even more important than inhibiting it at
the site of inflammation.14 Thus, the ability to penetrate into the CNS may
influence the efficacy of individual drugs.
Will they relieve acute pain and gout?
We have less evidence that COX 2-selective
inhibitors are effective in relieving acute pain not due to "flares" subsequent
to withdrawal of NSAID therapy. In unpublished studies, these drugs demonstrated some
analgesic effect in relieving the acute pain of molar extraction. The degree of analgesia
achieved with celecoxib was greater than with placebo, but perhaps slightly less than with
nonselective NSAIDs such as naproxen or ibuprofen at early time points. Rofecoxib is more
effective than placebo, and equally efficacious as nonselective NSAIDs in the relief of
pain following molar extraction.15 Additional studies are also underway with
celecoxib. The time of onset and degree of analgesia in specific situations need to be
closely studied before these medications are broadly used for acute analgesia.
There are no data addressing the utility of COX
2-selective NSAIDs for treating acute crystal-induced arthritis, ie, gout. While I expect
that they should be effective, their potency and time to onset of effect will be critical
issues. Individual agents will need to be evaluated, rather than assuming they all have
clinical utility in this setting. These drugs may offer an advantage for chronic
maintenance therapy in older patients with chronic gout who cannot tolerate colchicine, or
who achieve a less than optimal benefit from this drug but have a high risk for
complications with nonselective NSAIDs.
COX 2-selective NSAIDs
cause less gastropathy
than other NSAIDs
Clinical trials demonstrated that the COX
2-selective NSAIDs celecoxib and rofecoxib cause far fewer acute gastric erosions seen on
upper endoscopy than did several nonselective NSAIDs.13 More important, in
trials lasting 3 months that were presented to the FDA, the occurrence of clinically
significant perforations, gastric obstructions, and upper GI hemorrhages was significantly
less with celecoxib than with the nonselective NSAIDs diclofenac, ibuprofen, or naproxen,
close to the rate seen with placebo.
Longer evaluation with general use is needed to
determine whether the delayed mucosal healing caused by COX 2-selective inhibition seen in
animals has any clinical relevance. We should not assume that COX 2-selective NSAIDs will
be totally devoid of toxicity in patients with prior GI mucosal problems such as Helicobacter
pylori infection. Clinical studies are underway to address this issue.
Are they safe in perioperative patients?
COX 2-selective NSAIDs do not affect platelet
aggregation or bleeding time. However, these are surrogate markers—the real issue is
clinically significant bleeding episodes.
Bleeding time and platelet aggregation studies do
not provide sufficient information to predict postoperative bleeding complications,16 and
no clinical trials to date have indicated that COX 2-selective NSAIDs have any advantage
over nonselective NSAIDs in terms of perioperative bleeding complications. (Some studies
have failed to demonstrate that aspirin or nonselective NSAIDs adversely affect
perioperative bleeding, although preoperative administration of the nonselective NSAID
ketorolac has recently been shown to increase bleeding in children undergoing
tonsillectomy.17)
COX 2-selective NSAIDs given before anesthesia
conceivably may improve postoperative pain control without increasing bleeding, but this
will need to be formally studied to see if they do so safely and as effectively as
narcotics or other nonnarcotic analgesics. If an NSAID is required in the perioperative
setting, a COX 1-sparing NSAID would seem to be the reasonable choice.
Are they safe in patients receiving warfarin?
Celecoxib does not interfere with the INR in
patients receiving long-term warfarin therapy. (Neither do the nonselective NSAIDs
oxaprozin and nabumetone.) However, if the new COX 2-selective NSAIDs even slightly
increase the risk of gastric injury or decrease healing of coexistent mucosal ulcerations,
their co-administration with warfarin could still in theory increase the risk of
clinically significant gastrointestinal bleeding. Celecoxib should still be safer in this
setting than nonselective NSAIDs.
Other questions and concerns
Do they affect renal function? Steady-state and
inducible expression of COX 2 in the kidney has been demonstrated in some animal studies,
although renal COX 2 expression is very species-dependent. A preliminary study of
celecoxib in humans demonstrated only slight adverse physiological effects on renal
function in salt-depleted patients.18 Whether the COX 2-selective drugs will
cause decreased renal function in patients with renal insufficiency or flow-related type 4
renal tubular acidosis remains to be seen. There is no reason to expect any increased
renal complications from these drugs compared with non-selective NSAIDs. Differences in
the propensity of different NSAIDs to cause renal insufficiency may be due to differential
access or penetration into renal cells.
Do they induce bronchospasm? Non-selective NSAIDs
can induce bronchospasm, particularly in patients with asthma or rhinitis made worse by
aspirin. There have been no published data on the relative risk of this occurring in
patients given COX 2-selective inhibitors. However, there is no a priori reason to believe
that these drugs cannot elicit such an adverse response, and they should be avoided in
patients with the triad of aspirin sensitivity, nasal polyposis, and asthma until their
safety is assessed.
Other concerns. The controversial possibility
that cartilage damage in patients with osteoarthritis may be accelerated by certain NSAIDs
has not been fully explored with COX 2-selective drugs.
Some elderly patients suffer confusion from even
low doses of propoxyphene, tramadol, and some NSAIDs (eg, indo-methacin). Since COX 2 is
present in the brain and brain blood vessel walls, this may be a similar problem, though
uncommon, with selective drugs.
The new COX 2-selective NSAIDs still seem to be
variably associated with some of the nuisance side effects exhibited by currently
available NSAIDs such as dyspepsia and diarrhea, but not to a major degree in clinical
trials. The significance of these nuisance symptoms will need to be evaluated in
post-marketing surveillance studies. Whether there will be any significant differences
between the COX 2-selective NSAIDs remains to be determined.
Recommendations
The first decision facing the physician when
deciding whether to use one of the newer NSAIDs remains whether any NSAID is the most
appropriate therapy.
If analgesia is the goal, first consider using
acetaminophen or a mild narcotic analgesic, for reasons of cost, safety, and extensive
clinical experience using these drugs. When treating inflammation, the specific disease
needs to be evaluated and the requirement for anti-inflammatory therapy should be
individually assessed. For example, in patients with chronic inflammatory diseases such as
rheumatoid arthritis, consider the benefits of using disease-modifying drugs. NSAIDs,
which provide partial symptom relief, should not be used instead of appropriately dosed
disease-modifying agents, appropriate exercise, and orthotics.
Does the patient need a selective NSAID?
In prescribing a COX 2-selective NSAID instead of
a nonselective NSAID (with or without a gastric protective drug such as a proton pump
inhibitor or misoprostol), the clinician should consider efficacy and cost of the NSAID,
and the possibility of additional side effects and cost of the protective drug (eg,
diarrhea from misoprostol).
In a patient with a high risk for gastropathy,
COX 2-selective NSAIDs will provide useful alternatives to combination therapy with a
gastric protective drug and a nonselective NSAID. However, in a patient at very low risk,
it is difficult to justify using a more expensive drug with equivalent efficacy,
especially for short-term use.
The COX-1-sparing drugs have an obvious advantage
over the nonselective NSAIDs in patients with mild or moderate thrombocytopenia who
require NSAID therapy, but this benefit will be lost if these patients require low-dose
aspirin therapy for vascular protection. Similar platelet-sparing effects can be obtained
with less-expensive, nonacetylated salicylates. The COX 1-sparing NSAIDs will likely offer
no cardiovascular protective activity and cannot replace low-dose aspirin.
The monthly cost to the patient is approximately
the same or less with celecoxib than with a generic NSAID plus a proton pump inhibitor,
slightly greater than with a generic NSAID plus twice-daily doses of misoprostol, and much
more expensive than using a generic NSAID alone. Thus, using a COX 2-selective drug alone
is a reasonable financial choice in those high-risk GI patients who require
coadministration of a proton pump inhibitor with a nonselective NSAID in order to limit
the symptomatic side effects of the NSAID.
Comprehensive reading and
reference list.
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ADDRESS: Brian F. Mandell, MD, PhD, Department of
Rheumatic and Immunologic Diseases, A50, The Cleveland Clinic Foundation, 9500 Euclid
Avenue, Cleveland, OH 44195.
John D. Clough, M.D., editor-in-chief
Linda K. Hengstler, editor and publisher
Phillip E. Canuto, executive editor
Ray Borazanian, managing editor |
