+++
Mechanism-Based
Adverse Effects
+++
Risk for Anaphylaxis
and Pulmonary Effects
++
Many adverse
reactions attributed to NSAIDs are due to inhibition of prostaglandin
synthesis in local tissues (Table 61-2). For example, patients with
allergic rhinitis, nasal polyposis, and/or a history of
asthma, in whom all NSAIDs effectively inhibit prostaglandin synthase,
are at increased risk for anaphylaxis. In high doses, even nonacetylated
salicylates may sufficiently decrease enough prostaglandin synthesis
to induce an anaphylactic reaction in sensitive patients.43 Although
the exact mechanism for this effect remains unclear, it is known
that E prostaglandins serve as bronchodilators. When COX activity
is inhibited in patients at risk, a decrease in synthesis of prostaglandins
that contribute to bronchodilation results. Another explanation
implicates other enzymatic pathways that utilize the arachidonate
pool after it is converted from phospholipase, whereby shunting
of arachidonate into the leukotrienne pathway occurs when cyclooxygenase
is inhibited.44 The leukotriene pathway converts
arachidonate by 5-lipoxygenase, leading to products such as LTB4 as
well as others clearly associated with anaphylaxis. This explanation
implies that large stores of arachidonate released in certain inflammatory
situations lead to excess substrate for leukotriene metabolism.
This results in release of products that are highly reactive, leading
to increased bronchoconstriction and the risk for anaphylaxis in
the right patient. Whether the main mechanism of effect is inhibition
of prostaglandin synthesis or shunting of arachidonate into conversion
by 5-lipoxygenase or a combination of the two, it is clear that
patients who are sensitive are at great risk when NSAIDs are used.
The nonacetylated salicylates as a group have been considered a
safe choice for these patients because they are known to possess
anti-inflammatory activity, but are relatively weak cyclooxygenase
inhibitors.
++
++
Platelet aggregation and thus the ability to clot is primarily
induced through stimulating thromboxane production with activation
of platelet COX-1. There is no COX-2 in the platelet. NSAIDs and
aspirin inhibit the activity of COX-1 but the COX-2 specific inhibitors
(or COX-1 sparing drugs) have no effect on COX-1 at clinically effective
therapeutic doses.19,20
++
The effect of the nonsalicylate NSAIDs on platelet function is
reversible and related to the half-life of the drug; whereas the
effect of ASA is to acetylate the COX-1 enzyme, thereby permanently
inactivating it. Since platelets cannot synthesize new cyclooxygenase
enzyme after exposure to ASA, the platelet does not function appropriately
for its lifespan. Therefore, the effect of ASA on the platelet does
not wear off as the drug is metabolized as with the nonsalicylate NSAIDs.
Patients awaiting surgery should therefore stop their NSAIDs at
a time determined by 4 to 5 times their serum half-life; whereas
ASA needs to be discontinued 1 to 2 weeks before the planned procedure
to allow for re-population of platelets that have been unexposed
to ASA.
++
We also have little information about the use of the COX-2 specific
inhibitors in patients at risk for thrombosis.19 The
randomized clinical trials of the COX-2 specific inhibitors were
not designed to address this question. Furthermore, we have little
information demonstrating that the traditional NSAIDs are safer
or more useful than the COX-2 specific inhibitors in this regard. Only
aspirin has been studied prospectively, and low-dose aspirin (<325
mg/day) should be given concomitantly with either NSAIDs
or specific COX-2 inhibitors in patients at risk for thrombosis.45 Secondary
prophylaxis of cardiovascular events with aspirin has been shown
to be important. There is about a 23% to 33% decrease
in atherothrombotic events in patients with a history of ischemic
heart disease when they are treated with <325-mg
aspirin/day.45 There are less data about
the effectiveness of low-dose aspirin in primary prophylaxis. There
is little evidence that the non-aspirin NSAIDs have a role in primary
or secondary prophylaxis of cardiovascular or cerebrovascular events.
Given the additive ulcerogenic potential associated with the use
of multiple NSAIDs, it would be advisable to use specific COX-2
inhibitors with aspirin when considering combination cardioprotective
and anti-inflammatory therapies. In the two large bleeding trials describing
the effects of celecoxib and rofecoxib, there was a statistically
significant difference between the incidence of acute myocardial
infarctions (MIs) with rofecoxib (0.4%) and naproxen (0.1%),
whereas there was no difference in the incidence of acute MIs with
celecoxib as compared with diclofenac or ibuprofen.46,47 It
is impossible to know whether these data suggest that rofecoxib
induced more MIs than naproxen or whether naproxen exerted a protective
effect. The study was too short with relatively too few patients
to answer this question.
+++
Gastrointestinal
Tract
++
The most clinically significant adverse effects associated with
NSAIDs occur in the GI tract, affecting the GI mucosa.48–57 These
events appear to be due to local or systemic inhibition of prostaglandin
synthesis. NSAIDs cause a wide range of GI problems including symptoms
of intolerance such as dyspepsia, nausea, vomiting, as well as esophagitis,
esophageal stricture, gastritis, mucosal erosions, hemorrhage, peptic
ulceration and/or perforation, obstruction, and death.27,48,49,58–62 The
unpleasant symptoms may be observed in about 40% to 60% of
patients but are not related to COX-1 inhibition in the GI mucosa.27,28 The
exact cause of these symptoms remains unknown; however, use of H2-receptor
antagonists and proton pump inhibitors typically alleviates these
unpleasant effects. Erosions and ulcers as well as ulcer complications
are predominantly due to the effects of NSAID-induced inhibition
of COX-1, thus those prostaglandins that serve to protect the stomach mucosa
from toxins. This protection consists of a mucous layer serving
as a barrier, a bicarbonate gradient serving to buffer the mucosa
layer from the effects of the extremely acidic lumen, developing
glutathione to serve as a scavenger of superoxides, prostaglandin-mediated
inhibition of gastric acid, and prostaglandin-mediated increases
in mucosal blood flow. All of these effects are inhibited by the
NSAIDs, which inhibit COX-1 activity. However, in an experiment
with mice both COX-1 and COX-2 have to be inhibited in order for
mice to have an ulcer. The exact effect of inhibiting COX-2 in this
experiment is unknown, but some investigators have speculated that COX-2
plays an important role in healing of mucosal lesions.63,64
++
The mucosa of the large and small bowel may also be affected
by NSAIDs. These agents in the small or large bowel may also induce
stricture formation,13,27,52–54,61–63 which
may manifest as diaphragms precipitating small or large bowel obstruction,
and can be hard to detect on contrast radiographic studies.
++
Additionally, there is evidence to suggest that NSAIDs interfere
with permeability of the GI mucosa. The weakly acidic NSAIDs rapidly
penetrate the superficial lining cells of the GI mucosa leading
to oxidative uncoupling of cellular metabolism, local tissue injury,
and ultimately cell death. This can result in local erosions, hemorrhages,
and formation of clinically significant ulcers in the right patients.13
++
Endoscopic studies have clearly demonstrated that NSAID administration
results in shallow erosions and/or submucosal hemorrhages
that are observed in the stomach near the prepyloric area and the
antrum, although they may occur at any site in the GI tract.27 Typically,
these lesions are asymptomatic, making prevalence data difficult
to determine.58 As a result, we do not know the number
of lesions that spontaneously heal or which will progress to ulceration,
frank perforation, gastric or duodenal obstruction, serious gastrointestinal
hemorrhage, or subsequent death. Risk factors for the development
of GI toxicity in patients receiving NSAIDs include age >60 years, prior
history of peptic ulcer disease, prior use of antiulcer therapies
for any reason, concomitant use of glucocorticoids, particularly
in patients with rheumatoid arthritis, comorbidities such as significant
cardiovascular disease, or patients with severe rheumatoid arthritis
(Table 61-3).25,27,48,49,64,65 Other risk factors
include increasing dose of specific and singular NSAIDs.
++
++
The magnitude of risk for GI adverse events is controversial.
The US Food and Drug Administration (FDA) reports an overall risk
of 2% to 4% for NSAID-induced gastric ulcer development
and its complications.25,27,28 In general, based
on multiple clinical trials, the relative risk is estimated to be
4.0 to 5.0 for gastric ulcer, 1.1 to 1.6 for duodenal ulcer, and
4.5 to 5.0 for clinically significant gastric ulcers with hemorrhage,
perforation, obstruction, or death. The accurate absolute risk is
harder to determine.
++
As noted, other sites in the GI tract, including the esophagus
and small and large bowel, may also be affected. Exposure to NSAIDs
is probably a major factor in the development of esophagitis and
subsequent stricture formation.58,59 Effects on
small and large bowel have increasingly been reported.27,53 An
autopsy study on 713 patients showed that small bowel ulceration
defined as ulcers >3 mm in diameter were observed
in 8.4% of patients exposed to NSAIDs compared with 0.6% of
nonusers of NSAIDs.61 Ulcerations of stomach and
duodenum were observed in 22% of NSAID users compared with 12% of
nonusers.
++
Before the COX-2 selective inhibitors became available, the epidemiologic
studies suggested that the nonacetylated salicylates are least likely
to result in a NSAID-induced adverse GI event. Agents such as nebumatone
are usually considered to be less likely to induce effects.56,57 However,
as higher doses of “safe” NSAIDs are used, then
more GI damage is reported.57 Thus at equally efficacious
doses the non-selective NSAIDs all induce ulcers at variable rates,
and any of these ulcers in the right patient could develop a complicated
course. NSAIDs with prominent enterohepatic circulation and significantly
longer half-lives such as sulindac and piroxicam have been linked
to increased potential for GI toxicity attributed to prolonged re-exposure
of gastric and duodenal mucosa to bile reflux and the active moiety
of the drug.27
++
Endoscopic data from large numbers of patients treated with COX-2
selective inhibitors strongly suggest that ulcers occur at the same
rate as in patients who received placebo; whereas the traditional
NSAID active comparators induced ulcers (as documented by endoscopy)
in 15% (diclofenac 75 mg twice daily, ibuprofen 800 mg
three times daily) to 19% (naproxen 500 mg twice daily)
following 1 week of treatment in healthy volunteers and in 26% (naproxen
500 mg twice daily) of patients with OA and RA after 12 weeks of
treatment.5–8 Two large outcome trials
with rofecoxib and celecoxib have now been published and have shown
that rofecoxib and celecoxib both at suprapharmacologic doses (two
to four times the treating doses) are associated with about two-
to three-fold fewer GI complications than naproxen or ibuprofen,
respectively, at standard therapeutic doses.46,47 These
data clearly show that compared with the effects of two widely used
NSAIDs (ibuprofen 1.2%, naproxen 1.6%), that the
COX-2 inhibitors induce bleeding complications at a lower rate (celecoxib
0.4%, rofecoxib 0.6%).46,47 It
is possible that patients with preexisting ulcer may experience
delay in healing when treated with a COX-2 specific inhibitor, but
only long-term outcome clinical trials will clarify if this is a
risk.63
+++
Approach to
the Patient at Risk for NSAID-Induced GI Adverse Events
++
The approach to the patient with pain and or inflammation who
is about to embark on the use of a NSAID is partly related to dose,
consistency, and planned length of therapy. For most patients who
will take standard doses of nonselective NSAIDs for less than 10
days, there is little risk unless they have multiple significant
risk factors noted previously. However, for the patient with OA
or other chronic condition at risk for an NSAID-induced GI event,
the decision remains somewhat controversial. Many patients with
dyspepsia or upper GI distress have superficial erosions evident
on endoscopy that frequently heal spontaneously without change in
therapy. Even more difficult to evaluate is whether cytoprotective
agents actually alter NSAID-associated symptoms, which may or may
not predict significant GI events. Although one clinical study demonstrated that >80% of
patients who developed significant NSAID-induced endoscopic abnormalities
were asymptomatic,58 several prospective observational
trials indicated that patients were more symptomatic with NSAID-induced
toxicities than previously thought.55
++
The patient who develops a gastric or duodenal ulcer while taking
NSAIDs should have treatment discontinued and therapy for ulcer
disease, either H2-antagonist or proton pump inhibitors,
instituted.27–29 If NSAIDs must be continued
concomitantly, then the patient will be required to receive antiulcer
therapy for longer periods.28 Typically, most patients
with uncomplicated gastric or duodenal ulcers will heal within 8
weeks of initiating H2-antagonists. If NSAID treatment
is continued, then perhaps 16 weeks of therapy may be necessary
for adequate healing. Diagnostic tests to determine if the patient
is Helicobacter pylori positive should be performed, and if the
patient has positive studies, then specific antibiotic therapy to eradicate
the infection should be administered.28
++
Prophylaxis to prevent NSAID-induced gastric and duodenal ulcers
is more complicated. To date there has been no evidence that agents
other than concomitant misoprostol therapy will prevent NSAID-induced
gastric ulceration and its complications.66–69 Although
high-dose H2-antagonists or proton pump inhibitors have
been demonstrated to prevent NSAID-induced gastric and duodenal
ulcers, prevention of ulceration complications has not been clearly
shown. Endoscopic trials have shown that famotidine at twice the
approved dose (40 mg twice daily) significantly decreased the incidence
of both gastric and duodenal ulcers.69 Similarly,
an endoscopy trial demonstrated that treatment with omeprazole (a
proton pump inhibitor) decreased gastroduodenal ulcers.68 Both
H2-antagonists and proton pump inhibitors decrease dyspeptic
symptoms quite effectively.
++
Misoprostol is a prostaglandin analogue, believed to locally
replace prostaglandins whose synthesis in the gastroduodenal mucosa
is inhibited by the nonselective NSAIDs.64–66 A
large prospective trial evaluated 8,843 patients with rheumatoid
arthritis to determine whether misoprostol would decrease the incidence
of ulcers and their complications.64,65 Patients
received various NSAIDs and were followed for 6 months either on
misoprostol co-therapy or placebo. The study was powered on the
basis of endoscopic observations of an 80% decrease with
concomitant misoprostol therapy in endoscopically proven ulcers >0.3
to 0.5 cm in diameter in the gastric and duodenal mucosa.66 Misoprostol
successfully inhibited development of ulcer complications such as
bleeding, perforation, and obstruction. There was a 40% reduction
in patients treated with misoprostol as opposed to those receiving
placebo.64 Further analysis demonstrated that patients with
health assessment questionnaire (HAQ) scores >1.5
(thus worse disease) had an 87% reduction in risk for a
NSAID-induced toxic event if concomitantly treated with misoprostol.65
++
These data suggest that high-risk patients may benefit from concomitant
misoprostol therapy if NSAID treatment is indicated. Gabriel and
colleagues have demonstrated the pharmacoeconomic utility of such
therapy in the high-risk patient.70 Unfortunately,
the major adverse event causing withdrawal in approximately 10% of
patients was diarrhea, and 30% of patients complained of diarrhea.
Therefore medications such as stool softeners and cathartics should
be stopped. There are data suggesting that concomitant treatment
with misoprostol once an ulcer develops will allow the ulcer to
heal.68
+++
Renal Adverse
Effects
++
The NSAIDs also have effects on the kidneys. The effects of the
NSAIDs on renal function include changes in the excretion of sodium,
changes in tubular function, the potential for interstitial nephritis,
and reversible renal failure due to alterations in filtration rate
and renal plasma flow.71,72 Prostaglandins and
prostacyclins are important for maintenance of intrarenal blood
flow and tubular transport. All NSAIDs, except nonacetylated salicylates,
have the potential to induce reversible impairment of glomerular
filtration rate; this effect occurs more frequently in patients with
congestive heart failure; established renal disease with altered
intrarenal plasma flow including diabetes, hypertension, or atherosclerosis;
and with induced hypovolemia, salt depletion or significant hypoalbuminemia.19,71,72 Triamterene-containing
diuretics, which increase plasma renin levels, may predispose patients prescribed
NSAIDs to acute renal failure. NSAIDs have been implicated in the
development of acute and chronic renal insufficiency, due to inhibition
of vasodilating prostaglandins, thereby reducing renal blood flow.
++
NSAID-associated intersitial nephritis is typically manifested
as nephrotic syndrome, characterized by edema or anasarca, proteinuria,
hematuria, and pyuria. The usual stigmata of drug-induced allergic
nephritis such as eosinophilia, eosinophiluria, and fever may not
be present. Interstitial infiltrates of mononuclear cells are seen
histologically with relative sparing of the glomeruli. Phenylproprionic
acid derivatives, such as fenoprofen, naproxen, and tolmetin along with
the indoleacetic acid derivative indomethacin, are most commonly
associated with the development of interstitial nephritis.
++
Inhibition of prostaglandin synthesis intrarenally by NSAIDs
decreases renin release and thus produces a state of hyporeninemic
hypoaldosteronism with resulting hyperkalemia.71 This
effect may be amplified in patients taking potassium-sparing diuretics.
Salt retention precipitated by some NSAIDs leading to peripheral
edema in some patients is likely due to both inhibition of intrarenal
prostaglandin production, which decreases renal medullary blood
flow and increases tubular reabsorption of sodium chloride as well
as other direct tubular effects. NSAIDs have also been reported
to increase antidiuretic hormone effects, thereby reducing excretion
of free water, resulting in hyponatremia.71 Thiazide
diuretics may produce an added effect on the NSAID-induced hyponatremia.
All NSAIDs have been demonstrated to interfere with medical management
of hypertension and heart failure.
++
All NSAIDs, including the COX-2 inhibitors with the exception
of the nonacetylated salicylates, have been associated with increases
in mean blood pressure in hypertensive patients but not in patients
with normal blood pressure.74 Patients receiving
antihypertensive agents including beta blockers, ACE inhibitors,
thiazide, and loop diuretics must be checked regularly when initiating
therapy with a new NSAID to ensure that there are no significant
continued and sustained rises in blood pressure.
++
The mechanism of acute renal failure induced in the at-risk patient
treated with NSAIDs is believed to be prostaglandin mediated.71–73 However,
the role of COX-2 in maintenance of renal homeostasis in the human
remains unclear. COX-2 activity is notably present in the macula densa
and tubules in animals and man, and is upregulated in salt-depleted
animals.75 In humans, COX-1 is an important enzyme
for control of intrarenal blood flow. It is believed that COX-2
activity importantly modulates salt and water homeostasis, whereas
COX-1 activity seems important in modulating renal plasma flow.
In the patient who has decreased renal plasma flow, both COX-1 and
COX-2 are upregulated and therefore there is not sufficient evidence
to indicate that the COX-2 specific inhibitors will be safer than
traditional NSAIDs in terms of renal function. Until the appropriate
clinical trials are done, any patient at high risk for renal complications
should be monitored very carefully. No patient with a creatinine
clearance of <30 mL/minute should be treated with either
a NSAID or a COX-2 specific inhibitor.
+++
Nonmechanism-Based
Adverse Events
++
Elevations in
hepatic transaminase levels induced by NSAIDs are not uncommon,
although it occurs more often in patients with juvenile rheumatoid
arthritis or systemic lupus erythematosus. Unless elevations exceed
two to three times the upper limit of normal, or serum albumin falls, or prothrombin
times are altered, these effects are usually not considered clinically
significant.76–78 Nonetheless, overt liver
failure has been reported following use of many NSAIDs, Including diclofenac,
flurbiprofen, and sulindac.77,78 Of all NSAIDs,
sulindac has been associated with the highest incidence of cholestasis.76 Therefore
it is recommended that patients at risk for liver toxicity be followed
very carefully. When initiating NSAID treatment, all patients should
be evaluated again within 8 to 12 weeks and serious consideration
given to performing a blood analysis for serum transaminase changes.
+++
Idiosyncratic
Adverse Effects
++
Many of the toxic effects of NSAIDs are related to their mechanism
of action via prostaglandin inhibition, but there are also important
potential idiosyncratic effects. A typical nonspecific reaction
includes skin rash and photosensitivity, which is associated with
all currently available NSAIDs, particularly the phenylproprionic
acid derivatives.79 This same class of NSAID derivative
may also induce aseptic meningitis, especially in patients with
systemic lupus erythematosus. The underlying mechanism of action
remains unknown. Ibuprofen has also been associated with a reversible
toxic amblyopia.79
++
Owing to the antiplatelet effects of all NSAIDs, except the nonacetylated
salicylates, concomitant therapy with warfarin (Coumadin) puts patients
at greater risk for bleeding. As concomitant NSAID therapy would
displace warfarin from its albumin binding sites, the prothrombin
time may be prolonged. In addition, given the increased relative
risk for NSAID-induced gastroduodenal ulcers and bleeding, there
is an increased risk for bleeding when the NSAIDs are used concomitantly
with warfarin. In that the COX-2 specific inhibitors do not cause
ulcers of the GI tract, nor do they alter platelet function, the
patient on warfarin would have less risk for a significant GI bleed
when treated with these drugs than traditional nonselective NSAIDs.
Effects such as these may also be seen with dilantin or other highly
protein-bound drugs such as antibiotics.
++
The NSAIDs inhibit the renal excretion of lithium and should
be used with caution in patients taking this drug. Cholysteramine,
an anion-exchange resin, reduces the rate of NSAID absorption and
its bioavailability.
++
The CNS side effects of NSAIDs include aseptic meningitis, psychosis,
and cognitive dysfunction.1,41,42 The latter changes
are more commonly seen in elderly patients treated with indomethacin, whereas
the phenylproprionic acid derivatives are more commonly associated
with the development of aseptic meningitis and toxic amblyobia.
Tinnitus is a common problem with higher doses of salicylates as
well as the nonsalicylate NSAIDs. The mechanism is unknown. Interestingly,
the young and the elderly may not complain of tinnitus but only
of hearing loss. Other NSAIDs may also induce tinnitus in specific
patients. Decreasing the dose usually alleviates the effect.
++
It has been shown that COX-2 is important for ovulation through
the PPRA l receptor.19 In addition, COX-2 is upregulated
with implantation of a fertilized ovum or in decidualization. Although there
are a few case reports of reversible infertility associated with
the use of NSAIDs, given the large numbers of patients who regularly
use NSAIDs there does not appear to be a generalized epidemic of
infertility.80
++
Use of NSAIDs does not lead to osteoporosis.81–82 The
role of COX-1 remains unclear. Although inflammation in the joint
leads to juxtaarticular osteopenia, this is the result of increased
prostaglandin synthesis in the inflamed joint, which is likely directly
related to increased COX-2 activity.
++
Some of the early available NSAIDs have been associated with
an increased risk for bone marrow failure. This is particularly
true of phenylbutazone and indomethacin. Strom and colleagues have described
the incidence of neutropenia as a toxic effect of the NSAIDs.83 In
a case-controlled study performed using Medicaid claims data, these
investigators defined that the adjusted odds ratio for neutropenia
in patients treated with NSAIDs is 4.2 (confidence interval (CI),
2.0–8.7). When patients treated with either phenylbutazone
or indomethacin were excluded, the odds ratio for the development
of neutropenia remained quite robust: 3.5 (CI 1.6–7.6).
In general, given the common use of NSAIDs, the risk of neutropenia
is quite small.
++
There are little data documenting the effects of the NSAIDs on
pregnancy or the fetus. In animal models, the NSAIDs have been shown
to increase the incidence of dystocia, post-implantation loss, as
well as delay of parturition and miscarriage.80 The
effect of prostaglandin inhibition may result in premature closure
of the ductus arteriosus. ASA has been associated with smaller babies
and neonatal bruising; however, it has been used for many years
in the treatment of patients who require NSAIDs while pregnant.
Typically, therapy with ASA is stopped about 8 weeks prior to delivery
to decrease the risk for interfering with ductus closure. In animals,
there is no evidence that ASA is a teratogen. The NSAIDs are excreted
in breast milk. It is believed that salicylates in normally recommended
doses are not considered dangerous to nursing infants.