NSAID of choice for treatment of RA.
13,93 There is no significant difference among
the NSAIDs in efficacy, and it is difficult to predict a given patient’s response to a
particular agent. The selection of an NSAID is based primarily on patient preference,
convenience, cost, and safety.
39,40 A 1- to 2-week trial of any NSAID (Table 44-5) at
a moderate-to-high dose on a scheduled basis (i.e., not as needed) is the best method
of determining anti-inflammatory efficacy. The analgesic and antipyretic effects are
Although aspirin at high doses is just as effective as other NSAIDs, it is seldom
used today because of well-documented gastrointestinal (GI) toxicity and the
availability of other safer and more convenient NSAIDs.
levels correlate well with both efficacy and toxicity.
93 Anti-inflammatory effects of
aspirin can be achieved with dosages sufficient to provide serum salicylate
concentrations of 15 to 30 mg/dL. Typically, 5 to 7 days of therapy are needed before
steady-state serum concentrations of salicylate are attained. A reasonable initial
metabolism. Nonacetylated salicylates are weak inhibitors of COX in vitro and have
less GI toxicity than aspirin, but the risks of GI and renal toxicity are similar to
The nonaspirin NSAIDs have important differentiating properties, and
individualizing selection based on these characteristics is warranted in all patients
93 For example, several NSAIDs increase the risk of MI, with
diclofenac, meloxicam, and indomethacin showing the highest risk of thrombosis,
although celecoxib and ibuprofen at high doses also carry relatively high
cardiovascular risk. Naproxen appears to have the best cardiovascular safety
Longer-acting NSAIDs such as piroxicam and ketorolac have been associated with
a higher frequency of peptic ulcer disease and GI bleeding, and should be avoided.
Other NSAIDs, depending on their COX-2 selectivity, have varying GI toxicity
profiles with naproxen conferring moderate risk and ibuprofen lower risk.
selective COX-2 inhibitor celecoxib, at least with short-term use, is associated with
a 20% lower risk of GI bleeding than traditional NSAIDs.
not interfere with COX-1––the isozyme responsible for production of the stomach’s
mucous lining and for reduced acid secretion––in theory COX-2 inhibitors reduce
inflammation as effectively as nonselective NSAIDs while reducing the risk of GI
toxicity. However, concurrent daily low-dose aspirin use appears to negate any
benefit of COX-2 inhibitor therapy on lowering ulcer risk.
Indomethacin penetrates the blood–brain barrier better than any other NSAID,
achieving levels in the cerebrospinal fluid of up to 50% of serum levels. As a result,
the incidence of central nervous system side effects of indomethacin such as dizziness
often precludes the use of optimal anti-inflammatory doses, particularly in the
A low-cost NSAID (e.g., naproxen and ibuprofen) with a good safety profile is a
good choice for T.W. because she is relatively young and does not have any
concomitant illnesses. If convenience of administration is a more important
consideration, a longer-acting NSAID (e.g., naproxen) would be preferable. If the
first agent chosen is ineffective or not well tolerated, other NSAIDs can be tried to
identify the optimal one for this patient.
CASE 44-1, QUESTION 5: Naproxen 500 mg twice daily has been prescribed for T.W. If T.W. were to
regarding NSAID therapy should be provided to T.W., especially with regard to GI problems?
Patients should be informed that NSAID therapy is being prescribed to provide
relief of pain and inflammation associated with RA, but that it will not slow or stop
the progression of the disease. It should be explained that the latter can only be
to analgesic and antipyretic effects which can be achieved with single and low doses.
About 5% to 15% of patients with RA discontinue NSAID therapy because of
dyspepsia, and about 1.3% of patients taking NSAIDs for RA experience a serious
GI complication. As expected, the rate is somewhat lower for patients using NSAIDs
for osteoarthritis (0.7%) because these patients generally use analgesics only on an
as-needed basis. Serious NSAID-induced GI complications account for about
103,000 hospitalizations annually in the United States and approximately 16,500
NSAID-related deaths each year.
98,102 Although these figures warrant concern, most
an important focus, particularly in high-risk patients.
Patients should be taught to recognize the signs and symptoms of GI bleeding (e.g.,
nausea, vomiting, anorexia and gastric pain) including melena (described to the
patient as “dark, tarry stool”) and emesis of coagulated blood (described to the
patient as “coughing or vomiting up what seems to be coffee grounds”). It should be
emphasized that GI bleeding can occur without gastric pain. The patient should be
instructed to contact their health care provider immediately for further instructions if
any of these signs or symptoms occurs.
Gastroduodenal mucosal damage induced by NSAIDs primarily results from
inhibition of COX-1 in the mucosal lining.
102 This inhibition of COX-1 decreases
bicarbonate secretion, mucosal blood flow, formation of protective mucus,
proliferation of gastric epithelium, and the ability of the mucosa to resist injury.
Topical damage to the GI mucosa can occur from NSAIDs, but direct injury plays a
smaller role than COX-1 inhibition. Table 44-6 provides a comparison of COX-1
Some Nonsteroidal Anti-Inflammatory Drugs
(Brand Name) Product Availability
Salicylates (Acetylated and Nonacetylated)
b Tablets: 325 mg; 325, 500, 800, 975
b Tablets: 500, 750 mg BID–TID 4,800
Tablets: 500, 750, 1,000 mg Daily–TID 4,800
b Capsules: 200, 300 mg TID–QID 3,200
b Tablets: 50, 100 mg BID–QID 300
b Tablets: 200, 400, 600, 800 mg TID–QID 3,200
b Tablets: 250, 375, 500 mg; 375, 500
Naproxen sodium Tablets: 275, 550 mg BID 1,375
b Tablet or capsule: 600 mg Daily 1,800
Tablets: 25, 50, 75 mg DR; 100 mg
Capsules: 200, 300 mg BID–TID 1,200
Tablets: 400, 500 mg; 400, 500, 600
Suspension: 25 mg/5 mL TID–QID 200
Capsules: 25, 50 mg; 75 mg SR SR: Daily–BID SR: 150
b Tablet: 500, 750 mg Daily 2,000
b Tablets: 150, 200 mg BID 400
Capsules: 400 mg TID–QID 1,800
b Tablets: 7.5, 15 mg Daily 15
Celecoxib (Celebrex) Capsules: 50, 100, 200, 400 mg BID 400
Source: MedicalLetter.org. Drugs for rheumatoid arthritis. Treat Guidel Med Lett. 2009;7:37.
drug; QID, 4 times a day; SR, sustained release; TID, 3 times a day; XL/XR, extended release.
Dyspepsia can be managed by ingesting the NSAID with meals or a large glass of
water; however, these measures usually are ineffective in preventing GI ulcers. In
addition, dyspepsia correlates poorly with endoscopically confirmed mucosal
) receptor antagonists (e.g., ranitidine, famotidine)
significantly reduce dyspepsia among NSAID users; however, NSAID users with RA
-receptor antagonist as needed might have a higher risk of developing
serious GI complications compared with those who do not take these medications
(odds ratio, 2.14; 95% confidence interval, 1.06–4.32).
dyspepsia symptoms can give a false sense of security to the patient and physician,
leading to higher doses of NSAIDs and increased risk of major gastropathy. Also,
-receptor antagonists is associated with tachyphylaxis.
-receptor antagonists are not recommended for routine use in asymptomatic
patients receiving NSAIDs. Proton-pump inhibitors (PPIs; e.g., lansoprazole,
omeprazole) relieve dyspepsia better than H2
-receptor antagonists and prevent the
development of NSAID-induced gastroduodenal ulcers.
effective for the treatment of NSAID-induced dyspepsia and should be considered if
Comparison of Cyclo-Oxygenase-1 and Cyclo-Oxygenase-2 Isoforms
Primarily continuous, although
Primarily induced, but present continuously
Common organs/tissues Nearly all organs, including
Induced at sites of inflammation and
Continuously active in kidneys, small
intestine, pancreas, brain, ovaries, uterus
Primary role Housekeeping/maintenance Inflammation, repair, neoplasia
housekeeping/maintenance of organs that
Source: Hawkey CJ. COX-2 inhibitors. Lancet. 1999;353:307.
Effective prevention options for reducing the risk of NSAID-induced ulcers and
related complications include a PPI, double the maximal dose of H2
antagonists, and misoprostol. PPIs are the most efficacious and best tolerated
cotherapies with NSAIDs to reduce the risk of peptic ulcers and ulcer complications.
-receptor antagonists have demonstrated a reduction in
NSAID-induced endoscopic peptic ulcers; however, no study has demonstrated that
-receptor antagonists prevent ulcer complications and PPIs remain
significantly more effective. Misoprostol, a prostaglandin E1 analog, is most
effective when given at the full dose of 200 mcg 4 times daily; however, intolerable
GI upset, particularly diarrhea and abdominal cramping, frequently leads to
discontinuation of therapy at this dose. Lower doses are usually prescribed (200 mcg
2 or 3 times daily) with better tolerance but lower efficacy. Sucralfate or antacids
are not effective in preventing NSAID-related GI injury.
Routine concomitant antiulcer prophylactic therapy is not warranted for all
patients taking NSAIDs; rather the risk for GI ulcer development must be assessed to
complicated ulcers, particularly recent, puts patient at high risk), concurrent use of
other ulcer-promoting medications (e.g., corticosteroids, aspirin and anticoagulants),
and high-dose NSAID therapy. Patients can be grouped into high, moderate, or low
risk of NSAID-induced GI toxicity based on these risk factors. High-risk patients (>2
risk factors) should avoid NSAID therapy or take a COX-2 inhibitor instead along
with either a PPI or a misoprostol. Moderate-risk patients (one or two risk factors)
should take a PPI or misoprostol with an NSAID; naproxen is the preferred NSAID
for high–cardiovascular-risk patients. Low-risk patients (no risk factors) do not need
concurrent GI protective therapy and should receive a relatively less GI toxic NSAID
107 Without risk factors other than NSAID use, T.W. does
not need concurrent ulcer prophylaxis or a COX-2 selective NSAID at this time,
although a less toxic agent such as naproxen or ibuprofen should be chosen.
Helicobacter pylori infection increases the risk of peptic ulcers in individuals
107 A meta-analysis demonstrated that H. pylori eradication
significantly reduced the risk of endoscopic ulcers among patients who had not
started NSAID therapy; however, eradication did not lower risk among patients who
were already receiving NSAIDs.
108 Therefore, H. pylori testing, and treatment if
positive, should be considered for all patients prior to starting chronic NSAID
Active NSAID-induced gastroduodenal ulcers are best treated by discontinuing the
NSAID and initiating a PPI. PPIs are preferred over H2
of greater efficacy, rapid healing rates, and a shorter duration of treatment (4–8
If discontinuation of the NSAID is not feasible, ulcer healing can still be
accomplished with a PPI but requires a longer duration of therapy (8–12
109,110 Patients who test positive for H. pylori should undergo H. pylori
eradication therapy. Other GI treatments, such as misoprostol and antacids, are
ineffective for managing active NSAID-induced ulcers.
aspirin allergy. Are other NSAIDs contraindicated for this patient?
C.S. should be asked to describe his reaction to aspirin to determine whether his
symptoms are consistent with a hypersensitivity reaction or with a less serious
intolerance issue. Many patients who claim to be allergic to aspirin merely
experience GI distress. Aspirin is not contraindicated in these patients and tolerance
may be improved if the medication is administered with food or as an enteric-coated
True aspirin hypersensitivity, especially in association with asthma, is a cause for
serious concern because exposure can precipitate an acute, life-threatening,
111 Between 6% and 15% of asthmatics have a history of
aspirin-induced bronchospasm; it occurs more often among women than men and
rarely in children. The prevalence of aspirin-induced asthma increases with the
presence of nasal polyps. Aspirin-sensitive patients can experience a high degree of
cross-reactivity to all nonselective NSAIDs; therefore, these agents should be
avoided especially in patients who have a history of aspirin-induced asthma.
On the other hand, COX-2 inhibitors have been used safely in aspirin-sensitive
In theory, COX-2 inhibitors might be safer because they allow
COX-1 to continue producing prostaglandin E2
mediator of multiple physiologic processes, including reduction of leukotriene
synthesis, suppression of the release of inflammatory mediators from mast cells, and
prevention of aspirin-induced bronchoconstriction.
Aspirin desensitization, which is followed by daily aspirin therapy, is an effective
treatment option for most patients with aspirin-induced asthma.
appear to benefit the most include those who rely heavily on systemic corticosteroids
or with recurrent nasal polyps.
because of “ringing in my ears all the time!” Is this a symptom related to aspirin?
Aspirin-induced tinnitus (i.e., a ringing or high-pitched buzzing sensation in the
head) is noticeable to most patients with normal hearing when aspirin serum levels
reach 10 to 30 mg/dL; however, in some patients tinnitus might not be encountered
until serum levels exceed 25 mg/dL.
93 Serum salicylate concentrations are usually
within therapeutic range when tinnitus is apparent. As a result, tinnitus has been used
to titrate patients on aspirin to therapeutic doses. It is important to note that patients
with preexisting hearing loss might not experience tinnitus despite potentially toxic
Aspirin, nonacetylated salicylates, nonaspirin NSAIDs, and COX-2 inhibitors
have differing effects on platelet function. Nonaspirin NSAIDs can prolong bleeding
times by inhibiting platelet aggregation, but these drugs bind reversibly to COX,
resulting in transient platelet inhibition.
93 As a result, if A.L. is taking a nonaspirin
NSAID, it should be discontinued approximately 5 half-lives before surgical
procedures. For most NSAIDs, the impairment of platelet aggregation is reversed
within 2 days after the discontinuation.
Nonacetylated salicylates have minimal effects on COX and platelet function and
are of little concern in presurgical patients. Likewise, COX-2 inhibitors are not
expected to alter platelet function because COX-2 is not found in platelets.
Aspirin is an irreversible inhibitor of COX and impairs platelet aggregation
throughout the life of the platelet. It can prolong bleeding time for several days,
which may not normalize until new, unbound platelets are released into circulation.
This process may take 3 to 6 days after discontinuation of aspirin; however, this does
not always necessitate holding aspirin prior to every procedure. If A.L. is also taking
low-dose aspirin chronically, whether or not aspirin may be continued prior to
surgery depends on the indication for aspirin and type of surgery. For minor dental
procedures, low-dose aspirin can usually be continued.
What are maternal- and lactation-related effects of these medications?
Although NSAIDs, including aspirin, are not teratogenic, they must be used
cautiously in women who are pregnant and who plan to breast-feed infants.
effects of NSAIDs include possible premature ductus arteriosus closure, increased
cutaneous and intracranial bleeding, transient renal impairment, and a reduction in
urine output. High doses of aspirin (greater than 3 g/day) and NSAIDs can inhibit
uterine contractions, resulting in prolonged labor. The use of NSAIDs can also
increase peripartum blood loss and anemia. Aspirin and nonaspirin NSAIDs should
be used sparingly and at the lowest effective doses during pregnancy and
discontinued at least 6 to 8 weeks before delivery to minimize adverse fetal and
Aspirin generally should be avoided for women who plan to nurse their baby
because salicylate serum concentrations in breast-fed neonates raise concerns about
the potential for metabolic acidosis, bleeding, and Reye syndrome. Nonaspirin
NSAIDs are generally compatible with breast-feeding, with the best evidence
supporting the use of ibuprofen, indomethacin, and naproxen.
QUESTION 1: T.Z., a 68-year-old man with heart failure previously managed with furosemide 40 mg/day,
these signs and symptoms be associated with ibuprofen use?
should be avoided, if possible, in patients with preexisting heart failure, kidney
If a patient with these conditions requires NSAID therapy, or
patients are taking angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers, serum creatinine should be checked soon after NSAID initiation. Inhibition
of COX by NSAIDs within the kidney reduces prostaglandin concentrations and
unopposed vasoconstriction. Consequently, urine output declines, serum blood urea
nitrogen and serum creatinine levels rise, and fluid is retained. In addition, ibuprofen
at higher doses is associated with an increased risk of MI, a concern for T.Z. because
of his risk of thrombotic cardiovascular events.
cardiovascular care should be informed of his symptoms of fluid overload, and an
alternative to NSAID therapy should be pursued.
CASE 44-5, QUESTION 2: If NSAID therapy is discontinued, what analgesic or anti-inflammatory
alternatives are there for T.Z.? What other renalsyndromes are associated with NSAID use?
In several studies, sulindac has been associated with fewer adverse effects on the
123 The reasons for this are unclear, but one explanation is
that the active sulfide metabolite undergoes renal metabolism and, therefore, might
not achieve tissue concentrations within the kidney sufficient to reduce prostaglandin
124 Unfortunately, patients do not seem to benefit from sulindac as much as
from other NSAIDs, and the evidence overall supporting the safety of sulindac in
renal impairment is weak. COX-2 inhibitors do not appear to offer an advantage for
123 Although celecoxib has been associated with a slightly
lower risk of death and heart failure exacerbation when compared with traditional
NSAIDs, it is not a reasonable initial option for T.Z. because celecoxib is also
associated with an increased risk of MI and it may contribute to worsening of heart
NSAIDs should be used at their lowest effective doses for minimal periods for
T.Z. High-dose NSAIDs should be avoided owing to increased MI risk. Although
acetaminophen is not an anti-inflammatory agent, it can provide analgesic relief.
Intra-articular corticosteroid injections can be useful if inflamed joints are limited in
number, or a short course of oral corticosteroids can provide rapid control of
inflammation while reducing the need
for longer courses of anti-inflammatory therapy. If T.Z. is not yet being treated
meantime, if an NSAID or short course of systemic corticosteroid is used, close
monitoring of renal function and fluid retention status is warranted.
In addition to acute renal failure, NSAIDs can induce various adverse renal effects
(e.g., nephrotic syndrome, interstitial nephritis, hyponatremia, abnormalities of water
metabolism, and hyperkalemia).
126 The nephrotic syndrome, unlike NSAID-induced
acute renal failure, can appear anytime (i.e., from days to years) after initiation of
therapy and can resolve as quickly as 1 month, or as long as 1 year, after
discontinuation of the NSAID. Hematuria, pyuria, and proteinuria without prior renal
disease differentiates nephrotic syndrome from other NSAID-induced renal
problems. Histologically, NSAID-induced nephrotic syndrome is characterized by
interstitial lymphocytic infiltrates, vacuolar degeneration of proximal and distal
tubules, and fusion of epithelial foot processes of glomeruli.
Prostaglandin-mediated inhibition of active chloride transport, regulation of
medullary blood flow within the kidney, and antagonism of antidiuretic hormone can
be suppressed by NSAIDs. As a result, urine is maximally concentrated, free water
clearance is limited, and water retention that is disproportionate to sodium retention
can occur. The resulting hyponatremia can be severe and could be potentiated by
126 Local prostaglandin synthesis can also stimulate renin
production within the kidney. NSAID therapy can critically attenuate this regulatory
mechanism in some situations, resulting in reduced aldosterone-mediated potassium
Although the mechanism is poorly understood, some NSAIDs have been associated
with sustained mean arterial pressure increases of 5 to 6 mm Hg,
result of COX-2 inhibition and sodium and water retention. Several studies suggest
that only patients taking antihypertensive medications experienced NSAID-induced
mean arterial pressure elevations, but it is now clear that even normotensive
individuals can experience elevations in blood pressure from NSAID use.
CASE 44-5, QUESTION 3: How frequently should T.Z.’s renal and liver function be tested during his
Patients at high risk for NSAID-induced renal disease, like T.Z. (see Case 44-5,
Questions 1 and 2), should have their serum creatinine levels checked regularly (e.g.,
weekly) for several weeks after initiation of NSAID therapy because renal
insufficiency more commonly occurs early in the course of therapy rather than
128 NSAID-induced nephrotic syndrome and allergic interstitial nephritis occur,
on average, about 6.6 months and 15 days after NSAID initiation, respectively.
In most cases, liver function testing (LFT) is unnecessary.
elevate liver enzymes, severe hepatotoxicity is rare. Abnormal LFTs without clinical
symptoms have no impact on patient outcome and have not been associated with
severe hepatotoxicity. Patients who seem to be at greatest risk for hepatotoxicity are
those with established or suspected intrinsic liver disease and those taking
diclofenac. These patients should have LFTs performed no later than 8 weeks after
initiation of therapy because liver toxicity manifests early in therapy, if at all.
TRADITIONAL DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
CASE 44-5, QUESTION 4: T.Z. was diagnosed with RA 18 months ago, shortly after symptoms began to
(csDMARD) therapies are most appropriate for him?
According to ACR, regardless of disease duration, every RA patient should
receive DMARD therapy. Monotherapy with MTX is considered the preferred initial
treatment for most RA patients. A high and rapid response rate for all levels of RA
severity, relatively low cost and toxicity, and radiographic evidence of slowing joint
erosion (which is most rapid during the first several years of active disease) are
(Fig. 44-6). Other csDMARDs to consider are
HCQ, SSZ, and LEF. Although most DMARDs are associated with potentially
serious adverse effects, these generally are reversible and seldom lead to serious
complications if the patient is monitored appropriately.
In addition, low-dose oral corticosteroids or NSAIDs are often prescribed on an
as-needed basis for brief periods of severe disease activity or while awaiting the
onset of DMARD action. During periods of disease remission, corticosteroid or
NSAID therapy can be discontinued. Safety and efficacy data, which reflect several
years of DMARD therapy combined with biologic agents, have been excellent, and
the combination is now commonly prescribed for patients who fail MTX
monotherapy (see Case 44-7, Questions 9-11).
28 Guidelines for DMARD selection
were discussed previously (see Treatment section). Combination DMARD therapy is
indicated for more severe or more advanced RA patients (see Case 44-7, Question
CASE 44-5, QUESTION 5: Although MTX is considered the initial DMARD of choice for newly diagnosed
RA, treatment was initiated with HCQ. What dosages would be appropriate, and when should clinical
Although the manufacturer’s literature recommends an initial HCQ adult dose of
400 to 600 mg/day (310–465 mg of base), dosages for HCQ generally range from 2
If the patient responds well, the maintenance dose can be reduced
by 50% and the medication continued at a dose of 200 to 400 mg/day (155–310 mg of
base). About two-thirds of patients who tolerate HCQ respond favorably. Benefits
usually are apparent within 2 to 4 months of therapy, but it can vary between 1 and 6
months. About 37% of patients discontinued HCQ within a year and 54% within 2
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