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NSAIDs vs. Naproxen
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Peer Feedback:
“Suggest naproxen as only NSAID given relative safety profile”
Literature Review Question:
What is the safest NSAID available?
Literature Search:
eCPS – Acute Pain
Pubmed – “Non-steroidal anti-inflammatory drugs AND efficacy AND (analgesia OR pain) AND (safety
OR complications OR tolerability) AND meta-analysis/review”; “(aspirin or ASA or acetylsalicylic acid)
AND (GI or gastrointestinal) AND safety”
CADTH - NSAIDs
New Insights into NSAIDs (2015)
Gastrointestinal safety and tolerability
A recent meta-analysis of data for more than 220,000 patients from 280 placebo-controlled trials of
NSAIDs showed that all evaluated NSAIDs (coxibs, diclofenac, ibuprofen, and naproxen) increased the
early risk of upper gastrointestinal complications (eg, ulcer perforations, bleeding, obstructions) to some
extent.20 There is, however, considerable variability in the risk of gastrointestinal complications between
NSAIDs.29,71,72 Results of a 2012 meta-analysis of 28 observational studies showed:
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a low risk (relative risk [RR] ,2) of upper gastrointestinal complications for aceclofenac, celecoxib,
and ibuprofen;
intermediate risk (RR 2–4) for diclofenac, meloxicam, and ketoprofen, among others;
high risk (RR 4–5) for tenoxicam, naproxen, indomethacin, and diflunisal;
highest risk (RR >5) for piroxicam, ketorolac, and azapropazone.71
In keeping with results for individual NSAIDs, drugs that have greater selectivity for COX-2 than COX-1
generally have been associated with a lower risk of upper gastrointestinal complications than other
NSAIDs.20,29,73 In the recent meta-analysis of data from more than 220,000 patients, the predicted
absolute annual risk of upper gastrointestinal complications was lower for NSAIDs with greater COX-2
selectivity (coxibs and diclofenac) compared with non-selective NSAIDs (Figure 5).20
Cardiovascular safety and tolerability
Although aspirin confers cardioprotective effects, most other NSAIDs are associated with an increased
risk of cardiovascular adverse events, including hypertension, myocardial infarction, stroke, and heart
failure.10,11,75–77 In the meta-analysis of data from more than 220,000 patients, a significant increase
in the risk of major vascular events was observed for high doses of coxibs and diclofenac, and was
largely related to increased risk of major coronary events; in contrast, neither ibuprofen or naproxen were
associated with an increased risk of major vascular events, although ibuprofen was associated with an
increase in major coronary events comparable with that of coxibs and diclofenac (Figure 5).20
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Figure 5 Predicted annual absolute risks of major vascular events or upper gastrointestinal complications
with long-term, high-dose therapy.
The cardiovascular risk conferred by non-aspirin NSAIDs is likely associated with inhibition of COX-2–
mediated production of PGI2 , which has a cardioprotective role in the circulatory system, promoting
vasodilation, preventing platelet activation and cell adhesion,22,23 and counteracting the action of TxA2 ,
as well as several other stimuli.22 The antiplatelet effects of aspirin are mediated by irreversible inhibition
of COX-1, resulting in profound and persistent reduction of TxA2 production and TxA2 -dependent
platelet activation (for several days after aspirin administration).38,66 However, for most other traditional
NSAIDs and coxibs, COX-1 inhibition is only transient and insufficient to translate into inhibition of
atherothrombosis.23 The exception is naproxen, which has a long half-life and potently inhibits platelet
COX-1 activity sufficiently to prevent platelet aggregation at high doses;44,80 however, unlike aspirin,
naproxen is a reversible inhibitor of COX-1 with variable effects across dosing intervals.80 Moreover,
naproxen profoundly affects systemic PGI2 biosynthesis, while aspirin (at a low dosage) has only a
marginal effect on biosynthesis of PGI2 . 80 Thus, as shown in the clinical data, naproxen is neutral with
regard to cardiovascular risk, while aspirin is associated with a protective role.19
Interactions of NSAIDs with other drugs
Aspirin irreversibly acetylates the COX active site, preventing generation of TxA2 , a prothrombotic
prostanoid involved in platelet activation and aggregation.38,39 NSAIDs characterized by a high affinity
for platelet COX-1 (eg, ibuprofen, naproxen) may interfere with the antiplatelet effects of aspirin; in
contrast, this effect has not been detected with NSAIDs having intermediate or high selectivity for COX2.65–67 Moreover, no interaction has been detected with low-dose paracetamol.66 Although further
randomized controlled trials are needed to confirm the clinical relevance of these pharmacodynamic
interactions, an analysis of the medical records of 7,107 patients with cardiovascular disease who
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received aspirin alone or aspirin plus an NSAID indicated that the risks of all-cause mortality and
cardiovascular-related mortality were significantly higher for patients who received aspirin plus ibuprofen
compared with those who received aspirin alone (P,0.05), but not for patients who received aspirin plus
diclofenac or aspirin plus any other NSAID (drugs not specified).68
NSAID therapy in patients taking anticoagulant therapy with coumarins (vitamin K antagonists) should
also be approached with caution. Coadministration of NSAIDs with coumarins may be associated with an
increased risk of bleeding complications, particularly for naproxen.69 The increased risk of bleeding
associated with concomitant use of NSAIDs and coumarins (eg, warfarin) results from displacement of the
anticoagulant from plasma proteins by the NSAID, thereby increasing the plasma concentration of free
coumarin and associated anticoagulant activity and bleeding risk.70
Figure 2 Selectivity of NSAIDs for COX-1 and COX-2.
Brune, Kay, and Paola Patrignani. "New insights into the use of currently available non-steroidal antiinflammatory drugs." Journal of pain research 8 (2015): 105.
CADTH (2013)
Numerous studies have been conducted that examined the safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in the past five years. In total, five systematic reviews and
one health technology assessment were included in this review. Most of these studies evaluated the use
of celecoxib and nsNSAIDs in patients with osteoarthritis and rheumatoid arthritis.
It was found that the combined risk of major vascular events (including non-fatal myocardial infarction,
non-fatal stroke or vascular death) were similar for celecoxib, diclofenac or ibuprofen, but there was some
evidence of increased risk for celecoxib compared with naproxen. Celecoxib compared with nsNSAIDs
(as a drug class) seems to be associated with a similar risk of cardiovascular adverse events, heart
failure, or all-cause mortality.
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Compared to nsNSAIDs, celecoxib was reportedly associated with statistically significantly fewer
gastrointestinal (GI) adverse events including GI bleeding or ulcers, within 6 months of treatment.
Comparisons between individual nsNSAIDs showed similar risks of serious GI events, and all except
naproxen (with lower serious CV risk), were associated with similar risks of serious CV events.
CADTH; Non-steroidal Anti-inflammatory Drugs for Pain: A Review of Safety; 20 August 2013
Individual NSAIDs and UGI complications (2012)
The results from this meta-analysis confirmed the variability of RRs among individual NSAIDs. The lowest
RRs were observed for the use of aceclofenac, celecoxib and ibuprofen, and the highest for the use of
piroxicam, ketorolac and azapropazone. Intermediate RRs, between approximately 2 and 4, were
observed for the rest of the NSAIDs for which at least three estimates were available: rofecoxib, sulindac,
diclofenac, meloxicam, nimesulide, ketoprofen, tenoxicam, naproxen, indometacin and diflunisal.
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The use of high daily doses of individual NSAIDs was associated with approximately a 2- to 3-fold
increase of RRs for UGIC compared with the use of low-medium doses, except for celecoxib, for which
we did not observe a doseresponse relationship. For most NSAIDs, there were no major differences
between studies restricted to patients without a history of peptic ulcer and those that included all patients,
and between studies conducted before and after the year 2000. Data from the studies included in the
meta-analysis were insufficient to estimate pooled RRs for the duration of use of individual NSAIDs and
for the concurrent use of gastroprotective agents.
The benefit-risk balance of individual NSAIDs is mainly driven by their GI and CV safety profile. Recent
meta-analyses of observational studies on the CV risk associated with individual NSAIDs show that
rofecoxib and diclofenac are associated with the highest RR and naproxen and ibuprofen with the lowest
RR.[76,77] For cerebrovascular events, the increase in risk appears to be similar between naproxen,
ibuprofen and diclofenac, and higher for rofecoxib.[78]In our study, ibuprofen was in the lowest range of
pooled RRs for UGIC; rofecoxib and diclofenac were in the middle range; and naproxen was associated
with a higher RR. However, estimates for individual NSAIDs varied by dose. The pooled RR of UGIC for
high-dose ibuprofen was similar to the RR for high-dose rofecoxib and diclofenac, and the use of highdose naproxen was associated with a higher RR.
Fig. 2. Pooled relative risks and 95% CIs of upper gastrointestinal complications associated with the use of
individual NSAIDs. Vertical bars denote 95% CIs
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Fig. 3. Pooled relative risks and 95% CIs of upper gastrointestinal complications associated with the daily dose of individual NSAIDs. See table IV for
cut-off values used in each study to define high dose and low-medium dose. Vertical bars denote 95% CIs. HD = high dose; LD = low-medium dose.
Castellsague, Jordi, et al. "Individual NSAIDs and upper gastrointestinal complications." Drug
safety 35.12 (2012): 1127-1146.
Aspirin and NSAIDs (2012)
Gastrointestinal (GI) bleeding is perhaps the most notorious complication of long-term aspirin use. This is
thought to occur via inhibition of the COX-1 enzyme, thereby reducing synthesis of prostaglandins, which
protect the gastric mucosa from acid-induced damage. A recent meta-analysis of 35 randomised
controlled trials demonstrated an increased risk of major GI haemorrhage in subjects using low-dose
aspirin alone (75–325 mg/day) compared with placebo (odds ratio (OR) 1.55). This decreased
significantly in patients taking regular PPI therapy in combination with lowdose aspirin (OR 0.34) [16].
Whilst some studies have shown no dose-dependent between aspirin and risk of gastrointestinal side
effects, recent work by Huang and colleagues followed up approximately 87,700 patients, demonstrating
that the multivariate relative risk (RR) of GI bleeding was directly related to frequency of aspirin use (RR
1.30 in patients using 1 325 mg tablet/week, compared with RR 2.24 for patients using 14 tablets/week, p
< 0.01) [17]. The risk of GI haemorrhage increases with age in the general population; so too does the
risk of Barrett’s oesophagus and colonic neoplasia [15].
Thiagarajan, Prarthana, and Janusz A. Jankowski. "Aspirin and NSAIDs; benefits and harms for the gut." Best
Practice & Research Clinical Gastroenterology 26.2 (2012): 197-206.
NSAIDs in Older Adults (2010)
Renal Risks
In the renal tract, both COX-1 and COX-2 are constitutively expressed and mediate renal function through
effects on the macula densa, podocytes, afferent and efferent arterioles, the ascending loop of Henle and
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the glomerulus.[75-77] Normal GFR is maintained through the activity of vasodilatory prostaglandins in
efferent capillaries and vasoconstricting angiotensin II in afferent capillaries. COX-1 inhibition reduces the
prostaglandin production, and as a result, angiotensin II acts unopposed, perfusion pressure decreases
and GFR declines.[78] COX-2 is also constitutively expressed in the kidney.[79-82] Research suggests
that COX-2 expression may be more evident in older patients[81] and those with diabetic nephropathy or
hypertension.[82]
Both nonselective and COX-2 selective NSAIDs have been associated with renal toxicity,[13,83,84]
particularly in older patients.[13,84] COX-1[83,85] and to a lesser extent COX-2[85] inhibition each
appear to be associated with reduced GFR. COX-1 is expressed in the collecting ducts of the nephron,
suggesting a role in sodium excretion.[86] COX-1 inhibition may therefore be linked to the hypertensive
effects observed with NSAIDs. COX-2 inhibition (i.e. with celecoxib) also appears to cause sodium and
potassium retention, the former being a potential source of fluid retention with resulting increases in blood
pressure.[75,87]
Haematological Risks
COX-1 inhibition reduces expression of the prothrombotic thromboxane A2 (TXA2),[51] which protects
against thrombotic events but may also contribute to bleeding, particularly in the GI tract. COX-2 inhibits
the production of PGE2, [52] which is both an inhibitor of platelet aggregation in inflamed tissues and a
vasodilator. Collectively, the data suggest that the haematological risks of NSAIDs depend on the balance
of COX-1 mediated TXA2 and COX-2 mediated PGE2, and inhibitors of either COX isoenzyme can
disrupt that balance, increasing the risk for either bleeding (e.g. GI bleeding) or thrombotic events (e.g.
stroke and myocardial infarction).
Hepatic Risks
According to meta-analyses, hepatic AEs with NSAIDs are infrequent.[15,55] In a 2004 systematic
review, the rate of hospitalizations for acute liver injury with NSAIDs ranged from 3.1 to 23.4 per 100 000
patient-years of treatment.[55] The excess risk of hepatic AEs with NSAIDs compared with controls in this
analysis was 4.8 to 8.6 per 100 000 patient-years of treatment. In a second systematic review, the rates
of liver test elevations ‡3 times the upper limit of normal did not differ from placebo with any NSAIDs
except oral diclofenac and rofecoxib.[15] However, only one hospitalization in a patient treated with
naproxen was reported in 37 000 patients treated with oral NSAIDs in studies reporting that outcome, and
only one death related to hepatotoxicity in >50 000 patients was reported. Although serious hepatic AEs
with NSAIDs are rare, it should be noted that lumiracoxib was withdrawn from European and other
markets because of reports of irreversible liver damage.[92]
Borderline elevations in one or more liver enzyme parameter occur in up to 15% of patients taking
NSAIDs.[91,93] Elevations ‡3 times the upper limit of normal have been reported in approximately 1% of
treated patients.[15] These abnormalities may be transient, remain the same, or progress with continued
treatment. Therefore, careful monitoring of liver function should be undertaken in patients taking NSAIDs
who have signs or a history of hepatic dysfunction.
Barkin, Robert L., et al. "Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older
adult?." Drugs & aging 27.10 (2010): 775-789.
eCPS 2015
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of medications with analgesic,
antipyretic and anti-inflammatory properties. Medications from all 5 classes of nonselective NSAIDs (i.e.,
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salicylates, fenamates, propionic acid derivatives, oxicams, acetic acid derivatives) are effective for mild
to moderate pain. Full single doses of most NSAIDs provide more effective analgesia than full doses of
ASA or acetaminophen.5 Choosing an NSAID can be difficult; some patients respond well to a certain
class but not to others and cost can be an important factor.
Adverse effects associated with single (or a few) doses of nonselective NSAIDs are limited and are
qualitatively similar to those of ASA. Chronic use is associated with GI effects (ulceration, bleeding and
perforation) and renal failure. Combining a proton-pump inhibitor (PPI) once daily or misoprostol 200 µg
QID po with an NSAID effectively provides protection from GI toxicity.6 Some combinations are
commercially available in Canada (e.g., naproxen/esomeprazole, Vimovo; diclofenac/misoprostol,
Arthrotec). Unlike other NSAIDs, ASA irreversibly inhibits platelet function for the lifetime of the platelet
(8–10 days) even after a single therapeutic dose. In contrast, platelet function returns to normal when
other NSAIDs have been eliminated from the body (within approximately 24 hours for most NSAIDs).
NSAIDs can precipitate asthma in ASA-sensitive patients. Avoid NSAIDs in patients with a history of
peptic ulcer disease, renal failure or heart failure. COX-2 selective NSAIDs such as celecoxib may cause
less severe GI toxicity than nonselective NSAIDs, but are more expensive and have a poorly-defined role
and unstudied adverse effect profile in the treatment of acute pain.
ASA can be given with opioids for additive analgesic effect. Avoid using ASA in children less than 18
years of age if they have a fever or viral illness such as flu or chickenpox or any unidentified infection,
because of a possible increased risk of Reye's syndrome—a rare but serious condition that causes brain
and liver damage. ASA can also precipitate asthma in ASA-sensitive patients.
Ibuprofen 200 mg provides equivalent analgesia to ASA 650 mg or acetaminophen 650 mg; a dose of
400 mg is superior and longer acting, and provides comparable analgesia to the combination of
acetaminophen/codeine.5,7 A 10 mg/kg dose of ibuprofen is as safe as a 15 mg/kg dose of
acetaminophen, although GI bleeding has been reported with ibuprofen. 8
Naproxen has a longer duration of action than ASA.5 Compared to ASA 650 mg, naproxen 250 mg is
equally effective and naproxen 500 mg is superior.9 Naproxen is available as oral tablets or rectal
suppositories. Naproxen sodium 220 mg (equivalent to naproxen 200 mg) is available as an oral
nonprescription analgesic.
During pregnancy, the use of NSAIDs should be restricted to the first or second trimester; even shortterm NSAID use after 32 weeks is associated with a substantial increase in the risk of premature closure
of the ductus arteriosus, and is not recommended.22 NSAIDs can be used safely during breastfeeding.
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Drug
Dosage
Adverse Effects
Drug Interactions
Costa
ASA
Aspirin, Coated
Aspirin,generics
Children: 10–15
mg/kg/doseQ4H po
Maximum: 5 doses/day
Adults: 325–650 mg Q4H po
Maximum: 4 g/day
GI upset. Avoid in patients with
renal failure, peptic ulcer disease,
heart failure and ASA-sensitive
asthma.
Warfarin: increased anticoagulant effect.
Antihypertensives (diuretics, beta-blockers,
ACE inhibitors, alpha-blockers): possible
reduction in antihypertensive effect; may
require additional antihypertensive therapy.
$
Lithium may interfere with sodium/water
balance. Monitor lithium levels when NSAID
added.
Increased risk of GI bleeding with SSRIs.
ibuprofen, oral
Advil, Motrin, Motrin
(Children's), generics
Children: 10 mg/kg/dose Q6–
8H po; oral suspension
available
Maximum: 40 mg/kg/day, not
to exceed adult dose
Adults: 200–400 mg Q6–8H
po
Maximum: 1.2 g/day
GI upset. Avoid in patients with
renal failure, peptic ulcer disease,
heart failure and ASA-sensitive
asthma.
Warfarin: increased anticoagulant effect.
Antihypertensives (diuretics, beta-blockers,
ACE inhibitors, alpha-blockers): possible
reduction in antihypertensive effect; may
require additional antihypertensive therapy.
$
Lithium may interfere with sodium/water
balance. Monitor lithium levels when NSAID
added.
Increased risk of GI bleeding with SSRIs.
naproxen
Naprosyn, Pediapharm
Naproxen
Suspension,generics
Children: 5–7
mg/kg/doseQ8–12H po; oral
suspension available
Maximum: 1000 mg/day
Adults: 500 mg initially,
then250 mg Q6–8H po
Maximum: 1250 mg/day
Legend: $ <$10
$$10–20
GI upset. Avoid in patients with
renal failure, peptic ulcer disease,
heart failure and ASA-sensitive
asthma.
$$$ 20–30
Warfarin: increased anticoagulant effect.
Antihypertensives (diuretics, beta-blockers,
ACE inhibitors, alpha-blockers): possible
reduction in antihypertensive effect; may
require additional antihypertensive therapy.
Lithium may interfere with sodium/water
balance. Monitor lithium levels when NSAID
added.
Increased risk of GI bleeding with SSRIs.
$
$$$$ 30–40
Neurologic Disorders: Acute Pain; Benoit Bailey, MD, MSc, FRCPC; Date of Revision: February 2015
Medication
Uses
acetylsalicylic
acid
analgesia,
antiplatelet,
ischemic heart
disease,
atherosclerosis
analgesia,
antiinflammatory
naproxen
ibuprofen
analgesia, antiinflammatory
Contraindications (CI), drug
interactions (DI) or cautions
CI: bleeding disorders, allergy,
ulcers
Adverse Effects
(common and severe)
gastrointestinal (GI) bleed,
decreased renal function (if
CrCl<30ml/min)
Initial dose; typical
dose
325mg; 325-640mg
every 4 hours
CI: GI bleeds, ulcers, allergy
GI bleeds, renal insufficiency
250mg; 250-500mg
two times a day
CBC, LFTs, serum
creatinine (SCr),
blood pressure (BP)
CI: GI bleeds, ulcers, allergy
hepatic insufficiency,
increased cardiovascular
event risk
Adults: 200-800mg
every 8 hours
Children: 4 to 10
mg/kg orally every
6-8 hours
blood pressure (BP)
Monitoring
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