NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

• ACRONYMS AND DEFINITIONS

• AHA - American Heart Association
• COX - Cyclooxygenase enzyme
• EC - Enteric coated
• ER - Extended release
• IR - Immediate release
• MAP - Mean arterial pressure - MAP = 1/3 SBP + 2/3 DBP
• NSAIDs - Nonsteroidal anti-inflammatory drugs
• Nonselective NSAIDs - NSAIDs that are not selective for COX-2
• OTC - Over-the-counter
• P = Drugs with pediatric dosing
• Partially-selective NSAIDs - NSAIDs that are partially selective for COX-2
• RCT - Randomized controlled trial
• Selective NSAIDs - NSAIDs that are selective for COX-2
• SPAQI - Society for Perioperative Assessment and Quality Improvement
• USPSTF - U.S. Preventive Services Task Force

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• NONSELECTIVE NSAIDs

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• PARTIALLY-SELECTIVE NSAIDs

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• SELECTIVE NSAIDs

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• MECHANISM OF ACTION

• Inflammatory pathway
• In a cell, inflammation is first initiated by physical, chemical, mitogenic, and/or other inflammatory stimuli. These stimuli activate the enzyme phospholipase A₂.
• Phospholipase A₂ causes the release of arachidonic acid, a 20-carbon fatty acid, from the cell membrane
• The enzyme prostaglandin G/H synthase has cyclooxygenase (COX) and hydroperoxidase (HOX) activity. Prostaglandin G/H synthase converts arachidonic acid to prostaglandin H₂.
• Prostaglandin H₂ is then converted by tissue-specific isomerases into a number of different inflammatory mediators called prostanoids. The type of prostanoid produced depends on the tissue/cell type.
• NSAIDs inhibit the cyclooxygenase (COX) component of phospholipase A₂ and block the formation of prostaglandin G₂. [4]



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• COX SELECTIVITY

• NSAIDs block the enzyme cyclooxygenase (COX). COX has two main subtypes, COX-1 and COX-2.
• COX-1 is found in most tissues and is present at all times. COX-2 is typically undetectable in most tissues and is only produced in response to inflammation.
• Both COX enzymes play a role in propagating an inflammatory reaction through the production of prostaglandins (see above). COX-1 also plays an important role in gastric mucosal integrity, platelet aggregation, and kidney function.
• COX-2 selective inhibitors like celecoxib do not inhibit COX-1, and therefore, are less likely to cause gastric irritation. COX-2 selective inhibitors also do not inhibit platelet aggregation. They do, however, inhibit renal prostaglandins and have similar renal effects as other NSAIDs. COX-2 inhibitors may also carry a higher risk of thromboembolic events when compared to other NSAIDs - see NSAIDs and cardiovascular risk for more.
• Some patients with NSAID allergies are allergic to the COX-1 inhibiting effect of NSAIDs. These patients will be allergic to all nonselective NSAIDs, but may tolerate NSAIDs that have COX-2 selectivity (see NSAID allergy below).
• In the U.S., Celecoxib (Celebrex®) is the only available COX-2 selective NSAID. Etodolac (Lodine®), meloxicam (Mobic®), piroxicam (Feldene®), and diclofenac (Voltaren®) are all partially selective for COX-2, but will inhibit COX-1 to some degree. Furthermore, there is a large amount of pharmacokinetic variability between patients with partially-selective COX inhibitors which makes their degree of selectivity difficult to quantify. [4,5]

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• NSAID ALLERGY

• Overview
• There are two basic types of allergic reactions to NSAIDs:
• Reaction to the mechanism of NSAIDs - blockade of COX-1 enzyme
• Reaction to the chemical structure of a class of NSAIDs - IgE-mediated allergic reaction to chemical structure of the drug

• COX-1 blockade reactions
• Some patients are sensitive to the main mechanism of NSAIDs which is blockade of the COX-1 enzyme
• This condition has been given the name "Aspirin-Exacerbated Respiratory Disease" (AERD)
• Symptoms of AERD include:
• Nasal congestion and runny nose (chronic sinusitis)
• Worsening asthma symptoms when taking NSAIDs. Alcohol may also exacerbate asthma.
• Itchy, watery, swollen eyes
• Nasal polyps that often recur after removal
• Occurs in late childhood or adulthood (median age of onset is 30 years)
• Aspirin is a strong, irreversible inhibitor of COX-1, so patients with this syndrome will typically react strongly when ingesting aspirin. Other NSAIDs reversibly inhibit COX-1 to different degrees. Reactions to these NSAIDs may vary among affected individuals.
• Patients with AERD may tolerate COX-2 selective inhibitors (e.g. celecoxib) and partially-selective COX-2 inhibitors (e.g. meloxicam, etodolac, diclofenac, piroxicam)
• AERD has been found to exist in 4 - 11% of patients diagnosed with asthma. Many asthmatics are unaware that they have the disease and that NSAIDs may be worsening their symptoms.
• The condition is diagnosed with an oral "aspirin-challenge test" which involves giving the patient escalating doses of aspirin and measuring their reaction
• Aspirin desensitization is the main treatment of AERD, and it should be performed within 3 - 4 weeks of nasal polyp debulking
• Aspirin desensitization involves giving escalating doses of aspirin under medical supervision and then continuing daily aspirin for life. Aspirin desentization also induces cross-desentization to all other NSAIDs [2,3,11]

• Allergic reactions to NSAID classes
• Some patients develop IgE-mediated allergic reactions to certain NSAIDs
• Reactions of this nature can range from rash and itching to anaphylaxis
• These reactions occur because the patient has developed antibodies to the chemical structure of the drug. These reactions are not related to the COX-inhibiting mechanism of NSAIDs.
• The main distinguishing feature of this syndrome is that patients will react to one NSAID, but tolerate other NSAIDs without problem. Patients may react to several NSAIDs that are chemically related, and tolerate other NSAIDs that are not chemically-related. [2,3]
• The chart below shows which NSAIDs are chemically related

• References [12,13]

Salicylates	Propionic acids
Aspirin Salsalate Diflunisal	Ibuprofen (Motrin®, Advil®) Naproxen (Naprosyn®, Aleve®) Ketoprofen Flurbiprofen (Ansaid®) Fenoprofen (Nalfon®) Oxaprozin (Daypro®)
Enolic acids	Acetic acids
Meloxicam (Mobic®) Piroxicam (Feldene®)	Diclofenac (Voltaren®) Etodolac (Lodine®) Indomethacin (Indocin®) Ketorolac (Toradol®) Sulindac (Clinoril®) Tolmetin
Fenamic acids	Nonacidic
Meclofenamate Mefenamic acid (Ponstel®)	Nabumetone (Relafen®)

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• CARDIOVASCULAR RISK WITH NSAIDs

• Overview
• In 2004, the COX-2 selective drug Vioxx® was removed from the U.S. market over concerns that the drug increased the risk of cardiovascular events, particularly heart attacks. The following year, another COX-2 selective drug called Bextra® was removed from the market for similar reasons. All NSAIDs currently carry a boxed warning which states that they cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal.
• The proposed mechanism behind NSAID-induced cardiovascular events is discussed below
• The problems with Vioxx® and Bextra® increased scrutiny of both selective and nonselective NSAIDs, and studies were conducted to evaluate the association between cardiovascular outcomes and NSAID use. A large, randomized controlled trial (PRECISION Study) that compared the cardiovascular risk of celecoxib to ibuprofen and naproxen is detailed below along with a Lancet meta-analysis that evaluated the risk of a handful of NSAIDs.

• Mechanism
• The proposed mechanism behind the cardiovascular risk seen with NSAIDs has to do with the COX-1 and COX-2 enzymes and their contrasting effects in different cells
• In platelets, COX-1 is a major enzyme involved in the production of thromboxane A₂. Thromboxane A₂ promotes platelet activation and thrombosis. COX-1 inhibition thus inhibits thrombosis.
• In endothelial tissue, COX-2 is a major enzyme involved in the production of prostacyclin. Prostacyclin inhibits platelet aggregation and promotes vasodilation. COX-2 inhibition thus promotes thrombosis.
• Nonselective NSAIDs inhibit both COX-1 and COX-2 and their overall effect on thrombosis is related to their proportional effects on each enzyme
• Very low doses of aspirin irreversibly inhibit COX-1 in platelets, and aspirin therefore has the greatest effect on COX-1 of any NSAID. Not surprisingly, aspirin has been proven to prevent thromboembolic events.
• The selective COX-2 inhibitors Vioxx® and Bextra® inhibit COX-2 in endothelial tissue and smooth muscle cells, but they have no meaningful effect on COX-1 in platelets. This tips the scale in favor of thrombosis, and they were found to increase the risk of cardiovascular events in trials. Contrarily, the COX-2 selective inhibitor celecoxib (Celebrex®) was evaluated in the PRECISION trial (see below), and it was not found to increase the risk of cardiovascular events when compared to ibuprofen and naproxen.
• The risk of events with nonselective NSAIDs is not well-defined, although a number of observational studies have found that many popular NSAIDs (e.g. ibuprofen) likely increase the risk of cardiovascular events to a small degree. Excluding aspirin, all nonselective NSAIDs reversibly inhibit COX-1 in platelets and this effect does not appear to counterbalance the pro-thrombotic effects of COX-2 inhibition in endothelial cells and smooth muscle. There is also some concern that nonselective NSAIDs may compete with aspirin for COX-1 inhibition and therefore may lower the effectiveness of low-dose daily aspirin. [5,6,8]

• STUDY
  Lancet meta-analysis - Vascular and Upper Gastrointestinal Effects of NSAIDs [PubMed abstract]
• In 2013, a meta-analysis was published in the Lancet that evaluated cardiovascular events among individual NSAIDs. The analysis included 280 randomized controlled trials that compared NSAIDs to placebo and 474 trials that compared NSAIDs to other NSAIDs.
• Based on their findings, the authors quantified the risk of a major vascular event (defined as nonfatal myocardial infarction, nonfatal stroke, or vascular death) among a handful of popular NSAIDs. Their findings are presented in the table below.

• Summary
• The PRECISION study found that celecoxib does not increase the risk of cardiovascular events when compared to naproxen and ibuprofen. This finding is reassuring given the previous history of other COX-2 selective drugs (e.g. Vioxx, Bextra).
• As expected, celecoxib was associated with significantly fewer gastrointestinal events. A weakness of the study is that esomeprazole adherence was not measured.
• One unexpected and interesting finding was that celecoxib was associated with significantly fewer renal events than ibuprofen. Celecoxib also had fewer events than naproxen, but the difference was not significant (p=0.19). Renal events were defined as any of the following: Scr ≥ 2 mg/dl with ≥ 0.7 mg/dl increase from baseline, hospitalization for acute renal failure, or initiation of dialysis.
• No interaction between daily aspirin use and naproxen or ibuprofen was identified. This is an interesting finding since it has been hypothesized that ibuprofen and naproxen may interfere with the antiplatelet activity of aspirin.
• The Lancet meta-analysis found that naproxen was the safest NSAID in patients with cardiovascular disease. These findings are observational and should be considered as such.

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• NSAIDs AND GI BLEEDING / ULCERS

• Overview
• NSAIDs increase the risk of peptic ulcer disease and gastrointestinal bleeding
• The mechanism of this effect is believed to occur through the inhibition of the COX-1 enzyme which plays an important role in gastric mucosal integrity
• COX-2 selective NSAIDs (e.g. celecoxib) have been shown to have a lower risk of peptic ulcer disease when compared to nonselective NSAIDs
• Despite the increased risk, it is often necessary for patients with a history of peptic ulcer/bleeding to receive an NSAID. Recommendations for these patients are detailed below.

• Celecoxib
• In the U.S., the only COX-2 selective NSAID available is celecoxib. A handful of other NSAIDs are partially selective for COX-2 (e.g. meloxicam, etodolac, diclofenac), but these medications display a large amount of inter-patient variability in COX-1 inhibition, and this makes it difficult to quantify and predict their associated risks.
• In trials, the risk of peptic ulcer disease with celecoxib is only slightly higher than placebo and much less that what is seen with nonselective NSAIDs. Three studies are summarized below, and the PRECISION study which also measured gastrointestinal outcomes is reviewed above.

• STUDY
  CONCERN trial - Celecoxib vs Naproxen for Peptic Ulcers in Patients with History of Upper GI Bleed and CVD, Lancet (2017) [PubMed abstract]
• Design: Randomized, controlled trial (N=514, length = 18 months) in patients with arthritis, history of upper GI bleed, and CVD
• Treatment: Celecoxib 100 mg twice a day + esomeprazole 20 mg/day vs Naproxen 500 mg twice a day + esomeprazole 20 mg/day. All patients also received aspirin 80 mg/day.
• Primary outcome: Recurrent upper gastrointestinal bleeding within 18 months
• Results:
• Primary outcome: Celecoxib - 5.6%, Naproxen - 12.3% (p=0.008)
• Findings: In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety.

• STUDY
  Celecoxib vs Naprosyn for Peptic Ulcers in Patients with RA or OA, Am J Gastroenterol (2001) [PubMed abstract]
• Design: Randomized controlled trial (N=537 | length = 12 weeks) in patients with RA or OA
• Treatment: Celecoxib 200 mg twice daily vs Naproxen 500 mg twice daily
• Primary outcome: Gastroduodenal ulcers at 4, 8, and 12 weeks as assessed by endoscopy
• Results:
• Primary outcome (cumulative 12 weeks incidence): Group 1 - 9%, Group 2 - 41%
• Findings: As compared to naproxen (500 mg b.i.d.), use of celecoxib (200 mg b.i.d.), a COX-2 specific agent, at the recommended RA dose and twice the most frequently prescribed OA dose, was associated with lower rates of gastric, duodenal, and gastroduodenal ulcers but had comparable efficacy, in patients with OA and RA.

• STUDY
  Celecoxib vs Naprosyn for Peptic Ulcers in Patients with RA, JAMA (1999) [PubMed abstract]
• Design: Randomized controlled trial (N=688 | length = 12 weeks)
• Treatment: Celecoxib 100 mg twice daily vs Celecoxib 200 mg twice daily vs Celecoxib 400 mg twice daily vs Naproxen 500 mg twice daily vs Placebo
• Primary outcome: Gastroduodenal ulcers at 12 weeks as assessed by endoscopy before and after treatment
• Results:
• Primary outcome: Cel 100 mg - 6%, Cel 200 mg - 4%, Cel 400 mg - 6%, Naproxen - 26%, Placebo - 4% (Cel vs Naproxen p<0.001)
• Findings: In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

• Professional recommendations
• Low dose daily aspirin for heart disease
• See AHA recommendations for aspirin in patients with history of GI complications


• NSAIDs for osteoarthritis
• The American College of Rheumatology published recommendations for NSAID use in osteoarthritis in 2012
• The guidelines state that in general, NSAIDs should be avoided in patients with a history of GI complications
• If NSAIDs are still deemed necessary, the following recommendations may help prevent future events:
• For patients ≥ 75 years, topical NSAIDs are preferred over oral
• In patients with a history of upper GI ulcer who have not had a GI bleed in the past year, use a COX-2 selective NSAID or a nonselective NSAID with a PPI
• In patients with a history of upper GI ulcer who have had a GI bleed in the past year, use a COX-2 selective NSAID with a PPI [7]
• NOTE: Results from the CONCERN trial detailed above support these recommendations

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• PERIPROCEDURAL RECOMMENDATIONS

• Overview
• Most NSAIDs inhibit platelets and can prolong procedural bleeding. Aspirin irreversibly inhibits platelets and is primarily used for this purpose. All other NSAIDs reversibly inhibit platelets, which means their antiplatelet effect is gone once they are cleared (typically 4 - 5 drug half-lives).
• Recommendations for managing aspirin are provided here - perioperative aspirin recommendations. For all other NSAIDs, the SPAQI guidelines state that they should be held for 7 days before surgery, except for celecoxib, which has no antiplatelet effect and can be continued. The guidelines do note, however, that holding NSAIDs for 5 half-lives before a procedure may also be sufficient. The table below gives the half-lives of some commonly prescribed NSAIDs.

• Drugs are typically cleared after 4 - 5 half-lives
• ^✝No antiplatelet activity. Does not need to be held.
• *The manufacturer states that in trials, nabumetone had little effect on collagen-induced platelet aggregation and no effect on bleeding time
• ‡ At a daily dose of 7.5 mg, it is relatively COX-2 selective and could be continued in the absence of high bleeding risk surgery
• References [Manufacturer PI, 14]

NSAID half-lives
Drug	Half-life
Ibuprofen (Motrin®, Advil®)	2.2 hours
Naproxen (Aleve®, Anaprox®, etc.)	12 - 17 hours
Meloxicam (Mobic®)‡	15 - 20 hours
Celecoxib (Celebrex®)✝	11 hours
Indomethacin (Indocin®)	4.5 hours
Ketorolac (Toradol®)	5 - 6 hours
Nabumetone (Relafen®)*	24 hours
Etodolac (Lodine®)	7 - 11 hours

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• NSAID SIDE EFFECTS

• All NSAIDs
• NOTE: Strength of association is not well-defined
• Gastrointestinal upset - abdominal pain, heartburn, dyspepsia, nausea, vomiting, constipation, diarrhea
• Gastrointestinal ulcers - gastric and duodenal
• Gastritis and esophagitis
• Gastrointestinal bleeding
• Decreased kidney function
• Increased bleeding time
• Worsening heart failure
• Increase in blood pressure
• Tinnitus
• Dizziness
• Itching
• Rashes
• Elevated liver enzymes

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• NSAID CONTRAINDICATIONS / PRECAUTIONS

• All NSAIDs
• Increased risk of thromboembolism - all NSAIDs (except aspirin) may increase the risk of cardiovascular thrombotic events including heart attack and stroke. The risk may be greater with prolonged use. See NSAIDs and cardiovascular risk for more.


• Coronary Artery Bypass Grafting (CABG) - all NSAIDs (except aspirin) are contraindicated in the perioperative period around CABG surgery. Studies have shown an increased risk of heart attack and stroke in patients who took NSAIDs in the first 10 - 14 days following CABG surgery.


• Recent myocardial infarction (MI) - observational studies have shown that NSAIDs (excluding aspirin) increase the risk of reinfarction, cardiovascular-related death, and all-cause mortality in patients who have suffered a recent MI. NSAIDs should be avoided in patients with a recent MI unless the benefits outweigh the risks.


• Gastrointestinal (GI) risk - all NSAIDs increase the risk of gastrointestinal bleeding, ulceration, and perforation. These events can occur at any time during NSAID use. Eighty percent of patients who develop serious upper GI events on NSAIDs are asymptomatic. In patients treated for 3 - 6 months with NSAIDs, 1% will develop serious upper GI events. In patients treated for a year, 2 - 4% will develop serious events. The risk continues to increase with longer durations of use. Patients with a prior history of GI ulcer or bleeding are at greatest risk. Elderly patients are also at increased risk. COX-2 selective NSAIDs (e.g. celecoxib) have a lower risk of GI complications than nonselective NSAIDs. See NSAIDs and peptic ulcers/GI bleeding for more.


• Hypertension - NSAIDs may raise blood pressure through several mechanisms. A meta-analysis that looked at the effects of NSAIDs on blood pressure found that indomethacin, naproxen, and piroxicam increased MAP by 3.59, 3.74, and 0.49 mmHg, respectively. Aspirin, ibuprofen, and sulindac did not increase MAP. [PMID 8435027] Patients with uncontrolled hypertension should use caution when taking NSAIDs.


• Hypersensitivity reaction to any NSAID - patients with a history of asthma, urticaria, or other allergic-type reactions to any NSAID may be allergic to all NSAIDs (COX-1 reaction), or they may be allergic to chemically-related NSAIDs. See NSAID allergy for more.


• Prolonged bleeding - NSAIDs inhibit platelet activation and may prolong bleeding. The effect is greatest with aspirin which irreversibly inhibits platelet function. Other NSAIDs inhibit platelets to a lesser degree, and unlike aspirin, their effect is reversible. COX-2 selective NSAIDs do not inhibit platelets.


• Asthma - a small subset of asthmatics have "aspirin-exacerbated respiratory disease." These patients may be sensitive to other NSAIDs as well. See NSAID allergy for more.


• Smoking - smoking can cause gastrointestinal (GI) inflammation and increase the risk for NSAID-induced GI adverse events including ulceration, bleeding, and perforation


• Hepatotoxicity - borderline elevations (greater than the upper limit of normal [ULN] to 3 X ULN) of liver enzymes may occur in up to 15% of NSAID-treated patients. In trials, severe elevations (> 3 X ULN) have been seen in 1% of NSAID-treated patients. Rare cases of NSAID-induced liver failure have been reported. Patients who develop significant liver disease while taking NSAIDs should discontinue NSAIDs indefinitely.


• Heart failure and edema - NSAIDs may raise blood pressure and promote fluid retention. Patients with heart failure and/or edema should use caution.


• Kidney disease - long-term NSAID use has been associated with renal papillary necrosis and other kidney diseases. In addition, renal prostaglandins play a compensatory role in maintaining renal perfusion. Prostaglandin inhibition by NSAIDs may decrease renal perfusion and lead to renal decompensation. The risk for NSAID-induced decompensation is greatest in patients with kidney disease, heart failure, liver disease, advanced age, and in those taking diuretics and ACE inhibitors.


• Serious skin reactions - NSAID use has been associated with serious skin reactions including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN)


• Drug reactions with eosinophilia and systemic symptoms (DRESS) - NSAID use has been associated with DRESS syndrome. DRESS syndrome is a rare drug reaction that can present with fever, rash, lymphadenopathy, facial swelling, organ system inflammation (e.g. hepatitis, nephritis, myocarditis), hematologic abnormalities (e.g. eosinophilia, lymphocytosis), and myositis. Early manifestations such as fever and/or lymphadenopathy may be present before a rash is evident. If DRESS is suspected, NSAIDs should be stopped immediately and the patient should be evaluated.


• Female fertility - NSAID use may prevent or cause a delay in ovulation that is reversible upon discontinuation. Women who are trying to become pregnant may want to avoid NSAID use.


• Pregnancy - NSAIDs should be avoided after 30 weeks of gestation because they may cause premature closure of the ductus arteriosus. Use of NSAIDs at ≥ 20 weeks gestation may cause fetal renal dysfunction that leads to oligohydramnios and neonatal renal impairment. In most cases, these adverse effects occur after days to weeks of treatment, but cases of oligohydramnios have been reported after only 48 hours of NSAID exposure. If NSAID treatment is necessary after 20 weeks, consider ultrasound monitoring of amniotic fluid.


• Ocular effects - in rare cases, NSAID use has been associated with vision and ocular changes


• Celecoxib
• Sulfa allergy - celecoxib contains a sulfonamide group. Patients who are allergic to sulfa drugs may also be allergic to celecoxib.
• CYP2C9 poor metabolizers (e.g. CYP2C9*3/*3) - initiate treatment with half of the lowest recommended dose
• Kidney disease
• CrCl ≥ 30ml/min: use caution
• CrCl < 30ml/min: not recommended
• Liver disease
• Mild (Child-Pugh A): no adjustment necessary
• Moderate (Child-Pugh B): reduce dose by 50%
• Severe (Child-Pugh C): not recommended


• Diclofenac
• Bovine protein allergy (Zipsor®) - Zipsor contains gelatin with bovine protein. Do not take if allergic.
• Phenylketonuria (Cambia®) - Cambia contains aspartame equivalent to phenylalanine 25 mg per packet
• Pregnancy (Arthrotec®) - misoprostol is contraindicated in pregnancy


• Ibuprofen
• Aseptic meningitis - rare cases of aseptic meningitis have been reported in patients taking ibuprofen. Patients with systemic lupus erythematosus may be at greater risk.


• Indomethacin
• CNS effects - indomethacin may aggravate psychiatric disorders, epilepsy, and parkinsonism. It may also cause drowsiness.

• Ketoprofen
• Kidney disease
• Mild kidney disease: do not exceed 150 mg/day
• Severe kidney disease (CrCL < 25 ml/min): do not exceed 100 mg/day
• Liver disease - ketoprofen is highly protein-bound (> 99%). Starting dose should not exceed 100 mg/day in patients with liver disease or hypoalbuminemia.

• Ketorolac
• Kidney disease - do not use in patients with advanced kidney disease or in patients at risk for kidney failure due to volume depletion


• Oxaprozin
• Photosensitivity - may cause photosensitivity. Avoid sun exposure or wear protection (e.g. sunscreen, clothing)


• Sulindac
• Kidney stones - sulindac metabolites have been found in kidney stones. Use caution in susceptible patients.
• Pancreatitis - rare cases of pancreatitis have been reported in patients receiving sulindac
• Aseptic meningitis - sulindac may increase the risk of aseptic meningitis in patients with systemic lupus erythematosus and mixed connective tissue disease

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• DRUG / LAB INTERACTIONS

• All NSAIDs
• ACE inhibitors - NSAIDs may attenuate the effects of ACE inhibitors. Monitor blood pressure when combining.
• Alcohol - alcohol can cause gastrointestinal (GI) inflammation and increase the risk for NSAID-induced GI adverse events including ulceration, bleeding, and perforation
• Angiotensin receptor blockers (ARBs) - NSAIDs may attenuate the effects of ARBs. Monitor blood pressure when combining.
• Corticosteroids - corticosteroids can cause gastrointestinal inflammation and increase the risk for NSAID-induced GI adverse events including ulceration, bleeding, and perforation
• Beta blockers - NSAIDs may attenuate the effects of beta blockers. Monitor blood pressure when combining.
• Cyclosporine - NSAIDs may inhibit renal prostaglandins and increase the risk of cyclosporine-induced nephrotoxicity. Use caution when used concomitantly.
• Digoxin - NSAIDs may increase blood levels of digoxin
• Diuretics - NSAIDs may attenuate the effects of loop diuretics and thiazide diuretics. Monitor blood pressure when combining.
• Drugs that increase the risk of bleeding - most NSAIDs inhibit platelet activation and prolong bleeding. The package inserts for celecoxib and nabumetone both state that their respective products had no effect on reduction of platelet aggregation or increase in bleeding time in studies. When NSAIDs are taken with other drugs that inhibit coagulation, the risk of bleeding may be increased.
• Drugs that may increase the risk of bleeding include:
• Anagrelide (Agrylin®)
• Aspirin
• Direct thrombin inhibitors (dabigatran)
• Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
• Fish oil (e.g. Vascepa®)
• P2Y12 inhibitors (e.g. clopidogrel, ticagrelor, prasugrel)
• SSRIs and SNRIs (e.g. fluoxetine, venlafaxine)
• Vorapaxar (Zontivity®)
• Warfarin (Coumadin®)
• Lithium - NSAIDs may decrease lithium clearance and increase lithium levels. In studies, average trough lithium levels increased by 15 - 20% in patients taking NSAIDs. Lithium levels should be monitored closely in patients who are taking NSAIDs on a long-term basis.
• Methotrexate - NSAIDs may reduce the elimination of methotrexate and increase the risk of methotrexate toxicity. Use caution when used concomitantly.
• Pemetrexed - NSAIDs may increase blood levels of pemetrexed and increase the risk of myelosuppression, renal toxicity, and GI toxicity. No dose adjustment of pemetrexed is needed with concomitant NSAIDs in patients with normal renal function (≥ 80 ml/min). NSAIDs with short elimination half-lives (e.g. diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. NSAIDs with longer half-lives (e.g. meloxicam, nabumetone) should be stopped for at least five days before, the day of, and two days following pemetrexed administration.


• Diclofenac
• CYP2C9 inhibitors, inducers, and substrates - diclofenac is primarily metabolized by CYP2C9. Inhibitors, inducers, and other substrates of CYP2C9 may alter diclofenac clearance. Diclofenac may affect the clearance of other CYP2C9 substrates.
• Antacids (Arthrotec®) - Antacids reduce the bioavailability of misoprostol. Magnesium-containing antacids may exacerbate misoprostol-induced diarrhea.
• Voriconazole - voriconazole may increase blood levels of diclofenac


• Diflunisal
• Acetaminophen - diflunisal may increase blood levels of acetaminophen by up to 50%
• Antacids - concomitant antacids may reduce diflunisal levels


• Etodolac
• False-positive urinary bilirubin - etodolac may cause false-positive urinary bilirubin on urine dipsticks


• Fenoprofen
• Highly protein-bound drugs - fenoprofen is highly bound to albumin (99%). It may displace other highly protein-bound drugs and vice versa.


• Indomethacin
• Probenecid - probenecid may raise indomethacin levels. Lower indomethacin doses may be appropriate when given with probenecid.


• Ketoprofen
• Probenecid - probenecid reduces ketoprofen clearance and increases levels. They should not be given together.


• Ketorolac
• Probenecid - probenecid reduces ketorolac clearance and increases levels. They should not be given together.
• Pentoxifylline - ketorolac should not be given with pentoxifylline because of increased risk of bleeding


• Meclofenamate
• Probenecid - probenecid may increase the half-life of meclofenamate. Lower doses of meclofenamate may be necessary.


• Mefenamic acid
• Antacids - magnesium hydroxide antacids may increase absorption of mefenamic acid
• CYP2C9 inhibitors, inducers, and substrates - mefenamic acid is a substrate of CYP2C9. Inhibitors, inducers and other substrates of CYP2C9 may alter mefenamic acid clearance. Mefenamic acid may affect the clearance of other CYP2C9 substrates.


• Meloxicam
• Sodium polystyrene sulfonate (Kayexalate®) - meloxicam suspension contains sorbitol. It should not be given with Kayexalate because cases of intestinal necrosis have been reported when kayexalate is given with sorbitol.
• CYP2C9 inhibitors, inducers, and substrates - meloxicam is a substrate of CYP2C9. Inhibitors, inducers and other substrates of CYP2C9 may alter meloxicam clearance. Meloxicam may affect the clearance of other CYP2C9 substrates.


• Naproxen
• Antacids - concomitant antacids may delay the absorption of naproxen
• Sucralfate - concomitant sucralfate may delay the absorption of naproxen
• Cholestyramine - concomitant cholestyramine may delay the absorption of naproxen
• Probenecid - probenecid reduces naproxen clearance and increases levels
• Highly protein-bound drugs - naproxen is highly protein-bound and may interact with other highly protein-bound drugs
• Acid-reducing agents (PPI, H2-blocker, etc.) - acid-reducing agents should not be given with enteric-coated naproxen
• Urinary 17-ketogenic steroids - naproxen may falsely increase urinary values of 17-ketogenic steroids with some assays
• Urinary 5-hydroxyindoleacetic acid (5HIAA) - naproxen may interfere with some urinary assays of 5HIAA


• Oxaprozin
• Urine drug screens - false-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking oxaprozin. False-positive results may persist for several days following discontinuation. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish oxaprozin from benzodiazepines


• Piroxicam
• Highly protein-bound drugs - piroxicam is highly protein-bound (99%). It may displace other highly protein-bound drugs and vice versa.


• Sulindac
• Probenecid - probenecid may increase levels of sulindac. Sulindac may cause a modest reduction in the uricosuric effect of probenecid.


• Tolmetin
• Urine proteinuria - tolmetin metabolites have been found to give false-positive results for proteinuria on tests which rely on acid precipitation as their endpoint (e.g. sulfosalicylic acid)


• Celecoxib
• CYP2C9 inhibitors, inducers, and substrates - celecoxib is primarily metabolized by CYP2C9. Inhibitors, inducers and other substrates of CYP2C9 may alter celecoxib clearance. Celecoxib may affect the clearance of other CYP2C9 substrates.
• CYP2D6 substrates - in vitro studies have shown that celecoxib is an inhibitor of CYP2D6. Celecoxib may inhibit the metabolism of CYP2D6 substrates.

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• PRICE ($) INFO

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• BIBLIOGRAPHY

• 1 - Package insert for listed drug
• 2 - Anaphylaxis and Hypersensitivity Reactions, 2011, pp 107-125, ISBN 978-1-60327-951-2
• 3 - PMID 20214589
• 4 - PMID 11496855 - NEJM COX review
• 5 - PMID 24566065 - COX and CV disease
• 6 - PMID 23726390 - CNT Collaboration
• 7 - PMID 22563589 - ACR OA Recs
• 8 - PMID 16613964 - BMJ review of COX selective NSAIDs
• 9 - Celebrex PI
• 10 - Nabumetone PI
• 11 - PMID 30207919 - Aspirin-Exacerbated Respiratory Disease, NEJM (2018)
• 12 - PMID 20214589
• 13 - Anaphylaxis and Hypersensitivity Reactions, 2011, pp 107-125, ISBN 978-1-60327-951-2
• 14 - PMID 35933139 - Preoperative Management of Medications for Rheumatologic and HIV Diseases: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement, Mayo Clin Proc (2022)