Non-steroidal anti-inflammatory drugs

Last Updated

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • Revised July 22, 2022; June 2020; June 2018; August 2016; June 2016; October 2014; February 2013; December 2012; March 2011; January 2011; October 2007; January 2006; August 2003; September 2002; August 2001; September 2000; August 2000; November 1999; October 1999; September 1998; September 1997; October 1996; October 1995.
  • Initially developed
    • January 1994

1. Dosage

Last Updated

Nonselective oral and rectal NSAIDs are FDA-approved for use in rheumatoid arthritis/juvenile rheumatoid arthritis (JRA), osteoarthritis, ankylosing spondylitis, pain management, dysmenorrhea, fever, migraines and cluster headaches. JRA is now also known as juvenile idiopathic arthritis (JIA) or juvenile arthritis (JA). Diclofenac, ibuprofen, and naproxen are also available as combination therapy with gastric acid suppressants to minimize the risk of NSAID-associated gastric ulcer development1-39.

1.1. Adults

Adult maximum daily NSAID dosages as monotherapy and combination therapy are summarized in Tables 1 and 2 and should not exceed these recommended maximum values.

Table 1. NSAID Maximum Recommended Daily Dosages for Adults: Monotherapy1-33, 37
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Daily Dosage
aspirin extended-release (ER) (Durlaza®) 162.5 mg ER capsule Reduce risk of death and myocardial infarction (MI) in patients with coronary artery disease (CAD) such as patients with a history of MI, unstable angina pectoris, or chronic stable angina 162.5 mg once daily
    Reduce risk of death and recurrent stroke in patients with previous ischemic stroke or transient ischemic attack (TIA) 162.5 mg once daily
aspirin (generics) 81 mg chewable/EC tablets; 325 mg regular/EC tablets arterial thromboembolism prophylaxis 325 mg once daily
  81 mg chewable/enteric-coated (EC) tablets; 325 mg, 500 mg regular/EC tablets; 300 mg, 600 mg rectal suppositories fever, pain (mild to moderate including dysmenorrhea) 4000 mg/day in divided doses
  81 mg chewable/EC tablets; 325 mg regular/EC tablets myocardial infarction 325 mg x1 dose, chewed
  81 mg chewable/EC tablets myocardial infarction prevention 162 mg once daily
  325 mg, 500 mg, regular/EC tablets osteoarthritis 3000 mg/day in divided doses
  325 mg, 500 mg, regular/EC tablets osteoarthritis 3000 mg/day in divided doses
  325 mg, 500 mg, regular/EC tablets rheumatoid arthritis titrate to a plasma salicylate level between 150- 300 mcg/ mL
  81 mg chewable/EC tablets; 325 mg regular/EC tablets stroke prevention in patients with TIA or other stroke risk factors 325 mg once daily
choline magnesium trisalicylate 500 mg, 750 mg, 1000 mg tablets; 500 mg/5 mL solution fever, mild/ moderate pain 3000 mg/day in divided doses
    osteoarthritis, rheumatoid arthritis, or acute painful shoulder 3000 mg/ day in divided doses
diclofenac potassium (Cambia®) 50 mg oral powder for solution acute migraine attack with or without aura 50 mg (1 packet) as single dose
diclofenac potassium immediate-release (IR) (Lofena®, Cataflam®, generics) 25 mg (Lofena®, generics), 50 mg (Cataflam®, generics) IR tablets osteoarthritis 150 mg/day in divided doses
    pain (mild to moderate) 150 mg/day in divided doses
    primary dysmenorrhea 150 mg/day in divided doses
    rheumatoid arthritis 200 mg/day in divided doses
diclofenac sodium delayed- release (DR) (generics) 25 mg, 50 mg, 75 mg DR tablets ankylosing spondylitis 125 mg/day in divided doses
    osteoarthritis 150 mg/day in divided doses
    rheumatoid arthritis 200 mg/day in divided doses
diclofenac sodium extended-release (ER) (generics) 100 mg ER tablets osteoarthritis 100 mg once daily
    rheumatoid arthritis 200 mg/day in divided doses
diclofenac potassium (Zipsor®, generics) 25 mg capsule pain (mild to moderate) 100 mg/day in divided doses
diclofenac (Zorvolex®, generics) 18 mg, 35 mg (Zorvolex®, generics) capsules osteoarthritis 105 mg/day in divided doses
    pain (mild to moderate) 105 mg/day in divided doses
diflunisal 500 mg tablets osteoarthritis 1500 mg/day in divided doses
    pain (mild to moderate) 1500 mg/day in divided doses
    rheumatoid arthritis 1500 mg/day in divided doses
etodolac IR (generics) 200 mg, 300 mg IR capsule; 400 mg, 500 mg IR tablet acute pain 1200 mg/day in divided doses
    osteoarthritis 1200 mg/day in divided doses
    rheumatoid arthritis 1200 mg/day in divided doses
etodolac ER (generics) 400 mg, 500 mg, 600 mg ER tablets osteoarthritis 1200 mg once daily
    rheumatoid arthritis 1200 mg once daily
fenoprofen capsules (Nalfon®, generics); tablets (Nalfon®, generics) 200 mg, 400 mg capsules; 600 mg tablets osteoarthritis 3200 mg/day in divided doses
    pain (mild to moderate) 3200 mg/ day in divided doses
    rheumatoid arthritis 3200 mg/day in divided doses
flurbiprofen (generics) 50 mg, 100 mg tablets osteoarthritis 300 mg/day in divided doses
    rheumatoid arthritis 300 mg/day in divided doses
ibuprofen (Advil®, Motrin®, generics) 100 mg chewable tablets; 200 mg, 400 mg, 600 mg, 800 mg tablets; 200 mg capsule; 100 mg/5 mL suspension dysmenorrhea 3200 mg/day in divided doses
    fever 3200 mg/day in divided doses
    headache 3200 mg/day in divided doses
    migraine 3200 mg/day in divided doses
    osteoarthritis 3200 mg/day in divided doses
    pain (mild to moderate) 3200 mg/day in divided doses
    rheumatoid arthritis 3200 mg/day in divided doses
indomethacin IR (generics) 25 mg, 50 mg capsules; 25 mg/5 mL suspension acute bursitis or tendinitis 200 mg/day in divided doses
    acute gouty arthritis 200 mg/day in divided doses
    ankylosing spondylitis 200 mg/day in divided doses
    osteoarthritis 200 mg/day in divided doses
    rheumatoid arthritis 200 mg/day in divided doses
indomethacin ER (generics) 75 mg ER capsules acute bursitis or tendinitis 150 mg/day in divided doses
    ankylosing spondylitis 150 mg/day in divided doses
    osteoarthritis 150 mg/day in divided doses
    rheumatoid arthritis 150 mg/day in divided doses
indomethacin (Tivorbex®, generics) 20 mg capsules acute pain (mild to moderate) 120 mg/day in divided doses
indomethacin rectal (Indocin®) 50 mg rectal suppository acute bursitis or tendinitis 150 mg/day in divided doses; no more than 100 mg per dose
    acute gouty arthritis 150 mg/day in divided doses; no more than 100 mg per dose
    ankylosing spondylitis 200 mg/day in divided doses; no more than 100 mg per dose
    osteoarthritis 200 mg/day in divided doses; no more than 100 mg per dose
    rheumatoid arthritis 200 mg/day in divided doses; no more than 100 mg per dose
ketoprofen IR (generics) 25 mg, 50 mg, 75 mg IR capsules osteoarthritis 300 mg/day in divided doses
    pain (mild/moderate, including acute dysmenorrhea) 300 mg/day in divided doses
    rheumatoid arthritis 300 mg/day in divided doses
ketoprofen ER (generics) 200 mg ER capsule osteoarthritis 200 mg once daily
    rheumatoid arthritis 200 mg once daily
ketorolac (generics) 10mg tablets acute pain (moderately severe) following IV or IM treatment 40 mg/day in divided doses
magnesium salicylate (Doans®, generics) 580 mg extended-release caplets pain (mild/moderate) 4640 mg/day (8 caplets) in divided doses
meclofenamate (generics) 50 mg, 100 mg capsules acute bursitis or tendinitis 400 mg/day in divided doses
    acute gouty arthritis 400 mg/day in divided doses
    ankylosing spondylitis 400 mg/day in divided doses
    dysmenorrhea and idiopathic heavy menstrual blood loss 300 mg/day in divided doses
    osteoarthritis 400 mg/day in divided doses
    pain (mild/ moderate) 400 mg/day in divided doses
    rheumatoid arthritis 400 mg/day in divided doses
mefenamic acid (generics) 250 mg capsules pain (mild/ moderate including dysmenorrhea) 1250 mg in divided doses on day 1; 1000 mg/day in divided doses on days 2-7
meloxicam (Mobic®, generics) 7.5 mg, 15 mg tablets, 7.5 mg/ 5 mL suspension osteoarthritis 15 mg/day once daily
    rheumatoid arthritis 15 mg/day once daily
meloxicam (Vivlodex®, generics) 5 mg, 10 mg capsules osteoarthritis 10 mg/day once daily
nabumetone (generics) 500 mg, 750 mg tablets osteoarthritis 2000 mg/day in single or divided doses
    rheumatoid arthritis 2000 mg/day in single or divided doses
naproxen IR (Aleve®, Naprosyn®,  generics) 220 mg IR capsule; 220 mg, 250 mg, 275 mg, 375 mg, 500 mg IR tablets; 125 mg/5 mL IR suspension acute gout 1500 mg/day in divided doses
    ankylosing spondylitis 1500 mg/day in divided doses
    bursitis/tendinitis 1500 mg/day in divided doses
    osteoarthritis 1500 mg/day in divided doses
    pain (mild/moderate including dysmenorrhea) 1500 mg/day in divided doses
    rheumatoid arthritis 1500 mg/day in divided doses
naproxen sodium (Anaprox DS®, generics) 220 mg, 275 mg, 550 mg IR tablets acute gout 1650 mg/day in divided doses
    ankylosing spondylitis 1650 mg/day in divided doses
    bursitis/tendinitis 1650 mg/day in divided doses
    osteoarthritis 1650 mg/day in divided doses
    pain (mild/moderate including dysmenorrhea) 1650 mg/day in divided doses
    rheumatoid arthritis 1650 mg/day in divided doses
naproxen DR (EC-Naprosyn®, generics) 375 mg, 500 mg DR tablets ankylosing spondylitis 1500 mg/day in divided doses
    osteoarthritis 1500 mg/day in divided doses
    rheumatoid arthritis 1500 mg/day in divided doses
naproxen ER (Naprelan®, generics 375 mg, 500 mg, 750 mg ER tablets acute gout 1500 mg/day in divided doses
    ankylosing spondylitis 1500 mg/day in divided doses
    bursitis/tendinitis 1500 mg/day in divided doses
    osteoarthritis 1500 mg/day in divided doses
    pain (mild/moderate including dysmenorrhea) 1500 mg/day in divided doses
    rheumatoid arthritis 1500 mg/day in divided doses
oxaprozin (Daypro®, generics) 600 mg tablets osteoarthritis 1800 mg/day (not to exceed 26 mg/kg/day) in divided doses
    rheumatoid arthritis 1800 mg/day (not to exceed 26 mg/kg/day) in divided doses
piroxicam (Feldene®, generics) 10 mg, 20 mg capsules osteoarthritis 20 mg once daily
    rheumatoid arthritis 20 mg once daily
salsalate (Disalcid®, generics) 500 mg, 750 mg tablets osteoarthritis 3000 mg/day in divided doses
    rheumatoid arthritis 3000 mg/day in divided doses
sulindac (generics) 150 mg, 200 mg tablets acute gouty arthritis 400 mg/day in divided doses
    ankylosing spondylitis 400 mg/day in divided doses
    bursitis/tendinitis of shoulder 400 mg/day in divided doses
    osteoarthritis 400 mg/day in divided doses
    rheumatoid arthritis 400 mg/day in divided doses
Table 2. NSAID Maximum Recommended Daily Dosages for Adults: Non-Opioid Combination Therapy1,2,34-36
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Daily Dosage
acetaminophen/ aspirin/caffeine (Excedrin® Migraine, generics) 250 mg/250 mg/65 mg tablets migraine headache 2 tablets/24 hours
    pain, including headache 8 tablets/24 hours in divided doses
acetaminophen/aspirin/caffeine (Goody’s®) 260 mg/520 mg/32.5 mg powders pain, including headache 4 powders/24 hours in divided doses
aspirin/butalbital/caffeine (Fiorinal®, generics) 325 mg/50 mg/40 mg capsules, tablets tension or muscle contraction headache 6 capsules/24 hours in divided doses (1 or 2 every 4 hours)
diclofenac/misoprostol  (Arthrotec®, generics) 50 mg/200 mcg, 75 mg/200 mcg delayed-release tablet osteoarthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers 150 mg/600 mcg/day in divided doses
    rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers 200 mg/800 mcg/day in divided doses
ibuprofen/famotidine (Duexis®, generic) 800 mg/26.6 mg tablet pain relief in osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers 2400 mg/79.8 mg/day in divided doses
    pain relief in rheumatoid arthritis and to decrease the risk of developing upper gastrointestinal ulcers 2400 mg/79.8 mg/day in divided doses
naproxen/esomeprazole (Vimovo®, generic) 375 mg/20 mg, 500 mg/20 mg delayed-release tablet ankylosing spondylitis in patients at risk of developing NSAID-associated ulcers 1000 mg/40 mg/day in divided doses
    osteoarthritis in patients at risk of developing NSAID-associated ulcers 1000 mg/40 mg/day in divided doses
    rheumatoid arthritis in patients at risk of developing NSAID-associated ulcers 1000 mg/40 mg/day in divided doses

1.2. Pediatrics

NSAID safety and efficacy in children have not been established for all available agents. Ibuprofen is FDA-approved for short-term management of fever and mild to moderate pain and long-term management of JRA/JIA/JA in pediatric patients; meloxicam and naproxen are FDA-approved for use in children as young as 2 years of age 1,2,24,25,29,37. Indomethacin is not FDA-approved in those less than 15 years of age, but JRA/JIA/JA patients between 2 and 14 years of age who have experienced toxicity/lack of benefit from other medications, may receive indomethacin up to a maximum dose of 3 mg/kg/day (no more than 200 mg/day orally)1,2,17,38. Aspirin, while FDA-approved for use in fever and pain for adolescents, should not be given for fever and muscle aches seen in viral illness due to the potential for Reye’s syndrome1,2,38. Aspirin in combination with acetaminophen and caffeine is FDA-approved for use in adolescent patients for mild to moderate pain, while naproxen/esomeprazole (Vimovo®) is approved for use in adolescents weighing at least 38 kg diagnosed with juvenile idiopathic arthritis at increased risk for NSAID associated gastric ulcers1,2,36 . NSAID dosages for pediatric indications are summarized in Tables 3 and 4. Dosages exceeding these recommendations will be reviewed.

Table 3. NSAID Recommended Maximum Daily Dosages for Pediatric Patients1,2,10,12,16,17,22-24,28-30
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Daily Dosage
aspirin* 81 mg chewable/EC tablets; 325 mg, 500 mg regular/EC tablets; 300 mg, 600 mg rectal suppositories fever/pain
  • Greater than or equal to 12 years of age:
    • 4000 mg/day in divided doses
choline magnesium trisalicylate 500 mg, 750 mg, 1000 mg tablets; 500 mg/5 mL solution juvenile rheumatoid arthritis (JRA)/ juvenile idiopathic arthritis (JIA)
  • Less than 37 kg:
    • 50 mg/kg/day
  • Greater than 37 kg:
    • 2250 mg/day
  • adolescents:
    • 2250 mg/day
diflunisal (generics) 500 mg tablets osteoarthritis
  • Greater than or equal to 12 years of age:
    • 1500 mg/day in divided doses
    pain (mild/moderate)
  • Greater than 12 years of age:
    • 1500 mg/day in divided doses
    rheumatoid arthritis
  • Greater than or equal to 12 years of age:
    • 1500 mg/day in divided doses
etodolac extended-release (ER) (generics) 400 mg, 500 mg, 600 mg ER tablets JIA/JRA
  • Greater than or equal to 6 years of age:
    • 20-30 kg: 400 mg/day
    • 31-45 kg: 600 mg/day
    • 46-60 kg: 800 mg/day
  • Greater than 60 kg:
    • 1000 mg/day
diflunisal (generics) 500 mg tablets osteoarthritis
  • Greater than or equal to 12 years of age:
    • 1500 mg/day in divided doses
    pain (mild/moderate)
  • Greater than 12 years of age:
    • 1500 mg/day in divided doses
    rheumatoid arthritis
  • Greater than or equal to 12 years of age:
    • 1500 mg/day in divided doses
etodolac extended-release (ER) (generics) 400 mg, 500 mg, 600 mg ER tablets JIA/JRA
  • Greater than or equal to 6 years of age:
    • 20-30 kg: 400 mg/day
    • 31-45 kg: 600 mg/day
    • 46-60 kg: 800 mg/day
  • Greater than 60 kg:
    • 1000 mg/day
ibuprofen (Motrin®, generics) 50 mg/1.25 ml oral drops fever, pain (mild to moderate)
  • 6 months to 11 months:
    • 200 mg/day in divided doses
  • 12 to 23 months:
    • 300 mg/day in divided doses
ibuprofen (Advil®, Motrin®, generics) 100 mg/5 ml suspension fever, pain (mild to moderate)
  • 6 months to 2 years:
    • 40 mg/kg/day in divided doses
  • 24-35 lbs (2-3 yrs):
    • 400 mg/day in divided doses
  • 36-47 lbs (4-5 yrs):   
    • 600 mg/day in divided doses
  • 48-59 lbs (6-8 yrs):
    • 800 mg/day in divided doses
  • 60-71 lbs (9-10 yrs):
    • 1000 mg/day in divided doses
  • 72-95 lbs (11 yrs):
    • 1200 mg/day in divided doses
ibuprofen (Advil®, generics) 100 mg chewable tablets fever, pain (mild to moderate)
  • 24-35 lbs (2-3 yrs):
    • 400 mg/day in divided doses
  • 36-47 lbs (4-5 yrs):
    • 600 mg/day in divided doses
  • 48-59 lbs (6-8 yrs):
    • 800 mg/day in divided doses
  • 60-71 lbs (9-10 yrs):
    • 1000 mg/day in divided doses
  • 72-95 lbs (11 yrs):
    • 1200 mg/day in divided doses
ibuprofen (Advil®, generics) 200 mg caplets, capsules, or tablets fever, pain (mild to moderate)
  • 12 years to 17 years:
    • 1200 mg/day in divided doses
ibuprofen (Advil®, Motrin®, generics) chewable tablets, suspension, tablets JIA/JRA
  • 1 to less than 16 years of age:
    • 50 mg/kg/day in divided doses up to 2400 mg/day
indomethacin IR+ (generics) 25 mg, 50 mg IR capsules; 25 mg/5 mL suspension arthritic disorders
  • 15 to 17 years of age:
    • 200 mg/day in divided doses
  50 mg rectal suppository  
  • 15 to 17 years of age:
    • 200 mg/day in divided doses; no more than 100 mg per dose
indomethacin ER+ (generics) 75 mg ER capsules  
  • 15 to 17 years of age:
    • 150 mg/day in divided doses
magnesium salicylate (Doans®, generics) 580 mg extended-release caplets pain (mild to moderate)
  • Greater than or equal to 12 years of age:
    • 4640 mg/day (8 tablets) in divided doses
meclofenamate (generics) 50 mg, 100 mg capsules dysmenorrhea
  • Greater than or equal to 14 years of age:
    • 300 mg/day in divided doses
    JIA/JRA
  • Greater than or equal to 14 years of age:
    • 400 mg/day in divided doses
    pain (mild/moderate)
  • Greater than or equal to 14 years of age:
    • 400 mg/day in divided doses
mefenamic acid (generics) 250 mg capsules pain (mild/moderate, including dysmenorrhea)
  • Greater than or equal to 14 years of age:
    • 1250 mg/day on day 1 (500 mg x1 followed by 250 mg every 6 hours); 1000 mg/day on days 2-7
meloxicam (Mobic®, generics) 7.5 mg tablets; 7.5 mg orally disintegrating tablets (ODT) JIA/JRA
  • 2-17 years of age, Greater than or equal to 60 kg:
    • 7.5 mg once daily
  7.5 mg/5 mL suspension  
  • Greater than or equal to 2 years of age: 
    • 0.125 mg/ kg once daily
    • 12 kg: 1.5 mg once daily
    • 24 kg: 3.0 mg once daily
    • 36 kg: 4.5 mg once daily
    • 48 kg: 6.0 mg once daily
  • Greater than or equal to 60 kg:
    • 7.5 mg once daily
naproxen (Aleve®, Naprosyn®, generics) 220 mg IR capsule; 220 mg, 250 mg, 275 mg, 375 mg, 500 mg IR tablets; 125 mg/5 mL IR suspension JIA/JRA
  • Greater than or equal to 2 years of age:
    • 15 mg/kg/day in divided doses up to 1000 mg/ day
    pain (mild to moderate including dysmenorrhea)
  • Greater than 12 years of age:
    • 1000 mg/day in divided doses
oxaprozin (Daypro®, generics) 600 mg tablets JIA/JRA
  • Greater than 6 years to 16 years of age:
    • 22-31 kg: 600 mg/day
    • 32-54 kg: 900 mg/day
  • Greater than 55 kg:
    • 1200 mg/day

Legend:

  • *Do not use in children less than 12 years of age with flu-like symptoms or chickenpox due to risk of Reye syndrome
  • +indomethacin not recommended in pediatric patients 2-14 years of age unless adverse effects/lack of efficacy with other NSAIDs justifies risk; maximum dose is 4 mg/kg/day or 200 mg/day, whichever is less
Table 4. NSAID Maximum Recommended Daily Dosages for Pediatrics: Non-Opioid Combination Therapy1,2,36
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Daily Dosage 
acetaminophen/aspirin/caffeine (Excedrin®, generics) 250 mg/250 mg/65 mg tablets pain, including headache 12-17 years of age: 8 tablets/24 hours in divided doses
acetaminophen/aspirin/caffeine (Goody’s®) 260 mg/ 520 mg/ 32.5 mg powders   12-17 years of age: 4 powders/24 hours in divided doses
naproxen/esomeprazole (Vimovo®, generic) 375 mg/20 mg, 500 mg/20 mg delayed-release tablet juvenile rheumatoid arthritis/ juvenile idiopathic arthritis in patients at risk of developing NSAID-associated ulcers
  • 12-17 years of age and Greater than or equal to 50 kg:
    • 1000 mg/40 mg/day in two divided doses
  • 12-17 years of age and 38 to 49 kg:
    • 750 mg/40 mg/day in two divided doses

2.1. Therapy Limits

The duration of therapy derived for NSAIDs may be long-term and indefinite when prescribed for chronic indications; however, the lowest effective dosages for the shortest possible time should be utilized. NSAIDs should be prescribed cautiously, if at all, to patients at high risk for gastrointestinal complications and patients with known cardiovascular disease. High-risk patients include those with a history of peptic ulcer disease or gastrointestinal bleeding, those with concurrent prescriptions for anticoagulants or corticosteroids, those prescribed high NSAID doses, those with a history of alcohol use and/or smoking, and the elderly. High-risk patients unable to discontinue or reduce NSAID use may benefit from adjunctive therapy with gastroprotective agents such as misoprostol, a histamine-2 receptor antagonist, or proton pump inhibitors.

Treatment duration is limited for mefenamic acid to minimize the occurrence of adverse events. Mefenamic acid should be prescribed for no longer than seven days for pain management and no longer than three days for dysmenorrhea to reduce the incidence of diarrhea associated with the use of this drug23.

Treatment duration of ketorolac should not exceed 5 total days due to increased risk of adverse events such as risk of gastric ulceration, bleeding, and perforation37.

Diclofenac powder for oral solution is indicated as a single 50 mg dose to treat acute migraine headache. Safety and efficacy of a second dose for an attack have not been established4.

2.2. NSAID Use in Elderly Patients

Elderly patients frequently utilize prescription and nonprescription NSAIDs to manage acute and chronic pain. Several issues surface with NSAID use in elderly patients, including potential adverse effects and drug interactions. NSAID-induced gastrointestinal and renal toxicity as well as adverse central nervous system effects are more prevalent in elderly patients due to changes in metabolism, underlying disease states, and concurrent drug therapy. The potential for increased cardiovascular risk with NSAID use is also a factor when evaluating NSAID therapy in elderly patients. Elderly patients prescribed NSAIDs, especially those at higher risk, should be evaluated for appropriateness of therapy as well as potential for drug-drug interactions. Appropriate therapy duration as well as appropriate dosages should also be evaluated. Preventive measures such as gastric antisecretory agents should be considered in some individuals to reduce GI complications40. Medication profiles of elderly patients greater than 60 years of age prescribed NSAIDs with increased risk factors for adverse events or drug-drug interactions will be reviewed.

2.3. NSAID Use and Cardiovascular Risk

Some clinical trials have shown that patients prescribed selective and nonselective NSAIDs may be at increased risk for serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, all of which can be fatal. Patients at greater risk are those with known CV disease or risk factors for CV disease. Due to the lack of long-term clinical trial data, CV risks associated with NSAID use remains controversial, especially in high-risk patients. Risk also varies between nonselective NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, as well as between individual NSAIDs. The Center for Drug Evaluation and Research has determined that the increased risk of CV events associated with NSAID use should be considered a class effect for both selective and nonselective NSAIDs until more results are available. Patients should be prescribed the lowest effective NSAID dose for the shortest possible treatment duration to minimize the potential for cardiovascular adverse events41-46.

NSAIDs may induce new onset hypertension or worsen pre-existing hypertension in some patients, which may contribute to the development of cardiovascular adverse events. Blood pressure should be routinely monitored in patients prescribed NSAIDs.

NSAIDs may cause fluid retention or edema in some patients and should be used cautiously in patients with a history of fluid retention or heart failure.

2.4. NSAID Use and Gastrointestinal Risk

All NSAIDs may be associated with an increased risk of serious gastrointestinal (GI) adverse events, including potentially fatal GI bleeding, ulceration, or gastric/intestinal perforation. The risk of NSAID-associated severe GI adverse events increases in patients with a history of peptic ulcer disease, GI bleeding, smoking, alcohol use, concurrent use of anticoagulants or oral corticosteroids, advanced age, poor health and prolonged NSAID use. However, COX-2 inhibitors like celecoxib may be associated with fewer GI adverse events due to selective COX-2 inhibition. Some trials have shown reduced ulcer complications and lower GI bleeding rates with celecoxib compared to nonselective NSAIDs. Further long-term studies are necessary to substantiate the perceived lower GI risk associated with COX-2 inhibitors47,48<./p>

3. Duplicative Therapy

The combination of two or more NSAIDs is not recommended except the use of less than 325 mg daily of aspirin plus another NSAID.

Concurrent administration of an NSAID and ketorolac, another NSAID utilized primarily for pain management with limited treatment duration, is contraindicated due to the potential for increased gastrointestinal adverse events.

The combined use of specific COX-2 inhibitors like celecoxib and nonspecific COX-1/COX-2 inhibitors does not provide additional therapeutic benefit and may result in additive adverse effects, including gastrointestinal toxicity. Concurrent therapy with specific COX-2 inhibitors and nonspecific COX-1/COX-2 inhibitors is not recommended and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically significant for NSAIDs are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 5. NSAID Drug-Drug Interactions
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
NSAIDs antihypertensive agents (e.g., ACE inhibitors, angiotensin receptor blockers, beta blockers, diuretics) potential for decreased antihypertensive effects, increased renal impairment risk (especially in patents dependent on renal prostaglandins for perfusion), with combined therapy; increased hyperkalemia risk with potassium-sparing diuretics; NSAIDs may block production of  vasodilator and  natriuretic prostaglandins monitor blood pressure, renal function; observe for hyperkalemia with potassium-sparing diuretics; modify therapy as necessary; use combination cautiously in elderly; sulindac, nonacetylated salicylates may be alternative NSAIDS – have less inhibitory effect on prostaglandin synthesis moderate (DrugReax) 3-moderate (CP)
NSAIDs antiplatelet drugs (e.g., clopidogrel, prasugrel) potential for increased bleeding risk due to additive inhibitory effects on platelet aggregation administer cautiously together; monitor for increased bleeding, especially gastrointestinal (GI) bleeding clopidogrel –major; prasugrel - moderate (DrugReax)
3-moderate (CP)
NSAIDs aspirin (ASA) combined therapy may result in reduced ASA antiplatelet/ cardioprotective effects due to competitive inhibition of COX-1 binding site ASA should be administered at least 30 minutes before or 8 hours after NSAID; NSAID should be given at least 1 hour after enteric-coated ASA moderate (DrugReax)
NSAIDs bisphosphonates combined therapy may result in additive GI, renal toxicity; NSAIDs also decrease bone mineral density, may attenuate bone mineral stabilizing effects by bisphosphonates administer combination cautiously; monitor for increased GI/renal adverse effects, reduced bone mineral density 2-major (CP)
NSAIDs corticosteroids potential for increased GI adverse effects with combined therapy monitor for adverse effects; avoid prolonged concurrent administration 3-moderate (CP)
NSAIDs cyclosporine increased risk for additive renal dysfunction with concurrent administration; potential for reduced cyclosporine elimination/ increased pharmacologic and adverse effects due to NSAID effects on renal prostaglandins; NSAIDs may mask signs of infection (e.g., fever, swelling) use cautiously together; monitor clinical status, renal function, serum potassium concentrations 3-moderate (CP)
NSAIDs fluoroquinolones increased risk for CNS stimulation and seizures administer cautiously together; consider alternative therapy in patients with predisposition to seizures moderate (DrugReax) 3-moderate (CP)
NSAIDs lithium NSAIDs may decrease lithium clearance most likely by blocking renal tubular prostaglandins; may result in increased lithium levels and potential for adverse effects avoid combination, if possible; if concurrent therapy necessary, monitor lithium levels and signs/symptoms of lithium toxicity; sulindac, aspirin do not affect lithium clearance -may be alternative NSAIDS moderate (DrugReax) 3-moderate (CP)
NSAIDs low molecular weight heparins potential for additive bleeding adverse effects; NSAIDs inhibit platelet aggregation and have increased GI bleeding risk, prolonged bleeding time avoid concurrent therapy, if possible; if drug combination necessary, use cautiously, monitor for signs/symptoms of bleeding major (DrugReax) 2-major (CP)
NSAIDs methotrexate (MTX) potential for increased MTX serum levels, risk of enhanced pharmacologic/toxic effects as NSAIDs can reduce MTX clearance avoid concurrent NSAIDs within 10 days of high-dose MTX; otherwise, use cautiously together; monitor for increased myelopsuppressive, GI adverse effects; may consider using longer leucovorin rescue major (DrugReax) 1-severe (CP)
NSAIDs phenytoin NSAIDs may inhibit phenytoin metabolism, with increased risk for enhanced phenytoin pharmacologic/toxic effects (e.g., ataxia, nystagmus, hyperreflexia) monitor for signs/symptoms of phenytoin toxicity, especially in patients with renal impairment; adjust doses as necessary moderate (DrugReax)
NSAIDs select azole antifungals  (e.g., fluconazole, voriconazole) for NSAIDs metabolized by CYP2C9, increased risk of elevated NSAID plasma levels and potential for enhanced pharmacologic/adverse effects; select antifungals inhibit CYP2C9 administer cautiously together; monitor for increased NSAID pharmacologic/adverse effects (e.g., bleeding, renal dysfunction); consider reduced NSAID doses, if necessary, or alternate NSAID/antifungal that does not affect metabolism moderate (DrugReax) 3-moderate (CP)
NSAIDs SSRIs/SNRIs (e.g., milnacipran) increased bleeding risk with combined therapy, especially GI bleeding;  SSRIs/SNRIs deplete platelet serotonin, which may impair platelet aggregation monitor for signs/symptoms of bleeding; may consider lower NSAID doses, shorter treatment durations, adding proton pump inhibitor, or substituting tricyclic antidepressant for SSRI/SNRI SSRIs –major; SNRIs-moderate (DrugReax) 3-moderate (CP)
NSAIDs sulfonylureas increased risk for additive hypoglycemia monitor serum glucose concentrations; adjust doses as necessary moderate (DrugReax) 4-minor (CP)
NSAIDs tacrolimus potential for additive nephrotoxicity with combined therapy due to NSAID inhibitory effects on renal prostaglandins avoid combination, if possible; if concurrent therapy necessary, closely monitor renal function major (DrugReax) 3-moderate (CP)
NSAIDs warfarin combined therapy may result in increased INR and increased risk of GI adverse effects, especially in elderly; mechanism unknown monitor anticoagulant activity, especially in first several days of combination therapy; adjust warfarin doses as necessary major (DrugReax) 2-major (CP)

Legend:

  • # CP = Clinical Pharmacology

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/ (cited: June 20, 2022). 
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2022. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu. Accessed June 20, 2022.
  3. Aspirin extended-release capsules (Durlaza®) package insert. New Haven Pharmaceuticals, September 2015.
  4. Diclofenac potassium powder for solution (Cambia®) package insert. Assertio Therapeutics, Inc. October 2019.
  5. Diclofenac potassium tablet (Lofena®) package insert. Carwin Pharmaceutical Associates, LLC. November 2021.
  6. Diclofenac potassium tablet (Cataflam®) package insert. Blucrest Pharmaceuticals, LLC. July 2021.
  7. Diclofenac potassium tablets package insert. Mylan Pharmaceuticals, October 2020.
  8. Diclofenac potassium liquid filled capsule (Zipsor®) package insert. Assertio Therapeutics, Inc. April 2021.
  9. Diclofenac capsules (Zorvolex®) package insert. Iroko Pharmaceuticals, LLC, April 2019.
  10. Diflunisal oral tablet package insert. Cadila Healthcare Limited. December 2019.
  11. Etodolac tablets and capsules package insert. Taro Pharmaceuticals U.S.A., Inc. March 2021.
  12. Etodolac extended-release tablets package insert. Northstar RX LLC. May 2021.
  13. Fenoprofen calcium oral capsule (Nalfon®) package insert. Xspire Pharma. May 2021.
  14. Fenoprofen calcium oral tablet (Nalfon®) package insert. Xspire Pharma. May 2021.
  15. Flurbiprofen oral tablet package insert. Teva Pharmaceuticals USA, Inc. November 2021.
  16. Ibuprofen oral tablets product information. Aero Healthcare. April 2022.
  17. Indomethacin oral capsule package insert. Cadila Healthcare Limited. August 2021.
  18. Indomethacin capsules (Tivorbex®) package insert. Iroko Pharmaceuticals, LLC, January 2018.
  19. Indomethacin (Indocin®) package insert. Zyla Life Sciences US Inc. November 2021.
  20. Ketoprofen oral capsule package insert. Misemer Pharmaceuticals, Inc. January 2022.
  21. Ketoprofen extended release oral capsule package insert. Mylan Pharmaceuticals Inc. March 2021.
  22. Meclofenamate oral capsule package insert. Mylan Pharmaceuticals Inc. May 2021.
  23. Mefenamic acid capsules package insert. Belcher Pharmaceuticals, LLC. December 2021.
  24. Meloxicam oral tablet (Mobic ®) package insert. Boehringer Ingelheim Pharmaceuticals, Inc. October 2018.
  25. Meloxicam capsules (Vivlodex®) package insert. Egalet US Inc. April 2021.
  26. Nabumetone oral tablet (Relafen®) package insert. Blucrest Pharmaceuticals LLC. July 2021.
  27. Nabumetone oral tablet (Relafen DS®) package insert. Carwin Pharmaceutical Associates, LLC. May 2022.
  28. Naproxen delayed-release tablets (EC-Naprosyn®), naproxen tablets (Naprosyn®), naproxen sodium tablets (Anaprox®/Anaprox® DS) package insert. Atnahs Pharma US. March 2017.
  29. Naproxen sodium controlled-release tablets (Naprelan®) package insert.  Almatica Pharma. April 2021.
  30. Oxaprozin caplets (Daypro®) package insert. Pfizer. January 2022.
  31. Piroxicam oral capsules (Feldene®) package insert. Pfizer. May 2021.
  32. Salsalate oral tablet package insert. Acella Pharmaceuticals, LLC. January 2020.
  33. Sulindac oral tablet package insert. Actavis Pharma, Inc. September 2021.
  34. Diclofenac sodium/misoprostol tablets (Arthrotec®) package insert. Pfizer. August 2021.
  35. Ibuprofen and famotidine oral tablet (Duexis®) package insert. Horizon Therapeutics USA, Inc. June 2021.
  36. Naproxen and esomeprazole magnesium oral tablet (Vimovo®) package insert. Horizon Therapeutics USA, Inc. March 2022.
  37. Ketorolac (Toradol®) package insert. Roche Pharmaceuticals. March 2013.
  38. Children’s ibuprofen suspension (100 mg/5 ml) product information. Amazon.com Services LLC. November 2021.
  39. AHFS Drug Information 2022. Bethesda, MD: American Society of Health-System Pharmacists. 2022. Available at: http://online.statref.com.ezproxy.lib.utexas.edu/document/F9-IjOEqk3ZluRgZSvZvmt!!. Accessed June 20, 2022. 
  40. Wongrakpanich S, Wongrakpanich A, Melhado K, Rangaswami J. A comprehensive review of non-steroidal anti-inflammatory drug use in the elderly. Aging Dis. 2018;9(1):143-150. 
  41. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. COX-2 selective (includes Bextra, Celebrex, and Vioxx) and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). (February 6, 2018) Available at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory. Accessed June 20, 2022.
  42. United States Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. (July 9, 2015)  Available at:  http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm. Accessed June 20, 2022.
  43. Joshi GP, Gertler R, Fricker R. Cardiovascular thromboembolic adverse effects associated with cyclooxygenase-2 selective inhibitors and nonselective antiinflammatory drugs. Anesth Analg. 2007;105:1793–804.
  44. Waksman JC, Brody A, Phillips SD. Nonselective nonsteroidal antiinflammatory drugs and cardiovascular risk: are they safe? Ann Pharmacother. 2007;41:1163-73.
  45. Hermann M, Ruschitzka F. Cardiovascular risk of cyclooxygenase-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs. Ann Med. 2007;39:18-27.
  46. Friedewald VE, Bennett JS, Christo JP, et al. AJC Editor's consensus: Selective and nonselective nonsteroidal anti-inflammatory drugs and cardiovascular risk. Am J Cardiol. 2010;106(6):873-84.
  47. Lazzaroni M, Battocchia A, Porro GB. COXIBs and non-selective NSAIDs in the gastroenterological setting: What should patients and physicians do?  Dig Liver Dis. 2007;39:589-96.
  48. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized trial. JAMA. 2000;284;1247-55.