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- 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
- NONSELECTIVE NSAIDs
Aspirin | Acetylsalicylic acid | ASA
Dosage forms
- Aspirin is available over-the-counter in many different brands (e.g. Bayer®, St. Joseph®, Bufferin®, etc.)
- Aspirin comes in tablets, caplets, buffered forms, enteric-coated forms, and chewable pills
- Most common dosage forms are 81, 325, and 500 mg
Dosing - Adults
Analgesic/antipyretic
- 325 - 1000 mg every 6 hours as needed
- Do not exceed 4000 mg/day
Acute heart attack
- 162 - 325 mg of non-enteric coated aspirin, chewed or swallowed
- AHA recommendation
Secondary prevention of coronary artery disease
- 75 - 162 mg once daily
- See coronary artery disease for more.
- AHA recommendation
Dual antiplatelet therapy (with P2Y12 inhibitor)
- 81 mg once daily
- See dual antiplatelet therapy for more
- AHA recommendation
Dosing - Children
- With a few exceptions, aspirin is not recommended in children and teenagers because of the risk of Reye's syndrome
Other
- See aspirin for a comprehensive review of aspirin including its use in cardiovascular disease and other disease prevention
Generic / Price
- YES/$Diflunisal (Dolobid®)
Dosage forms
Tablet
- 500 mg
Dosing
Mild to moderate pain
- Initial dose of 1000 mg followed by 500 mg every 12 hours as needed
- Some patients may require 500 mg every 8 hours
- Do not exceed 1500 mg/day
Osteoarthritis
- 500 -1000 mg/day given in two divided doses
- Do not exceed 1500 mg/day
Rheumatoid arthritis
- 500 -1000 mg/day given in two divided doses
- Do not exceed 1500 mg/day
Other
- Half-life: 8 - 12 hours
Generic / Price
- YES/$Fenoprofen (Nalfon®)
Dosage forms
Tablet
- 600 mg
Dosing
Mild to moderate pain
- 200 mg every 4 - 6 hours as needed
Osteoarthritis
- 400 - 600 mg three to four times a day as needed
- Do not exceed 3200 mg/day
Rheumatoid arthritis
- 400 - 600 mg three to four times a day as needed
- Do not exceed 3200 mg/day
Other
- Half-life: 3 hours
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
Generic / Price
- YES/$Flurbiprofen (Ansaid®)
Dosage forms
Tablet
- 50 mg
- 100 mg
Dosing
Osteoarthritis
- 50 - 100 mg two to four times a day as needed
- Recommended starting dose is 200 - 300 mg/day
Rheumatoid arthritis
- 50 - 100 mg two to four times a day as needed
- Recommended starting dose is 200 - 300 mg/day
Other
- Half-life: 5.7 hours
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
Generic / Price
- YES/$Ibuprofen | Advil® | Motrin®
Dosage forms
Tablet
- 200 mg (OTC)
- 400 mg
- 600 mg
- 800 mg
Suspension (Children's Motrin®)
- 100 mg/5 ml (OTC)
Drops (Infants' Motrin®)
- 50 mg/1.25ml (OTC)
Dosing (6 months - 2 years)
Pain/fever
- Dosing based on infant drops (50 mg/1.25ml)
- May repeat dose every 6 - 8 hours
- Do not give more than 4 doses a day
Weight (lbs) | Weight (kg) | Age (months) | Dose |
---|---|---|---|
Under 6 months | Not well studied | ||
12 - 17 | 5.4 - 8.1 | 6 - 11 | 1.25 ml (50 mg) |
18 - 23 | 8.2 - 10.8 | 12 - 23 | 1.875 ml (75 mg) |
Alternative: 5 - 10 mg/kg/dose |
Dosing (2 - 11 years)
Pain/fever
- May repeat dose every 6 - 8 hours
- Do not give more than 4 doses a day
Weight (lbs) | Weight (kg) | Age (years) | Dose (mg) |
---|---|---|---|
24 - 35 | 10.9 - 16.3 | 2 - 3 | 100 |
36 - 47 | 16.4 - 21.7 | 4 - 5 | 150 |
48 - 59 | 21.8 - 27.2 | 6 - 8 | 200 |
60 - 71 | 27.3 - 32.6 | 9 - 10 | 250 |
72 - 95 | 32.7 - 43.2 | 11 | 300 |
Alternative: 5 - 10 mg/kg/dose (max 400 mg) |
Dosing (Adults)
Mild to moderate pain
- 400 mg every 4 - 6 hours as needed
- In trials, doses above 400 mg were not more effective than 400 mg
Dysmenorrhea
- 400 mg every 4 hours as needed
Osteoarthritis
- 400 - 800 mg three to four times a day
- In trials, daily doses above 2400 mg were not more effective than 2400 mg/day
Rheumatoid arthritis
- 400 - 800 mg three to four times a day
- In trials, daily doses above 2400 mg were not more effective than 2400 mg/day
Efficacy
Arthritis
Other
- Half-life: 2.2 hours
- Taking after a meal may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
Generic / Price
- YES/$ (all forms)Ibuprofen + Famotidine (Duexis®)
Dosage forms
Tablet
- Famotidine : Ibuprofen
- 26.6 mg : 800 mg
Dosing
Osteoarthritis
- 1 tablet three times a day as needed
Rheumatoid arthritis
- 1 tablet three times a day as needed
Other
- Ibuprofen half-life: 2.2 hours
- Food may delay absorption
- Famotidine (Pepcid) is a H2 blocker that may help prevent NSAID-induced peptic ulcers
- Do not cut or crush tablets
Generic / Price
- YES/$$$$Indomethacin IR (Indocin®)
Dosage forms
Capsule
- 25 mg
- 50 mg
Suspension
- 25 mg/5 ml
- Comes in bottles of 237 ml
Suppository
- 50 mg
- Comes in box of 30
Dosing
Acute gout
- 50 mg three times a day until pain is tolerable then taper
Osteoarthritis
- Starting: 25 mg two to three times a day
- Increase daily dose by 25 - 50 mg at weekly intervals to a maximum of 200 mg/day
Rheumatoid arthritis
- Starting: 25 mg two to three times a day
- Increase daily dose by 25 - 50 mg at weekly intervals to a maximum of 200 mg/day
Ankylosing spondylitis
- Starting: 25 mg two to three times a day
- Increase daily dose by 25 - 50 mg at weekly intervals to a maximum of 200 mg/day
Painful shoulder
- 75 - 150 mg/day given in 3 - 4 divided doses
Other
- Half-life: 4.5 hours
- Suppositories should be refrigerated
Generic / Price
- Capsule (#30) - YES/$
- Suspension (#30) - NO/$$$$
- Suppository (#30) - NO/$$$$
Indomethacin IR (Tivorbex®)
Dosage forms
Capsule
- 20 mg
Dosing
Mild to moderate acute pain in adults
- Dosing: 20 mg three times daily or 40 mg two to three times daily
Other
- Not interchangeable with other formulations of indomethacin
- Taking with food decreases the rate of absorption but not the extent
Generic / Price
- YES/$$$$Indomethacin ER (Indocin SR®)
Dosage forms
Capsule, extended-release
- 75 mg
Dosing
Osteoarthritis
- Starting: 75 mg once daily
- May increase to 75 mg twice a day if necessary
Rheumatoid arthritis
- Starting: 75 mg once daily
- May increase to 75 mg twice a day if necessary
Ankylosing spondylitis
- Starting: 75 mg once daily
- May increase to 75 mg twice a day if necessary
Painful shoulder
- 75 mg given once or twice a day as needed
Other
- Give capsules with food to decrease gastric irritation
- Extended-release capsules are not recommended for acute gout
Generic / Price
- YES/$Ketoprofen (Orudis®)
Dosage forms
Capsule
- 25 mg
- 50 mg
- 75 mg
Dosing
Mild to moderate pain
- 25 - 50 mg every 6 - 8 hours as needed
- Do not exceed 300 mg/day
Osteoarthritis
- 75 mg three times a day as needed or 50 mg four times a day as needed
- Do not exceed 300 mg/day
Rheumatoid arthritis
- 75 mg three times a day as needed or 50 mg four times a day as needed
- Do not exceed 300 mg/day
Dysmenorrhea
- 25 - 50 mg every 6 - 8 hours as needed
- Do not exceed 300 mg/day
Other
- Half-life: 2 hours
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
- Doses above 200 mg/day have not been shown to increase effectiveness
- Dose should be reduced in kidney and liver disease. See precautions below.
- Use lower doses in patients ≥ 75 years
- Use lower doses in smaller individuals
Generic / Price
- YES/$Ketoprofen ER (Oruvail®)
Dosage forms
Capsule, extended-release
- 100 mg
- 150 mg
- 200 mg
Dosing
Osteoarthritis
- 200 mg once daily day as needed
- Do not exceed 200 mg/day
Rheumatoid arthritis
- 200 mg once daily day as needed
- Do not exceed 200 mg/day
Other
- Half-life: 5.4 hours
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
- Dose should be reduced in kidney and liver disease. See precautions below.
- Use lower doses in patients ≥ 75 years
- Use lower doses in smaller individuals
Generic / Price
- YES/$$$ (30 capsules)Ketorolac tromethamine (Toradol®)
Dosage forms
Tablet
- 10 mg
Dosing
Moderate to severe pain
- Ketorolac tablets are only recommended as continuation therapy after ketorolac has been started by the IV or IM route
- Total course of therapy (parenteral + oral) should not exceed 5 days
- The total daily dose should not exceed 40 mg in any patient
Patients | Recommended dose |
---|---|
Age 17 - 64 years |
|
Any of the following:
|
|
Other
- Half-life: 5 - 6 hours
Generic / Price
- YES/$Ketorolac (Sprix®)
Dosage forms
Nasal spray
- Comes in single-day sprayer that delivers 8 sprays
- Each spray delivers 15.75 mg of ketorolac
- Comes in box of 5 sprayers
Dosing
Moderate to severe pain
- Sprix may be initiated without prior parenteral ketorolac therapy
- Total course of therapy (parenteral + oral + spray) should not exceed 5 days
Patients | Recommended dose |
---|---|
Age 18 - 64 years |
|
Any of the following:
|
|
Other
- Half-life: 5 - 6 hours
- Do not use one spray bottle for more than 24 hours. After 24 hours, it will not deliver intended dose.
- Keep unopened sprayers refrigerated
- Open sprayers may be kept at room temperature. Protect from sunlight.
Generic / Price
- NO/$$$$ (5 bottles)Meclofenamate
Dosage forms
Capsule (Meclodium®)
- 50 mg
- 100 mg
Dosing
Mild to moderate pain
- 50 - 100 mg every 4 - 6 hours as needed
- Do not exceed 400 mg/day
Osteoarthritis
- 200 - 400 mg/day given in 3 -4 equal doses
- Do not exceed 400 mg/day
Rheumatoid arthritis
- 200 - 400 mg/day given in 3 -4 equal doses
- Do not exceed 400 mg/day
Dysmenorrhea and excessive menstrual blood loss
- 100 mg three times a day for up to 6 days
- Should be given at start of menstrual flow
Other
- Half-life: Parent compound - 1.3 hours | Active metabolite - 15 hours
- Food decreases the rate and extent of absorption
Generic / Price
- YES/$$-$$$$ (30 capsules)Mefenamic acid (Ponstel®)
Dosage forms
Capsule
- 250 mg
Dosing (≥ 14 years old)
Acute pain
- Give 500 mg initially followed by 250 mg every 6 hours as needed
- Therapy should not typically exceed a week
Dysmenorrhea
- Give 500 mg initially followed by 250 mg every 6 hours as needed
- Begin treatment with start of menses and take for 2 - 3 days
Other
- Half-life: 2 hours
Generic / Price
- YES/$$$ (30 capsules)Nabumetone (Relafen®)
Dosage forms
Tablet
- 500 mg
- 750 mg
Dosing
Osteoarthritis
- 1000 mg once daily as needed
- May increase dose up to 2000 mg/day if necessary
- Daily dose may be given in one or two divided doses
- Do not exceed 2000 mg/day
Rheumatoid arthritis
- 1000 mg once daily as needed
- May increase dose up to 2000 mg/day if necessary
- Daily dose may be given in one or two divided doses
- Do not exceed 2000 mg/day
Other
- Half-life: 24 hours
- The manufacturer states that in trials, nabumetone had little effect on collagen-induced platelet aggregation and no effect on bleeding time
- May take with or without food
- Patients who weigh < 50 kg (110 lbs) may respond to lower doses
Generic / Price
- YES/$Naproxen IR | Naprosyn® | Aleve® | Anaprox®
Dosage forms
Tablets, gelcaps, caplets (Aleve®, Anaprox®)
- Naproxen : Sodium
- 200 mg : 20 mg (OTC)
- 250 mg : 25 mg
- 500 mg : 50 mg
Tablet (Naprosyn®)
- 250 mg
- 375 mg
- 500 mg
Tablet, enteric-coated(EC-Naprosyn®)
- 375 mg
- 500 mg
Suspension (Naprosyn®)
- 25 mg/ml
Dosing (Children ≥ 2 years)
NOTE: Dosing based on naproxen component
Juvenile arthritis
- 5 mg/kg/dose twice a day as needed
Other (pain, fever, etc.)
- 2.5 - 5 mg/kg/dose two to three times a day as needed
- Do not exceed 15 mg/kg/day
Dosing (Adults)
Osteoarthritis, Rheumatoid arthritis, Ankylosing spondylitis
- 250 - 500 mg twice daily as needed
Pain, Dysmenorrhea, Tendonitis, Bursitis
- 500 mg initially followed by 500 mg every 12 hours as needed or 250 mg every 6 - 8 hours as needed
Acute gout
- 750 mg initially followed by 250 mg every 8 hours until pain subsides
Efficacy
Arthritis
Acute gout flare
Other
- Half-life: 12 - 17 hours
- May take with or without food
- Naproxen sodium has a quicker onset of action (30 minutes) than naproxen (1 hour)
- Enteric-coated naprosyn is not recommended in gout or acute pain because of delayed absorption
Generic / Price
- YES/$ (all forms)Naproxen ER (Naprelan®)
Dosage forms
Tablets, extended-release
- 375 mg
- 500 mg
- 750 mg
- Strength based on naproxen component
- Contains naproxen sodium
Dosing
Osteoarthritis, Rheumatoid arthritis, Ankylosing spondylitis
- 750 - 1000 mg once daily as needed
- Maximum dose is 1500 once daily
Pain, Dysmenorrhea, Tendonitis, Bursitis
- 1000 mg once daily as needed
- May increase to 1500 mg once daily for short period if necessary
Acute gout
- 1000 - 1500 mg once daily on Day 1, then 1000 mg once daily until attack resolves
Other
- Half-life: 15 hours
- May take with or without food
- For patients taking standard-release naproxen, the total daily dose of standard-release naproxen may be given as a once daily dose of extended-release naproxen
Generic / Price
- YES/$$$$ (60 tablets)Naproxen + Esomeprazole (Vimovo®)
Dosage forms
Tablets, enteric-coated
- Naproxen : Esomeprazole
- 375 mg : 20 mg
- 500 mg : 20 mg
Dosing
Osteoarthritis, Rheumatoid arthritis, Ankylosing spondylitis
- 375 - 500 mg twice a day as needed
Other
- Half-life (naproxen): 15 hours
- Take at least 30 minutes before meals
- Do not crush, cut, or chew tablets
- Vimovo is not recommended for acute pain because absorption is delayed
- Esomeprazole is a proton pump inhibitor (Nexium) that protects against gastrointestinal irritation
- See the Nexium PI for precautions, warnings, and drug interactions regarding esomeprazole
Generic / Price
- YES/$$$$Naproxen + Sumatriptan (Treximet®)
Dosage forms
Tablets
- Sumatriptan : Naproxen sodium
- 85 mg : 500 mg
Dosing
Migraine headache
- Initial: 1 tablet (85/500)
- May repeat one time in 2 hours if needed
- Do not exceed 2 tablets in 24 hours
- May take without regard to food
Other
- Sumatriptan is a migraine headache medication
Generic / Price
- YES/$$$$ (9 tablets)Oxaprozin (Daypro®)
Dosage forms
Tablet
- 600 mg
Dosing (6 - 16 years)
Juvenile rheumatoid arthritis
- Give as once daily dose
Body weight (kg) | Body weight (lbs) | Daily dose |
---|---|---|
22 - 31 | 48 - 68 | 600 mg |
32 - 54 | 69 - 119 | 900 mg |
≥ 55 | ≥ 120 | 1200 mg |
Dosing (Adults)
Osteoarthritis
- 1200 mg once daily as needed
- Maximum dose is 1800 mg/day or 26 mg/kg/day, whichever is lower. Give in divided doses.
- Patients with lower body weight should start with 600 mg once daily
- A one-time loading dose of 1200 - 1800 mg (not to exceed 26 mg/kg) may be given when a quicker onset of action is desired
Rheumatoid arthritis
- 1200 mg once daily as needed
- Maximum dose is 1800 mg/day or 26 mg/kg/day, whichever is lower. Give in divided doses.
- Patients with lower body weight should start with 600 mg once daily
- A one-time loading dose of 1200 - 1800 mg (not to exceed 26 mg/kg) may be given when a quicker onset of action is desired
Other
- Half-life: 55 hours (single dose) | 41 hours (multiple doses)
- Food may decrease the rate of absorption. Extent of absorption is not affected.
Generic / Price
- YES/$$ (60 tablets)Sulindac (Clinoril®)
Dosage forms
Tablet
- 150 mg
- 200 mg
Dosing
Osteoarthritis, Rheumatoid arthritis, Ankylosing spondylitis
- 150 - 200 mg twice a day as needed
- Do not exceed 400 mg/day
Painful shoulder, Tendonitis, Bursitis
- 200 mg twice a day as needed
- Do not exceed 400 mg/day
Acute gout
- 200 mg twice a day until satisfactory response, then taper
- Do not exceed 400 mg/day
Other
- Half-life: 16.4 hours
- Take with food
Generic / Price
- YES/$Tolmetin (Tolectin®)
Dosage forms
Tablet
- 200 mg
- 600 mg
Capsule
- 400 mg
Dosing (Children ≥ 2 years old)
Juvenile rheumatoid arthritis
- 20 mg/kg/day given in three or four divided doses
- Usual dosage range is 15 - 30 mg/kg/day
- Do not exceed 30 mg/kg/day
Dosing (Adults)
Osteoarthritis
- 400 mg three times a day as needed
- May increase to 600 mg three times a day
- Do not exceed 1800 mg/day
Rheumatoid arthritis
- 400 mg three times a day as needed
- May increase to 600 mg three times a day
- Do not exceed 1800 mg/day
Other
- Half-life: 5 hours
- Food decreases bioavailability
- Do not give with sodium bicarbonate antacids
Generic / Price
- Generic (60 tablets) - $$$$
- Generic (60 capsules) - $$-$$$
- PARTIALLY-SELECTIVE NSAIDs
Diclofenac potassium IR (Cataflam®)
Dosage forms
Tablet
- 50 mg
Dosing
Pain or primary dysmenorrhea
- 50 mg three times a day as needed
- Initial dose of 100 mg may be given
Osteoarthritis
- 50 mg two to three times a day as needed
Rheumatoid arthritis
- 50 mg three to four times a day as needed
Other
- Half-life: 1.9 hours
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
- Cataflam is diclofenac potassium. Cataflam is not bioequivalent with diclofenac sodium on a mg-to-mg basis
Generic / Price
- YES/$Diclofenac sodium EC (Voltaren®)
Dosage forms
Tablet, delayed-release
- 25 mg
- 50 mg
- 75 mg
- Tablets are enteric-coated
Dosing
Osteoarthritis
- 50 mg two to three times a day as needed or 75 mg two times a day as needed
Rheumatoid arthritis
- 50 mg three to four times a day as needed or 75 mg two times a day as needed
- Do not exceed 225 mg/day
Ankylosing spondylitis
- 25 mg four times a day with an extra 25 mg at bedtime if necessary
Other
- Half-life: 2 hours
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
- Voltaren is diclofenac sodium. Voltaren is not bioequivalent with diclofenac potassium on a mg-to-mg basis
- Tablets are enteric-coated
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- YES/$Diclofenac sodium ER (Voltaren XR®)
Dosage forms
Tablet, extended-release
- 100 mg
Dosing
Osteoarthritis
- 100 mg once daily as needed
Rheumatoid arthritis
- 100 mg once daily as needed
- In rare cases, 100 mg twice a day may be used
Other
- Taking with food may delay absorption and increase peak plasma levels. Extent of absorption is not affected.
- Voltaren is not bioequivalent with diclofenac potassium on a mg-to-mg basis
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- YES/$Diclofenac sodium (Voltaren® Gel)
Dosage forms
Gel
- 1%
- Comes in 100 gram tube
- Available OTC
Dosing
Osteoarthritis of knees, ankles, and feet
- Apply 4 grams to affected joint 4 times a day as needed
Osteoarthritis of elbows, wrists, and hands
- Apply 2 grams to affected joint 4 times a day as needed
Other
- Comes with dosing card for measuring and application
- Total dose should not exceed 32 g per day, over all affected joints
- Avoid bathing for at least 1 hour after application
- Avoid sunlight/heat exposure to treated joints
- Avoid clothing over treated joints for 10 minutes after applying
- Systemic exposure from gel is ∼ 6% of that seen with the oral form of diclofenac
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- YES/$ (100g tube)Diclofenac potassium (Zipsor®)
Dosage forms
Capsule, liquid filled
- 25 mg
- Diclofenac potassium
Dosing
Mild to moderate acute pain (adults and children ≥ 12 years)
- 25 mg four times a day as needed
Other
- Half-life: 1 hour
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
- Zipsor is diclofenac potassium. Zipsor is not bioequivalent with other diclofenac preparations on a mg-to-mg basis
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- NO/$$$$Diclofenac (Zorvolex®)
Dosage forms
Capsule
- 18 mg
- 35 mg
Dosing
Acute pain
- 18 - 35 mg three times a day as needed
Osteoarthritis
- 35 mg three times a day as needed
Other
- Half-life: 2 hours
- Taking with food may decrease absorption and lower effectiveness
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- NO/$$$$Diclofenac potassium (Cambia®)
Dosage forms
Powder for solution
- 50 mg packet of powder
- Comes in box of 9 packets
Dosing
Acute migraine with or without aura
- 50 mg (one packet) with start of acute migraine
- Safety and effectiveness of second dose has not been established
Other
- Half-life: 2 hours
- Mix contents of packet with 30 - 60 mls of water
- Only mix with water. Drink immediately.
- Taking with food may decrease absorption and lower effectiveness
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- NO/$$$$ (9 packets)Diclofenac + Misoprostol (Arthrotec®)
Dosage forms
Tablet
- Diclofenac : Misoprostol
- 50 mg : 200 mcg
- 75 mg : 200 mcg
- Contains diclofenac sodium
Dosing
Osteoarthritis
- 50 mg two to three times a day as needed or 75 mg twice a day as needed
Rheumatoid arthritis
- 50 mg two to four times a day as needed or 75 mg twice a day as needed
Other
- Half-life: 2 hours
- DO NOT GIVE to pregnant women. Misoprostol can cause maternal and fetal harm, including uterine rupture, abortion, premature birth, and birth defects.
- Misoprostol is a synthetic prostaglandin E1 analog with gastric antisecretory and mucosal protective properties
- Misoprostol may cause diarrhea, abdominal pain, nausea, and flatulence
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- YES/$ (30 tablets)Diclofenac (Flector®)
Dosage forms
Patch
- 1.3% patch
- Patch is 10 X 14 cm (3.9" X 5.5")
- Each patch contains 180 mg of diclofenac epolamine
- Comes in box of 30 patches
Dosing
Local acute pain due to strains, sprains, and contusions
- Apply 1 patch to most painful area twice a day
Other
- Do not wear when bathing or showering. Do not place on non-intact or damaged skin.
- May wear mesh sleeve over patch to hold in place
- Systemic exposure to diclofenac after repeated patch use for four days was lower (< 1%) than that of a single oral 50 mg diclofenac sodium tablet
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- NO/$$$$ (30 patches)Diclofenac (Licart®)
Dosage forms
Patch
- 1.3% patch
- Patch is 10 X 14 cm (3.9" X 5.5")
- Comes in box with 15 patches
- Licart is diclofenac epolamine
Dosing
Local acute pain due to minor strains, sprains, and contusions
- Apply 1 patch to most painful area once daily
Other
- Do not wear when bathing or showering. Do not place on non-intact or damaged skin.
- May wear mesh sleeve over patch to hold in place
- Systemic exposure to diclofenac after repeated patch use for four days was lower (< 1%) than that of a single oral 50 mg diclofenac sodium tablet
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- NO/$$$$ (15 patches)Diclofenac (Pennsaid®)
Dosage forms
1.5% solution
- 16.05 mg/ml (1.5%)
- Comes in 150 ml bottle
2% solution
- 20 mg/g (2%)
- Comes in 112 g pump
Dosing
Osteoarthritis of the knee
- 1.5% solution
- Apply 40 drops on each painful knee 4 times a day as needed
- To avoid spillage, dispense 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread solution evenly around the front, back, and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution.
- 2% solution
- Apply 40 mg of diclofenac sodium (2 pump actuations) on each painful knee 2 times a day as needed
- Deliver the product directly into the palm of the hand and then apply evenly around the front, back, and sides of the knee
- Each pump actuation delivers 20 mg of diclofenac sodium in 1 gram of solution
Other
- Avoid bathing for at least 30 minutes after application
- Avoid sunlight/heat exposure to treated joints
- Avoid clothing over treated joint until it is dry
- Systemic exposure does occur, but is much less than with oral forms
- Diclofenac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- 1.5% solution: YES/$
- 2% solution: NO/$$$$
Etodolac IR (Lodine®)
Dosage forms
Capsule
- 200 mg
- 300 mg
Tablet
- 400 mg
- 500 mg
Dosing
Acute pain
- 200 - 400 mg every 6 - 8 hours as needed
- Doses above 1000 mg/day have not been studied
Osteoarthritis
- 300 - 500 mg twice a day as needed or 300 mg three times a day as needed
- Doses above 1000 mg/day have not been studied
Rheumatoid arthritis
- 300 - 500 mg twice a day as needed or 300 mg three times a day as needed
- Doses above 1000 mg/day have not been studied
Other
- Half-life 6.4 hours
- Taking with food may delay absorption and decrease peak plasma levels. Extent of absorption is not affected.
- Etodolac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- YES/$Etodolac ER (Lodine XL®)
Dosage forms
Tablet, extended-release
- 400 mg
- 500 mg
- 600 mg
Dosing (6 - 16 years)
Juvenile rheumatoid arthritis
- 20 - 30 kg: 400 mg once daily
- 31 - 45 kg: 600 mg once daily
- 46 - 60 kg: 800 mg once daily
- > 60 kg: 1000 mg once daily
Dosing (Adults)
Osteoarthritis
- 400 - 1000 mg once daily as needed
Rheumatoid arthritis
- 400 - 1000 mg once daily as needed
Other
- Half-life: 8.4 hours
- Food may increase the rate of absorption. Extent of absorption is not affected.
- Etodolac is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- YES/$ (30 tablets)Meloxicam (Mobic®)
Dosage forms
Tablet
- 7.5 mg
- 15 mg
Suspension
- 7.5 mg/5 ml
- Comes in 100 ml bottle
Dosing (Children ≥ 2 years old)
Juvenile rheumatoid arthritis
- 0.125 mg/kg once daily
- Do not exceed 7.5 mg/day
Dosing (Adults)
Osteoarthritis
- 7.5 - 15 mg once daily
Rheumatoid arthritis
- 7.5 - 15 mg once daily
Other
- Half-life: 15 - 20 hours
- May take with or without food
- Meloxicam is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- 30 tablets - YES/$
- Solution 100 ml - YES/$$
Meloxicam (Vivlodex®)
Dosage forms
Capsule
- 5 mg
- 10 mg
Dosing
Osteoarthritis
- 5 - 10 mg once daily
- Do not exceed 10 mg/day
Other
- Half-life: 22 hours
- Food may decrease rate of absorption, but extent of absorption is not affected. May take without regard to meals.
Generic / Price
- YES/$$$$ (#30)Piroxicam (Feldene®)
Dosage forms
Capsule
- 10 mg
- 20 mg
Dosing
Osteoarthritis
- 20 mg once daily as needed
- Dose may be divided if desired
Rheumatoid arthritis
- 20 mg once daily as needed
- Dose may be divided if desired
Other
- Half-life: 50 hours
- Food may decrease the rate of absorption. Extent of absorption is not affected.
- Piroxicam has a long half-life (50 hours), therefore, the full effect of the drug may not be seen for 7 - 12 days
- Piroxicam is partially COX-2 selective. See COX selectivity for more.
Generic / Price
- YES/$- SELECTIVE NSAIDs
Celecoxib (Celebrex®)
Dosage forms
Capsule
- 50 mg
- 100 mg
- 200 mg
- 400 mg
Dosing (Children ≥ 2 years)
Juvenile rheumatoid arthritis
- Weight ≥ 10 kg - ≤ 25 kg: 50 mg twice a day
- Weight > 25 kg: 100 mg twice a day
Dosing (Adults)
Osteoarthritis
- 200 mg once daily as needed or 100 mg twice a day as needed
Rheumatoid arthritis
- 100 - 200 mg twice a day as needed
Acute pain and dysmenorrhea
- 400 mg initially followed by an additional 200 mg on the first day if needed. On subsequent days, 200 mg twice a day as needed.
Ankylosing spondylitis
- 200 mg once daily as needed or 100 mg twice a day as needed
- If necessary, may increase to 400 mg/day after 6 weeks
Liver disease
- Child-Pugh A: no adjustment necessary
- Child-Pugh B: reduce dose by 50%
- Child-Pugh C: not recommended
Poor CYP2C9 metabolizers
- Initiate treatment with half of the lowest recommended dose
Efficacy
Arthritis
Colon cancer
Other
- Half-life: 11 hours
- The manufacturer states that in trials, celecoxib had no effect on reduction of platelet aggregation or increase in bleeding time
- For doses up to 200 mg twice a day, celecoxib may be taken without regard to food. For doses ≥ 400 mg twice a day, celecoxib should be taken with food to improve absorption.
- Capsules may be opened and sprinkled on applesauce
- Celecoxib is a COX-2 selective NSAID
Generic / Price
- YES/$ (60 capsules)Celecoxib liquid (Elyxyb®)
Dosage forms
Liquid
- 120 mg/4.8 ml (25 mg/ml) glass bottle
- Comes in carton with 6 bottles
- Store at room temp
Dosing (Adults)
Acute migraine with or without aura
- Dosing: 120 mg (1 bottle) per 24 hour period
- Do not exceed 120 mg in a 24-hour period
- May take without regard to food
Liver disease
- Child-Pugh A: no adjustment necessary
- Child-Pugh B: 60 mg (2.4 ml) per 24 hour period
- Child-Pugh C: not recommended
Poor CYP2C9 metabolizers
- 60 mg (2.4 ml) per 24 hour period
Efficacy
Other
- Time to max level: 1 hour
- Half-life: 6 hours
- The manufacturer states that in trials, celecoxib had no effect on reduction of platelet aggregation or increase in bleeding time
- Celecoxib is a COX-2 selective NSAID
Generic / Price
- NO/$$$$ (6 bottles)Consensi® (amlodipine + celecoxib)
Dosage forms
Tablet
- Amlodipine - Celecoxib
- 2.5 mg - 200 mg
- 5 mg - 200 mg
- 10 mg - 200 mg
Dosing
Hypertension / Osteoarthritis
- Starting: 2.5 - 5 mg/200 mg once daily
- Maintenance: 2.5 - 10 mg/200 mg once daily
- Max: 10 mg/200 mg once daily
- Adjust dose every 7 - 14 days
- May take without regard to food
- Amlodipine is a calcium channel blocker
Generic / Price
- NO/$$$$Seglentis® (celecoxib + tramadol)
Dosage forms
Tablet
- Celecoxib - Tramadol
- 56 mg - 44 mg
Dosing
Acute pain
- Dosing: 2 tablets every 12 hours as needed
- May take without regard to food
- Tramadol is an opiate medication. See tramadol for more.
Generic / Price
- NO/$$$ for #30- 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]
Open scalable image

- 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]
- 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
Salicylates | Propionic acids |
---|---|
|
|
Enolic acids | Acetic acids |
|
|
Fenamic acids | Nonacidic |
|
|
- 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]
- The PRECISION study enrolled 24,081 patients with established CVD or risk factors for CVD who required daily treatment with NSAIDs
Main inclusion criteria
- Any of the following: established CVD, diabetes, three risk factors for CVD
- Requiring daily treatment with NSAIDs for arthritis pain
Main exclusion criteria
- CVD event within 3 months of randomization
Baseline characteristics
- Average age 63 years
- Female sex - 64%
- Arthritis diagnosis: Osteoarthritis - 90% | RA - 10%
- Established CVD - 23%
- Average creatinine - 0.9 mg/dl
- Current aspirin use - 46%
- Smoker - 21%
Randomized treatment groups
- Group 1 (8072 patients) - Celecoxib 100 mg twice a day
- Group 2 (7969 patients) - Naproxen 375 mg twice a day
- Group 3 (8040 patients) - Ibuprofen 600 mg three times a day
- Patients with RA could have their doses increased if necessary to 200 mg twice a day for celecoxib, 500 mg twice a day for naproxen, and 800 mg three times a day for ibuprofen
- Patients with OA could have their naproxen and ibuprofen doses increased, but not celecoxib
- Esomeprazole 20 - 40 mg was provided to all patients for gastric protection
- Daily aspirin therapy was permitted
Primary outcome: Composite of first occurrence of an adverse event that met Antiplatelet Trialists Collaboration
(APTC) criteria (i.e., death from cardiovascular causes, including hemorrhagic death; nonfatal myocardial infarction; or nonfatal stroke)
Results
Duration: Average of 34 months | ||||
Outcome | Celecoxib | Naproxen | Ibuprofen | Comparisons |
---|---|---|---|---|
Primary outcome | 2.3% | 2.5% | 2.7% | 1 vs 2 p=0.45 | 1 vs 3 p=0.12 |
Death from cardiovascular causes | 0.8% | 1.1% | 1.0% | 1 vs 2 p=0.13 | 1 vs 3 p=0.30 |
Overall mortality | 1.6% | 2.0% | 1.8% | 1 vs 2 p=0.052 | 1 vs 3 p=0.49 |
Serious gastrointestinal events | 1.1% | 1.5% | 1.6% | 1 vs 2 p=0.01 | 1 vs 3 p=0.002 |
Renal events | 0.7% | 0.9% | 1.1% | 1 vs 2 p=0.19 | 1 vs 3 p=0.004 |
Average daily doses | 209 mg | 852 mg | 2045 mg | N/A |
|
Findings: At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety
- STUDY
- 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.
Annual risk of major vascular event for patients taking select NSAIDs | ||
---|---|---|
Drug | Annual excess cases per 1000 patients with 2% baseline annual risk | Annual excess cases per 1000 patients with 0.5% baseline annual risk |
Ibuprofen 800 mg three times a day | 9 | 2 |
Diclofenac 75 mg twice a day | 8 | 2 |
Coxibs✝ | 7 | 2 |
Naproxen 500 mg twice a day | -1 | 0 |
- 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.
- 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
- 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
- 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
- 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
- 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
- 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.
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 |
- 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
- 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
- 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:
- 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.
- PRICE ($) INFO
Pricing legend
- $ = 0 - $50
- $$ = $51 - $100
- $$$ = $101 - $150
- $$$$ = > $151
- Pricing based on one month of therapy at standard dosing in an adult
- Pricing based on information from GoodRX.com®
- Pricing may vary by region and availability
- 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)