Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Comparison
- Types & classification
- Mechanism of action
- Side effects & toxicities
- Differences between NSAIDs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications worldwide.
Beneficial therapeutic effects of NSAIDs:
- 1. Anti-inflammatory
- 2. Analgesic (pain relieving)
- 3. Antipyretic (fever reducing)
- 4. Antiplatelet (inhibition of thrombocyte aggregation).
Types & classification of NSAIDs
There are many different types of NSAIDs, which are categorized according to their chemical structures. The following list presents medications grouped by types:
- Aspirin (Ascriptin®, Bayer®, Ecotrin®)
- Diflunisal (Dolobid®, Diflunisal®)
- Salsalate (Argesic® SA, Disalcid®, Salflex®, Salsitab®, Mono Gesic®)
- Diclofenac sodium (Voltaren®)
- Diclofenac potassium (Cataflam®)
- Indomethacin (Indocin®)
- Sulindac (Clinoril®)
- Tolmetin (Tolectin®)
- Ketorolac (Toradol®)
Arylpropionic acids (profens):
- Ibuprofen (Motrin®, Advil®)
- Ketoprofen (Orudis®, Oruvail®)
- Dexketoprofen (Keral®, Ketesse®)
- Naproxen (Naprosyn®, Alleve®)
- Fenoprofen (Nalfon®)
- Flurbiprofen (Ansaid®)
- Oxaprozin (Daypro®)
Enolic acids (oxicams):
- Piroxicam (Feldene®)
- Meloxicam (Mobic®)
- Lornoxicam (Xefo®)
- Tenoxicam (Mobiflex®)
- Mefenamic acid (Ponstel®)
- Meclofenamate (Meclomen®)
- Niflumic acid
- Tolfenamic acid
- Flufenamic acid
- Metamizole (dipyrone)
- Phenazone (antipyrine)
- Aminopyrine (aminophenazone)
- Nimesulide (Sulide®)
- Nabumetone (Relafen®)
- Celecoxib (Celebrex®)
- Etoricoxib (Arcoxia®)
- Parecoxib (Dynastat®)
Acetaminophen, ibuprofen, naproxen, and ketoprofen are available over-the-counter in the United States.
NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Nonsteroidal anti-inflammatory drugs are powerful analgesics and are especially effective for nociceptive pain. NSAIDs also are effective in some neuropathic pain syndromes when used in combination with other pain medications.
NSAIDs are indicated for the symptomatic treatment of the following conditions:
- Rheumatoid arthritis. NSAIDs are particularly useful in the inflammatory forms of arthritis (such as rheumatoid arthritis) and, sometimes, in the more severe forms of osteoarthritis.
- Acute gout
- Inflammatory arthropathies: ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome
- Dysmenorrhoea (painful menstruation), menstrual cramps
- Headache and migraine
- Postoperative pain
- Mild-to-moderate pain due to inflammation and tissue injury
- Back pain and sciatica
- Sports injuries, sprains, and strains
- Dental pain
- Pain from kidney stones (renal colic)
- Reduction of fever
- Prevention of blood clotting (Aspirin only)
NSAIDs also are included in many fever reducers, cough, cold and allergy preparations.
Note: NSAIDs do not cure the diseases or injuries.
Mechanism of action
NSAIDs work by suppressing the production of prostaglandins. Prostaglandins are chemical messengers that mediate inflammation, fever and the sensation of pain. NSAIDs block the production of prostaglandins by inhibiting the action of an enzyme, cyclooxygenase (COX). This enzyme is responsible for converting precursor acids into prostaglandins.
Prostaglandins generated by COX-1 promote platelet aggregation, control renal function, and provide gastroprotection by regulating mucous secretion. Prostaglandins generated by COX-2 mediate pain, inflammation, fever and inhibit platelet aggregation.
In the periphery NSAIDs work by decreasing the sensitivity of the nociceptor to painful stimuli induced by heat, injury, or inflammation. In the central nervous system, they are thought to function as antihyperalgesics and block the increased transmission of repetitive incoming signals to higher centers. In effect, they modulate perception of pain caused by repetitive stimulation from the periphery. Since they function by modulation of the perception of pain, NSAIDs may be useful in the preoperative period and may reduce the need for postoperative analgesia14.
The anti-inflammatory activity of NSADs in descending order:
indomethacin > diclofenac > piroxicam > ketoprofen > lornoxicam > ibuprofen > ketorolac > acetylsalicylic acid
NSAIDs that inhibit both COX-1 and COX-2 enzymes are named non-selective NSAIDs. NSAIDs that mainly inhibit COX-2 enzymes are named COX-2 inhibitors (Coxibs).
Classification of NSAIDs by selectivity to cyclooxygenase (according to “Drugs Therapy Perspectives”, 2000):
|Pronounced selectivity towards COX-1||Aspirin
|Moderate selectivity towards COX-1||Diclofenac
|Equal inhibition of COX-1 and COX-2||Etodolac
|Pronounced selectivity towards COX-2||Celecoxib|
Side effects & toxicities
NSAIDs can cause a number of side effects. The two main adverse reactions, associated with NSAIDs relate to gastrointestinal tract and renal function. The adverse effects are usually dose-dependent, and in some cases are severe enough to pose serious health risks.
Cardiovascular side effects
Both COX-2-selective and nonselective NSAIDs may cause adverse cardiovascular effects9, including:
- Increased risk of myocardial infarction. Risk is greatest during the first month of NSAID use and with higher doses 23.
- Increased risk of stroke10. NSAIDs affect vasoconstriction and sodium excretion, which can lead to elevated blood pressure, a risk factor for stroke.
Diclofenac has a cardiovascular risk very similar to rofecoxib, which was withdrawn from worldwide markets because of cardiovascular toxicity2.
Naproxen appears to have a better cardiovascular safety profile than other NSAIDs and does not appear to significantly increase the risk cardiovascular disease. Currently naproxen is considered to be the safest NSAID with respect to cardiovascular side effects.
NSAIDs rated by relative risk for cardiovascular events (in ascending order) 2:
Naproxen < Celecoxib < Piroxicam < Ibuprofen < Meloxicam < Indomethacin < Diclofenac < Rofecoxib (at doses more than 25 mg)
Gastrointestinal adverse effects
The main problem with of NSAIDs is gastrointestinal toxicity.
Common gastrointestinal side effects include:
- Peptic ulcers
- Perforations of the upper gastrointestinal tract
- Gastrointestinal bleeding.
Parts of the gastrointestinal tract that may be damaged by NSAIDs:
- Small intestine
Risk factors for NSAID related gastrointestinal damage:
- Age (especially over 70)
- History of ulceration
- First three months of treatment with NSAID
- Concomitant use with of corticosteroids and anticoagulants
- High dose and multiple NSAIDs.
Relative risks of gastrointestinal complications 3:
- Low Risk: ibuprofen, aceclofenac, nimesulide, fenoprofen, aspirin, diclofenac, sulindac, nabumetone etodolac
- Medium Risk: diflunisal, naproxen, indomethacin, tolmetin, meloxicam
- High Risk: piroxicam, ketoprofen, azapropazone, flurbiprofen, ketorolac
NSAIDs can damage gastric and duodenal mucosavia several mechanisms24:
- Topical irritation of epithelium.
- Impairment of the barrier properties of the mucosa and increased intestinal permeability alterations in gastric mucosal barrier function.
- Suppression of gastric prostaglandin synthesis.
- Reduction of gastric mucosal blood flow and bicarbonate secretion.
- Increase of acid secretion.
- Interference with the repair of superficial injury.
Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimize gastrointestinal side effects, it is prudent to use the lowest effective dose for the shortest period of time. To help protect the stomach, NSAIDs should always be taken with food or directly after a meal.
Hypertension (High blood pressure)
NSAIDs may potentially increase blood pressure or aggravate existing hypertension. All NSAID users experience some degree of salt and water retention, and hypertension occurs in less than 10% of users.
NSAIDs-induced hypertension is due to the effects on renal function. Specifically, NSAIDs cause dose-related increases in sodium and water retention. In addition, NSAID use may reduce the effect of antihypertensive drugs except calcium channel blockers.
Kidney damage (nephrotoxicity)
NSAIDs reduce the blood flow to the kidneys, which makes them work more slowly. This is due to the inhibition of production of the vasodilatory renal prostaglandins. When the kidneys are not working well, fluid builds up in the body leading to edema. The more fluid in the bloodstream -- the higher blood pressure. The reduced blood flow can permanently damage the kidneys. It can eventually lead to kidney failure and require dialysis.
Renal impairment is especially a risk if a patient concomitantly takes an ACE inhibitor, a diuretic, or other nephrotoxic agent.
NSAIDs are cleared from the blood stream by the kidney, so it is very important that patients over 65 years of age or patients with kidney disease consult a physician prior to taking them. If patients take an NSAID for an extended period of time (six months or more), a blood test needs to be performed to check for early signs of kidney damage.
Long-term use of oxicams (piroxicam, meloxicam) and ketorolac is associated with an increased risk of chronic kidney disease 12.
Most people with chronic kidney disease are advised to avoid all types of NSAIDs. For healthy persons at therapeutic dosages NSAIDs pose a negligible threat of renal toxicity.
Composite cardiovascular /renal risk (in ascending order):
rofecoxib > indomethacin > diclofenac > celecoxib > naproxen > ibuprofen > meloxicam15.
NSAIDs can also cause extreme allergy. People suffering from asthma are more likely to experience serious allergic reaction. Many specialists recommend that people who have asthma stay away from any NSAID, especially if they have sinus problems or nasal polyps. Individuals with a serious allergy to one NSAID are likely to experience a similar reaction to a different NSAID.
Use of aspirin in children and teenagers with chicken pox or influenza has been associated with the development of Reye's syndrome. Therefore, aspirin and nonaspirin salicylates (e.g. salsalate) should not be used in children and teenagers with suspected or confirmed chicken pox or influenza.
NSAIDs do not directly cause bleeding, but they make bleeding worse, for example, when there is a cut.
A meta-analysis of 11 case-control studies and one cohort study found that ibuprofen was significantly less toxic than other NSAID.
Serious side effects are especially likely with phenylbutazone. Patients of age 40 and over are especially at risk of side effects from phenylbutazone, and the likelihood of serious side effects increases with age. Because of these potential problems, it is especially important to check with a physician before taking this medicine.
Differences between NSAIDs
The principal differences among NSAIDs lie in the time to onset and duration of action. Also, these drugs vary in their potency and how they are eliminated from the body.
Another important difference is their ability to cause ulcers and promote bleeding. The more an NSAID blocks COX-1, the greater is its tendency to cause ulcers and promote bleeding.
- Unique antiplatelet effect. Aspirin is the only NSAID able to inhibit blood clotting for a prolonged period (4 to 7 days). This antiplatelet effect makes aspirin an ideal therapy for preventing the blood clots that cause heart attacks and strokes. Most other NSAIDs inhibit the clotting of blood for only a few hours.
- Aspirin may trigger respiratory reactions known as Aspirin-Exacerbated Respiratory Disease8.
- Long history of safety.
- Bromfenac ophthalmic solution is approved by the FDA for the treatment of postoperative inflammation and pain after cataract surgery.
- Hepatotoxicity 18. Earlier the oral formulation of bromfenac was removed from the market because of numerous reports of liver damage associated with its use.
- Currently, celecoxib is the only available NSAID marketed as a selective COX-2 inhibitor.
- Low risk of gasrointestinal damage. It is less likely than traditional NSAIDs to cause adverse gastrointestinal effects.
- Sulfonamide allergy. Celecoxib has a sulfonamide structure and is contraindicated for patients with known sulfonamide allergy.
- Dexketoprofen is available as the tromethamine salt -- dexketoprofen trometamol.
- Dexketoprofen is the S(+) enantiomer of the racemic compound ketoprofen.
- Clinical studies showed that dexketoprofen is safe and effective analgesic, comparable to other NSAIDs7.
- Very potent anti-inflammatory and pain relieving action. As an analgesic, diclofenac is 6 times more potent than indomethacin and 40 times as potent as aspirin in the phenyl benzoquinone-induced writhing assay in mice.
- Diclofenac is also a unique NSAID. There is some evidence that diclofenac inhibits lipoxygenase enzymes, and activate the nitric oxide-cGMP antinociceptive pathway16. There is also speculation that diclofenac may inhibit phospholipase A2. These additional actions may explain the high potency of diclofenac - it is one the most potent NSAIDs.
- Diclofenac is relatively long acting (6 to 8 hours) but it has a very short half-life.
- Cardiotoxicity. Diclofenac is associated with the highest risk of heart attack and stroke among noselective NSAIDs.
- Diclofenac is available in multiple preparations: oral immediate release, oral delayed release capsules, transdermal patch, topical gel, ophthalmic solition, injection.
- Etodolac preferentially inhibits COX-2. Has uricosuric action.
- Etodolac, with regard to its anti-inflammatory properties, is approximately 50 times more active than aspirin, three times more potent than sulindac, and one-third as active as indomethacin.
- Low risk of gastrointestinal damage. Although etodolac is no more potent than many other NSAIDs, a low incidence of gastrointestinal side effects is an important therapeutic advantage.
- Fenoprofen is available in U.S., Canada, and several other countries, but is not widely used.
- Fenoprofen has less potent anti-inflammatory action than ibuprofen, indomethacin, ketoprofen, or naproxen.
- Short half-life and frequent dosing.
- High rate of headaches (15% of patients).
- Flurbiprofen was found to be 536-fold more potent than aspirin and 100-fold more potent than phenylbutazone.
- Oral flurbiprofen is half as potent as methylprednisolone.
- Flurbiprofen is 26 times more potent than ibuprofen as an antinociceptive.
- Ibuprofen produces balanced inhibitory effects on both COX-1 and COX-2.
- At low dose ibuprofen has relatively low risk of causing GI bleeding. However, this advantage is lost at high doses11.
- Use of ibuprofen has been associated with reduced risk of Parkinson's diseas 19.
- Usually requires 3-4 times per day dosing due to short half-life.
- Available in multiple formulations and combination products.
- Widely available over the counter.
- Very potent. Indomethacin is still one of the most potent inhibitors of COX enzyme. It is also a more potent antipyretic than aspirin, and it has about 10 times the analgesic potency of aspirin.
- Severe adverse effects limit the usefulness of this drug.
- High cardiovascular risk.
- Significant GI toxicity.
- High incidence of severe headaches.
- Indomethacin is generally used only after less toxic medications have proven ineffective.
- Indomethacin should not be used by children <14 years and during pregnancy.
- Ketoprofen, unlike many NSAIDs, inhibits the synthesis of leukotrienes and leukocyte migration into inflamed joints in addition to inhibiting the biosynthesis of prostaglandins. Ketoprofen stabilizes the lysosomal membrane during inflammation, resulting in decreased tissue destruction. Although it is less potent than indomethacin, its gastrotoxicity is about the same. Ketoprofen may cause photosensitivity.
- Ketorolac is the most COX-1 selective NSAID.
- Most potent and most effective NSAID analgesic, with efficacy comparable to opioids4. The analgesic effect of 30 mg of ketorolac is similar to 10 mg of morphine.
- Only moderate anti-inflammatory activity. Anti-inflammatory activity is achieved only at doses higher than those needed for analgesia.
- Often used in multimodal analgesia to provide an opioid-sparing effect.
- Ketorolac has the highest incidence of side effects. This drug is about five times more gastrotoxic than other NSAIDs 20.
- The risk of adverse effects is higher when ketorolac is used in higher doses, in elderly patients, and for more than 5 days.
- Lornoxicam is unique among the enolic acid derivatives in that it has a rapid onset of action and a relatively short half-life (3 to 5 hours).
- Meloxicam was initially introduced as a selective COX-2 inhibitor. However, it is less selective for COX-2 than is celecoxib.
- Meloxicam causes fewer GI complications than piroxicam.
- Long half-life (~50 hours) permits daily or twice daily dosing.
- Metamizol is a potent and promptly acting analgesic and antipyretic.
- Its anti-inflammatory activity is poor.
- Metamizol was banned in the USA and some European countries due to several reported cases of agranulocytosis. But iIt has been extensively used in India and other European countries.
- However, adverse effects data collected over 4 decades shows that risk of toxicity with metamizol is lower than with aspirin.
- Nabumetone represents a new class of non-acidic prodrugs.
- Nabumetone offers distinct advantages over other NSAIDs with regard to low incidence of GI side effects, ulcers and bleeds.
- Based on available data, nabumetone does not appear to be associated with increased cardiovascular risk5.
- Nabumetone may cause photosensitivity.
- Cardiovascular safety. Naproxen has a lowest risk of provoking heart attacks and does not appear to significantly increase CV risks.
- Naproxen is considered to be the preferred nonselective NSAID for patients with high cardiovascular risk 21.
- Naproxen provides effective relief in acute traumatic injury and for acute pain associated with migraine, tension headache, postoperative pain, postpartum pain, pain consequent to various gynecologic procedures, and the pain of dysmenorrhea.
- May cause increase in blood pressure 22.
- Over-the-counter formulations are available.
- Nimesulide is currently approved in many countries worldwide, however several national health authorities have withdrawn nimesulide from the market and others have never approved this drug.
- Nimesulide exerts COX-2 selectivity similar to celecoxib.
- Nimesulide works also through a different non-COX pathways that contribute to its potent analgesic and antiinflammatory activity.
- Nimesulide has a short half-life and very rapid onset of analgesic action.
- Its use is restricted to several days due to the risk of hepatotoxicity13.
- Oxaprozin has a rapid onset of action and a prolonged duration of action (half-life ranges from 26 to 92 hours).
- It is mainly used as an anti-inflammatory agent.
- Oxaprozin also has uricosuric properties and is used in the treatment of gout.
- May cause rash and mild photosensitivity.
- Piroxicam is a long-acting potent NSAID with anti-inflammatory potency similar to indomethacin and good analgesic and antipyretic actions.
- The main advantage of piroxicam is its 50-hour plasma half-life, which permits a single daily dosing.
- Piroxicam is indicated for long-term use in rheumatoid arthritis and osteoarthritis. Its gastrotoxicity is relatively high.
- Sulindac, an analog of indomethacin, is unique among the NSAIDs in not inhibiting prostaglandin synthesis in the kidneys 6. So, it may be one of the safest drugs for treating osteoarthrosis in older people. Sulindac may cause increased liver enzymes and is associated with an increased risk of liver toxicity compared with other NSAID.
Comparative efficacy: which NSAID is the best?
Head-to head comparisons:
- Celecoxib vs Meloxicam
- Diclofenac vs Naproxen
- Ibuprofen vs Aspirin
- Nabumetone vs naproxen, diclofenac, meloxacam
It is a common misconception that all NSAIDs are therapeutically equally effective and any one of them could be used for the given condition. For example, ankylosing spondylitis responds better to a particular NSAID like indomethacin. It is probably related to its stronger inhibition of prostaglandin synthesis.
Oxaprozin, aspirin, ibuprofen, indomethacin, naproxen, and sulindac have comparable efficacy in the treatment of rheumatoid arthritis.
Oxaprozin, aspirin, naproxen, and piroxicam have comparable efficacy in osteoarthritis.
In a comparative single-blind trial17 of 10 anti-inflammatory drugs the greatest pain relief in rheumatoid arthritis was achieved by diclofenac, indomethacin, naproxen and tolfenamic acid. The least effective drugs were ketoprofen and proquazone. Acetylsalicylic acid, azapropazone, carprofen and ibuprofen were considered intermediate in efficacy.
NSAIDs cannot be used (are contraindicated) in the following cases:
- Allergy to aspirin or any NSAID
- Aspirin should not be used under the age of 16 years
- During pregnancy
- During breast feeding
- On blood thinning agents (anticoagulants)
- Suffering from a defect of the blood clotting system (coagulation)
- Active peptic ulcer
Numerous NSAIDs are available as generics and include: diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, naproxen, piroxicam, sulindac, and tolmetin. Only meloxicam (Mobic), nabumetone (Relafen), and oxaprozin (Daypro) are available by brand name only. Generics may be an equally effective and less expensive option.
All NSAIDs are similarly effective. The choice of which NSAID to try first is usually empiric. If one doesn't provide adequate pain control, try switching to another. All NSAIDs when used chronically can contribute to the development of ulcers. So follow with your doctor closely and watch for signs or symptoms of gastrointestinal bleeding such as stomach pain and blood in the stools.
NSAIDs have different selectivity to inhibit COX-1 and COX-2. As a result the drugs have different profiles of adverse effects.
Some NSAIDs are available in extended-release formulations that require less frequent dosing.
Head-to-head comparisons of NSAIDs:
References & Resources
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Published: May 05, 2007
Last updated: January 03, 2018