Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Comparison

Based on "Essential Pain Pharmacology"
written by Howard S. Smith MD, Marco Pappagallo MD

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 (classes):

Salicylates:

  • Aspirin (Ascriptin®, Bayer®, Ecotrin®)
  • Diflunisal (Dolobid®, Diflunisal®)
  • Salsalate (Argesic® SA, Disalcid®, Salflex®, Salsitab®, Mono Gesic®)

Arylalkanoic acids:

  • Diclofenac sodium (Voltaren®)
  • Diclofenac potassium (Cataflam®)
  • Indomethacin (Indocin®)
  • Sulindac (Clinoril®)
  • Tolmetin (Tolectin®)

Pyrroles:

  • 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®)

Fenamates:

  • Mefenamic acid (Ponstel®)
  • Meclofenamate (Meclomen®)
  • Niflumic acid
  • Tolfenamic acid
  • Flufenamic acid

Pyrazolones:

  • Metamizole (dipyrone)
  • Phenazone (antipyrine)
  • Aminopyrine (aminophenazone)
  • Propyphenazone
  • Phenylbutazone

Sulphonanilides:

  • Nimesulide (Sulide®)

Napthylalkanones:

  • Nabumetone (Relafen®)

COX-2 Inhibitors:

  • Celecoxib (Celebrex®)
  • Etoricoxib (Arcoxia®)
  • Parecoxib (Dynastat®)

List of OTC NSAIDs:

Medications that are available over-the-counter in the United States:

  • Acetaminophen
  • Aspirin
  • Ibuprofen
  • Naproxen
  • Ketoprofen

Uses

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.
  • 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.


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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
Indomethacin
Ketoprofen
Piroxicam
Sulindac
Moderate selectivity towards COX-1 Diclofenac
Ibuprofen
Naproxen
Equal inhibition of COX-1 and COX-2 Etodolac
Meloxicam
Nimesulide
Nabumetone
Pronounced selectivity towards COX-2 Celecoxib

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.

Aspirin

  • 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

  • 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.

Celecoxib

  • 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

  • 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.

Diclofenac

  • 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

  • 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

  • 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

  • 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

  • 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.

Indomethacin

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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.

Naproxen

  • 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

  • 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

  • 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

  • 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

  • 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?

List of head-to-head comparisons of NSAIDs:

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.

Contraindications

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
  • Concomitant use of blood thinning agents (anticoagulants)
  • Suffering from a defect of the blood clotting system (coagulation)
  • Active peptic ulcer

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Cost

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.

Conclusions

All NSAID drugs are similarly effective. The choice of which class of non-steroidal anti-inflammatory medications to try first is usually empiric. If one doesn't provide adequate pain control, try switching to another. All types of 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.

Further Reading

References & Resources

  • 1. The Merck Manual of Medical Information. Mark H. Beers et al., eds. 2nd Home Edition. Whitehouse Station, NJ: Merck; 2003.
  • 4. Gora-Harper ML, Record KE, Darkow T, Tibbs PA. Opioid analgesics versus ketorolac in spine and joint procedures: impact on healthcare resources. Ann Pharmacother. 2001 Nov;35(11):1320-6.
  • 5. Bannwarth B. Safety of the nonselective NSAID nabumetone : focus on gastrointestinal tolerability. Drug Saf. 2008;31(6):485-503.
  • 6. Dunn MJ, Patrono C, Cinotti GA: Prostaglandins and the Kidney: Biochemistry, Physiology and Clinical Applications. New York, Plenum Publishing Corp., 1983.
  • 7. Zippel H, Wagenitz A. A multicentre, randomised, double-blind study comparing the efficacy and tolerability of intramuscular dexketoprofen versus diclofenac in the symptomatic treatment of acute low back pain. Clin Drug Investig. 2007;27(8):533-43. PubMed
  • 8. Lee RU, Stevenson DD. Aspirin-exacerbated respiratory disease: evaluation and management. Allergy Asthma Immunol Res. 2011 Jan;3(1):3-10. PubMed
  • 9. Kohli P, Steg PG, Cannon CP, Smith SC Jr, Eagle KA, Ohman EM, Alberts MJ, Hoffman E, Guo J, Simon T, Sorbets E, Goto S, Bhatt DL; REACH Registry Investigators. NSAID use and association with cardiovascular outcomes in outpatients with stable atherothrombotic disease. Am J Med. 2014 Jan;127(1):53-60 PubMed
  • 11. Henry D, McGettigan P. Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs. Int J Clin Pract Suppl. 2003 Apr;(135):43-9. PubMed
  • 13. Donati M, Conforti A, Lenti MC. et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol. 2016 Mar 18. PubMed
  • 14. Gupta A, Bah M. NSAIDs in the Treatment of Postoperative Pain. Curr Pain Headache Rep. 2016 Nov;20(11):62.
  • 16. Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin. 2010 Jul;26(7):1715-31
  • 17. Isomäki H, Martio J, Kaarela K, et al. Comparison of the analgesic effect of ten nonsteroidal anti-inflammatory drugs. Br J Rheumatol. 1984 Feb;23(1):61-5.
  • 18. Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 Apr;15(4):213-20.
  • 19. Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 8;76(10):863-9.
  • 20. García Rodríguez LA1, Cattaruzzi C, Troncon MG, Agostinis L.Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med. 1998 Jan 12;158(1):33-9.
  • 21. Ray WA1, Varas-Lorenzo C, Chung CP, Cardiovascular risks of nonsteroidalantiinflammatory drugs in patients after hospitalization for serious coronary heart disease. CircCardiovascQual Outcomes. 2009 May;2(3):155-63. PubMed
  • 22. Pope JE, Anderson JJ, Felson DT.A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure.Arch Intern Med. 1993 Feb 22;153(4):477-84.

Published: May 05, 2007
Last updated: May 25, 2018

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