Non-Steroidal Anti-Inflammatory Drugs

Comparison
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed
medications worldwide. They relieve pain and inflammation in many disorders.
Nonsteroidal anti-inflammatory drugs have anti-inflammatory, analgesic, and antipyretic
effects and inhibit thrombocyte aggregation. NSAIDs are used primarily to treat
inflammation, mild-to-moderate pain, and fever. NSAIDs also are included in many cold and
allergy preparations.
NSAIDs block the Cox enzymes and reduce prostaglandins throughout the body. As a
consequence, ongoing inflammation, pain, and fever are reduced. Since the prostaglandins
that protect the stomach and support the platelets and blood clotting also are reduced,
NSAIDs can cause ulcers in the stomach and promote bleeding.
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,
especially for nociceptive pain. NSAIDs also are effective in some neuropathic pain
syndromes when used with other analgesics.
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)

Note: NSAIDs do not cure the diseases or injuries.

Type NSAID
There are many different types of NSAIDs, which are categorized according to their chemical
structures. The following list presents medications grouped by types:
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)

etodolac (Lodine)

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)

Acetaminophen, ibuprofen, naproxen, and ketoprofen are available over-the-counter in the

United States.
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 formed via COX-1 activity control renal perfusion, promote platelet
aggregation and provide gastroprotection by regulating mucous secretion. Prostaglandins
formed via COX-2 activity 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, trauma, 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, they may be useful when given in the preoperative period and may reduce the need
for postoperative analgesia.

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 NSADs 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 is a unique NSAID but because it is the only NSAID that is able to inhibit the
clotting of blood for a prolonged period (4 to 7 days). This prolonged effect of aspirin makes
it an ideal drug 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.
Bromfenac was recently approved by the FDA for the treatment of postoperative
inflammation and reduction of ocular pain in patients who have undergone cataract
extraction. Earlier bromfenac was removed from the market because of reports liver damage
associated with its use.
Celecoxib has a sulfonamide structure and is contraindicated for patients with known sulfa
allergy. Currently, celecoxib is the only available NSAID marketed as a selective COX-2
inhibitor. It is less likely than traditional NSAIDs to cause adverse gastrointestinal effects.
Dexketoprofen is available as the tromethamine salt -- dexketoprofen trometamol.
Dexketoprofen is the S(+) enantiomer of the racemic compound ketoprofen. Clinical studies

showed that dexketoprofen has good analgesic and safety profiles, comparable to those of
other NSAIDs7.
Diclofenac is relatively long acting (6 to 8 hours) but it has a relatively very short half-life.
Diclofenac is also a unique member of the NSAIDs. There is some evidence that diclofenac
inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes (also proinflammatory autacoids). 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.
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 use increases the risk of heart attack and stroke.
Etodolac, with regard to its anti-inflammatoryproperties, is approximately 50 times more
active than aspirin, three times more potent than sulindac, and one-third as active as
indomethacin. Although etodolac is no more potent than many other NSAIDs, a low
incidence of GI side effects is an important therapeutic advantage.
Fenoprofen has less potent in anti-inflammatory action than ibuprofen, indomethacin,
ketoprofen, or naproxen.
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 has the lowest risk of causing GI bleeding. However, this advantage is lost at high
doses11. Ibuprofen produces balanced inhibitory effects on both COX-1 and COX-2. It is
available in multiple formulations and combination products.
Indomethacin, a very potent COX inhibitor, besides its high cardiovascular risk, has a
significant GI toxicity and many central nervous system side effects. Indomethacin should
not be used by children <14 years and during pregnancy.
Indomethacin is still one of the most potent NSAIDs in use. It is also a more potent
antipyretic than either aspirin or acetaminophen, and it has about 10 times the analgesic
potency of aspirin. However, its beneficial analgesic effect is definitely overshadowed by
pronounced side effects. Indomethacin is mainly used for acute gout and osteoarthritis.
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 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. Antiinflammatory activity is achieved only at doses higher than those needed for analgesia.
Ketorolac has the highest incidence of side effects, and is, therefore, not used for more than
five 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.
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. It has been extensively used in India and other
European countries. Moreover 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 nonacidic 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 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. Naproxen has a lowest risk of
provoking heart attack. It may cause photosensitivity.
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. It 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. It also has uricosuric
properties and is used in the treatment of gout. Oxaprozin may cause rash and mild
photosensitivity.
Piroxicam has a long plasma half-life (38 hours), 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?
It is a common misconception that all NSAIDs are therapeutically equally efficacious 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.
The analgesic effect of 10 anti-inflammatory drugs was compared using a single-blind
method in 90 patients with rheumatoid arthritis. Each patient received two different drugs, for

three days each and each drug was evaluated in 18 patients. After the trial, the patients
considered which of the drugs they preferred. The greatest relief from pain was achieved by
diclofenac, indomethacin, naproxen and tolfenamic acid, each of these being preferred by the
majority of patients and being significantly better than the least effective drugs ketoprofen
and proquazone. Acetylsalicylic acid, azapropazone, carprofen and ibuprofen were
considered intermediate in efficacy.
Side Effects
NSAIDs are associated with a number of side effects. The two main adverse reactions,
associated with NSAIDs relate to gastrointestinal effects and renal effects. These effects are
dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper
gastrointestinal bleeding, and death, limiting the use of NSAID therapy.
Cardiovascular side effects
Both COX-2-selective and nonselective NSAIDs may cause adverse cardiovascular effects9,
including increased risk of myocardial infarction, stroke10, and thrombosis.
Diclofenac has a cardiovascular risk very similar to rofecoxib, which was withdrawn from
worldwide
markets
owing
to
cardiovascular
toxicity2.
Naproxen does not appear to increase cardiovascular risk suggesting that it is the safest
NSAID with respect to cardiovascular toxicity.
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 of NSAIDs is that they can cause ulcers and other problems in the esophagus,
stomach, or small intestine. Common gastrointestinal side effects include: nausea, vomiting,
dyspepsia, peptic ulcers, perforations of the upper gastrointestinal tract, and gastrointestinal
bleeding.
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

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 have potentially adverse effects on blood pressure. 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 renal effects of these drugs. 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.
Allergic reactions
NSAIDs can also cause extreme allergy. People with asthma are at a higher risk for
experiencing 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 Reyes'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 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 one nonsteroidal anti-inflammatory drug,
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. Never take it for anything other than the condition for which it was prescribed,
and never share it with another person.
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

On blood thinning agents (anticoagulants)

Suffering from a defect of the blood clotting system (coagulation)

Active peptic ulcer

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 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. Differences in adverse
effects seem to exist between different NSAIDs. Follow with your doctor closely and watch
for signs or symptoms of gastrointestinal bleeding such as stomach pain and blood in the
stools. Some NSAIDs are available in extended-release formulations that require less
frequent dosing.
References & Resources
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