Jahnavi et al Journal of Drug Delivery & Therapeutics.

2019; 9(1-s):442-448

Available online on 15.02.2019 at [Link]

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research
© 2011-18, publisher and licensee JDDT, This is an Open Access article which permits unrestricted
non-commercial use, provided the original work is properly cited

Open Access Review Article

Non-steroidal anti-inflammatory drugs: an overview
Jahnavi Kasturi, Pavani Reddy Palla, Vasudha Bakshi, Narender Boggula*
Department of Pharmaceutical Chemistry, School of Pharmacy, Anurag Group of Institutions, Venkatapur, Ghatkesar, Telangana, India.

ABSTRACT
Non-steroidal anti-inflammatory drugs (NSAIDs) including both traditional non-selective NSAIDs and the selective cyclooxygenase (COX)-2
inhibitors, are widely used for their anti-inflammatory and analgesic effects. NSAIDs are a necessary choice in pain management because of the
integrated role of the COX path way in the generation of inflammation and in the biochemical recognition of pain. NSAIDs are the competitive
inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs).
Their use is associated with the side effects such as gastrointestinal and renal toxicity. They are the most commonly employed first line drugs for
all these conditions and many others-like musculoskeletal trauma, minor aches and pains, and dysmenorrhoea. The therapeutic anti-
inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity.
Thus, it was though those more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors
(Rofecoxib, Celecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Several newer applications like prophylaxis of
stroke with aspirin are now common place. Use of these drugs for the prophylaxis of conditions like Alzheimer’s disease and colorectal cancer is
being evaluated. Unfortunately, they have several toxicities ranging from minor heartburn to severe gastrointestinal haemorrhage and
perforation. Therefore, newer NSAIDs have been introduced in recent years to circumvent this problem. In preliminary studies, these have
shown better safety, efficacy, and tolerability but the full spectrum of adverse reactions of these drugs is yet to be fully known. This review can
be used for further research as well as clinical purpose.
Keywords: Non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase inhibitors, prostaglandins, aspirin.

Article Info: Received 05 Jan 2019; Review Completed 29 Jan 2019; Accepted 01 Feb 2019; Available online 15 Feb 2019
Cite this article as:
Jahnavi K, Pavani Reddy P, Vasudha B, Narender B, Non-steroidal anti-inflammatory drugs: an overview, Journal of Drug
Delivery and Therapeutics. 2019; 9(1-s):442-448 [Link]

*Address for Correspondence:

Narender Boggula, Assoc. Professor, Department of Pharmaceutical Chemistry, School of Pharmacy, Anurag Group of
Institutions, Venkatapur, Ghatkesar, Telangana, INDIA-500088.

Introduction (COX) inhibitors, commonly called non steroidal anti-

inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac,
Non-steroidal anti-inflammatory drugs (NSAIDs) are a and naproxen, have anti-inflammatory and analgesic/
diverse group of compounds with similar biological antipyretic properties across a wide range of dosing
capabilities: all NSAIDs reduce or eliminate the erythema, regimens. Prescription-strength NSAIDs are effective for
swelling, elevated temperature and pain caused by a variety relief of chronic musculoskeletal pain and inflammation in
of inflammatory stimuli. The mechanisms of action of NSAIDs conditions such as rheumatoid arthritis (RA) or
have not yet been fully elucidated, but evidence suggests that osteoarthritis (OA). Lower, Over-The-Counter (OTC) doses of
their anti- inflammatory effects are primarily achieved NSAIDs are effective for short-term (e.g. ≤10 days) relief of
through inhibiting prostaglandin production. This mode of minor aches and pains due to headache, toothache, backache,
action is common to all NSAIDs1. The cyclooxygenase menstrual cramps, common cold, muscular aches, and
enzyme was first identified as the therapeutic target of arthritis. NSAIDs taken at OTC doses can also be effective at
NSAIDs by Vane in 1971, showing that these anti- relieving painful episodes in patients with chronic diseases
inflammatory substances block the biosynthesis of such as OA. Ibuprofen is an NSAID with a long history of safe
prostaglandins (PGs) that contribute to a variety of and effective use at both prescription (maximum 2,400–
physiological and pathophysiological functions2. The most 3,200 mg/d) and OTC (<1,200 mg/d) doses3. Single-dose
prominent NSAIDs are aspirin, and naproxen, all available studies using OTC doses have confirmed that ibuprofen (400
over the countries in most countries. Paracetamol mg) provides superior analgesic efficacy to acetaminophen
(acetaminophen) is generally not considered an NSAID (1,000 mg).
because it has only little anti-inflammatory activity. It treats
pain mainly by blocking COX-2 mostly in the central nervous All NSAIDs inhibit COX, an enzyme that converts arachidonic
system, but not much in the rest of the body. Cyclooxygenase acid to prostaglandins, thereby mediating pain,

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Jahnavi et al Journal of Drug Delivery & Therapeutics. 2019; 9(1-s):442-448

inflammation, and fever. In the process, prostaglandin H2 is Biological roles of prostaglandins

converted to five primary prostaglandins, including
Prostaglandins (PGs) are hormone-like bioactive substances
thromboxane A2 (which stimulates platelet aggregation and
mediating autocrine and paracrine signaling over the short
blood clot formation) in platelets and prostacyclin (a
distances and are involved in many physiological and
vasodilator that inhibits platelet aggregation) in the
pathological processes. They act via high-affinity G-protein-
endothelium. Two COX isoenzymes (COX-1 and COX-2) are
coupled receptors: four EP receptors for PGE2 termed EP1-
commonly recognized. In general, COX-1 is constitutively
EP4, IP receptor for prostacycline, DP receptor for PGD2, FP
expressed and is involved in gastroprotection from stomach
receptor for PGF2α. These receptors are linked to the
acid and in thromboxane formation by platelets. COX-2 is
different signal transduction pathways3. Once a prostanoid is
inducible by inflammatory mediators in a wide range of
formed, it exits the cell and then interacts with G protein-
tissues and has been associated with inflammation; however,
coupled receptors, either on the parent cell or on closely
it may also be constitutively expressed, where it contributes
neighboring cells to modulate the second messenger levels4.
to renal physiology, reproductive function, bone resorption,
Although their tissue distribution depends on the cellular
and neurotransmission.
enzymatic material, prostanoids are involved in a very broad
Classification range of physiological and pathophysiological responses5.

 Non-selective COX inhibitors: Enzymatic structure

- Salisylates : Aspirin, sodium salisylate The COX isoenzymes are membrane-bound enzymes in the
- Propionic acid derivatives: Ibuprofen, naproxen, endoplasmic reticulum (ER). The three dimensional
ketoprofen, flubiprofen structure of the ovine COX-1 was first reported in 1994 and
- Anthranilic acid derivatives: Mephanamic acid, the crystal structures of human and murine COX-2 quickly
meclofenamic acid followed. COX functions as a homodimer and attempts to
- Aryl-acetic derivatives: Diclofenac, aceclofenac create monomeric species which have yielded only inactive
- Oxicams: Piroxicam, tenoxicam enzyme. The crystal structures of the COX isoforms are quite
- Pyrolo-pyrol derivatives: Ketorolac structurally homologous and consistent with a high sequence
- Indole derivatives: Indomethacin identity (ca. 60%); the overall structures of COX-1 and COX-2
- Pyrozolone derivatives: Phenylbutazone, are highly conserved. The COX monomer consists of three
oxyphenbutazone structural domains: an N-terminal epidermal growth factor
 Preferentical COX-2 inhibitiors: Nimesulide, meloxicam, (EGF)-like domain, a membrane binding domain (MBD) of
nabumetone about 48 amino acids in length which anchors the protein to
 Selective COX-2 inhibitors: Celecoxib, rofecoxib, one leaflet of the lipid bilayer, and a large C-terminal
etoricoxib, parecoxib globular catalytic domain with the COX active site which
 Analgesics-anti-pyretics: accommodates the substrate or the inhibitors and the
- Paraminophenol: Paracetamol peroxidase one which contains the heme cofactor. These
- Pyrozolone derivative: Metamizol, propiphenazone sites are distinct but functionally and structurally
interconnected6.

Figure 1: General mechanism of NSAIDs

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Jahnavi et al Journal of Drug Delivery & Therapeutics. 2019; 9(1-s):442-448

Mechanism of action platelet therapeutic doses (75–100 mg daily), aspirin is up to

100-fold more potent in inhibiting platelet COX-1 than
COX enzymes (i.e., COX-1 and COX-2) catalyze the conversion
monocyte COX-210.
of arachidonic acid into prostaglandin (PG) G2, an unstable
intermediate that is rapidly converted to PGH2. The analgesic and anti-inflammatory actions of NSAIDs
Subsequently, PGH2 is metabolized into different including COX-2 selective inhibitors are due to their effective
structurally-related PGs, including PGE2, PGD2, PGF2, PGI2 inhibition of prostaglandin synthesis catalysed by the COX-2
and thromboxane (TX)A27. COX-1 is constitutively expressed isoenzyme (Figure 2). This isoenzyme is massively up-
in mammalian tissues, and COX-1-derived PGs are essential regulated in inflammatory states such as rheumatoid
for physiological functions, although studies in experimental arthritis, so inhibiting it reduces inflammation. Aspirin and
models of CRC have suggested that COX-1 could exert tumor- the non-selective NSAIDs inhibit COX-1 and COX-2
promoting effects8. In contrast, COX-2 is inducible by isoenzyme. The COX-1 isoenzyme is involved in the synthesis
inflammatory cytokines, growth factors and tumor of prostaglandins. These prostaglandins protect the gastric
promoters in several cell types. Upregulation of COX-2 mucosa from ulceration and participate in platelet
expression is seen in 40–50% of human colorectal adenomas aggregation via the prostaglandin derivative, thromboxane
and in 80–90% of carcinomas and results in enhanced PG A2. Inhibition of COX-1 has been strongly implicated in the
production9. COX-2 plays a pivotal role in tumor initiation, gastric ulceration and bleeding induced by the non-selective
promotion and progression by increasing the production of NSAIDs.
(1) reactive oxygen species, (2) PGE2 and other PGs that
In platelets, inhibition of COX-1 leads to inhibition of
promote cell proliferation, (3) vascular endothelial growth
thromboxane A2 synthesis. This very effectively inhibits
factor and platelet-derived growth factor and (4) matrix
platelet aggregation. Low-dose aspirin irreversibly inhibits
metalloproteinases. COX-2 also controls the expression of
platelet aggregation via this mechanism and is therefore
both pro- and anti-apoptotic proteins and restrains the
widely employed as prophylaxis against thrombotic
proliferation of immune cells with anti-neoplastic activity.
cardiovascular disease. At therapeutic doses, COX-2 selective
Among the NSAIDs, aspirin is the only drug that is able to
inhibitors have little effect on the COX-1 enzyme, so they do
permanently inhibit COX-1 and COX-2 activity. At anti-
not inhibit platelet aggregation.

Figure 2: MOA
Naproxen patient level, particularly to assess underlying conditions
that may increase the risk of events. Likewise, regulatory
Naproxen is a non-steroidal anti-inflammatory drug (NSAID).
authorities should revisit label information periodically to
It works by reducing hormones that cause inflammation and
ensure labeling reflects the current understanding of
pain in the body. Naproxen is used to treat pain or
benefits and risks. Musculoskeletal aches and pains are one
inflammation caused by conditions such as arthritis,
of the most common medical complaints around the world,
ankylosing spondylitis, tendinitis, bursitis, gout or menstrual
and increasing life expectancies are driving an increased
cramps. Naproxen sodium is an anti-inflammatory agent
incidence of degenerative joint disease, burdening patients
with analgesic and anti-pyretic properties. Both the acid and
and healthcare systems11. Naproxen binds reversibly with
its sodium salt are used in the treatment of rheumatoid
COX-1 and COX-2 to exert its effects but has an increased
arthritis and other rheumatic or musculoskeletal disorders,
selectivity for COX-1 inhibition, which is fivefold greater than
dysmenorrhea, and acute gout. Naproxen Sodium is
the level of COX-2 inhibition 12. Naproxen reaches peak
the sodium salt form of naproxen, a member of the aryl- plasma concentrations between 2 and 4 h (naproxen
acetic acid group of non-steroidal anti-inflammatory drugs
sodium C max at 1–2 h) and has a half-life of 12–17 h13.
(NSAIDs) with anti-inflammatory analgesic and antipyretic
Naproxen is a highly effective analgesic, and its long half-life
properties. Naproxen sodium reversibly and competitively
provides consistent blood levels and efficacy, making it a
inhibits cyclooxygenases (COX), thereby blocking the
choice comparator in many clinical trials. Naproxen's
conversion of arachidonic acid to pro-inflammatory
medical uses are related to its mechanism of action as an
prostaglandins. This inhibits the formation of prostaglandins
anti-inflammatory compound. Naproxen is used to treat a
that are involved in pain, inflammation and fever. The over-
variety of inflammatory conditions and symptoms that are
the-counter (OTC) use of naproxen is expected to pose
due to excessive inflammation such as pain and fever
minimal cardiovascular risk; however, the benefit–risk ratio
(naproxen has fever-reducing, or anti-pyretic properties in
and appropriate use should be considered at an individual
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addition to its anti-inflammatory activity). Notably, not all medical condition may affect the dosing and effectiveness of
medications that reduce fever are anti-inflammatory this medication.
compound Inflammatory sources of pain that may respond
Drowsiness/reduced alertness: As with other NSAIDs,
to naproxen's anti-inflammatory activity are conditions such
naproxen sodium can cause drowsiness, dizziness, and
as migraine, osteoarthritis kidney stones, rheumatoid
blurred vision. Avoid driving and other activities that require
arthritis, psoriatic arthritis, gout, ankylosing spondylitis,
alertness and concentration until you determine the effect
menstrual cramps tendinitis and bursitis.
this medication has on you.
Side effects
Fluid and electrolyte balance: NSAIDs such as naproxen
Naproxen side effects may include: sodium can cause fluid retention and edema (swelling). This
can lead to high blood pressure or worsening of heart failure.
 Indigestion, heartburn, stomach pain, nausea; If you have heart failure or high blood pressure. Naproxen
 Headache, dizziness, drowsiness; sodium may also cause high blood potassium levels. If you
are a senior; have diabetes or kidney failure; or are taking
 Bruising, itching, rash; beta-blockers (e.g., metoprolol, atenolol), angiotensin
converting enzyme (ACE) inhibitors (e.g., ramipril, enalapril),
 Swelling; or or some diuretics (e.g., triamterene, amiloride), you are more
at risk of high blood potassium.
 Ringing in your ears
Heart attack and stroke: This medication may be
 Swelling or rapid weight gain; associated with an increased risk of heart attack and stroke.
 The first sign of any skin rash, no matter how mild; The risk is increased with higher total daily doses and taking
the medication over long periods of time. If you have a
 Signs of stomach bleeding - bloody or tarry stools, history of heart disease (e.g., heart attack, stroke, heart
coughing up blood or vomit that looks like coffee failure) or have risk factors for heart disease (e.g., high blood
grounds; pressure, high cholesterol, diabetes, smoking, kidney
disease) discuss with your doctor how this medication may
 Liver problems - nausea, upper stomach pain, itching, affect your medical condition, how your medical condition
tired feeling, flu-like symptoms, loss of appetite, dark may affect the dosing and effectiveness of this medication,
urine, clay-colored stools, jaundice (yellowing of the and whether any special monitoring is needed.
skin or eyes);
Kidney function: Long-term use of naproxen sodium may
 Kidney problems - little or no urinating, painful or lead to kidney problems. If you have kidney problems, liver
difficult urination, swelling in your feet or ankles, feeling disease, or heart failure; or are dehydrated, on a salt
tired or short of breath; restricted diet, or are a senior, you have an increased risk for
kidney problems while taking this medication. If you are
 Low red blood cells (anemia) - pale skin, feeling light- taking medications such as diuretics (e.g., hydrochloro
headed or short of breath, rapid heart rate, trouble thiazide, triamterene, indapamide), ACE inhibitors (e.g.,
concentrating; or enalapril, ramipril), angiotensin receptor blockers (e.g.,
 Severe skin reaction - fever, sore throat, swelling in your valsartan, candesartan), or cyclosporine, you are also at an
face or tongue, burning in your eyes, skin pain followed increased risk.
by a red or purple skin rash that spreads (especially in Liver problems: Rarely, this medication causes liver
the face or upper body) and causes blistering and problems. If you have reduced liver function
peeling.
Skin reactions: This medication can cause skin reactions,
Adverse drug reactions of naproxen some of which may be severe. If you experience a skin rash,
Allergic reactions: If you have had a reaction to especially where the skin is blistering or peeling, This
acetylsalicylic acid (ASA) or other NSAIDs (e.g., ibuprofen, medication may make your skin more sensitive to sunlight
ketoprofen, ketorolac) that included a runny nose, itchy skin (including sunlamps) and may cause sunburn, skin blisters,
rash, nasal polyps, or shortness of breath and wheezing, you and skin redness, itching or discolouration.
should not take this medication. If you experience symptoms Ulcers or bleeding in the stomach or intestines: Naproxen
of a severe allergic reaction (e.g., hives; difficulty breathing; sodium can cause stomach ulcers, perforation (holes), and
wheezing; swelling of the face, tongue, or throat). bleeding from the stomach. These complications can occur at
Aseptic meningitis: This medication can rarely cause any time without warning and are sometimes severe enough
symptoms of aseptic meningitis (inflammation or swelling of to require immediate medical attention. The risk of ulcers
the membranes around the brain and spinal cord that is not and bleeding are increased if you are taking higher doses of
caused by bacteria). If you have an autoimmune condition this medication for longer periods of time. Other factors that
(e.g., systemic lupus erythematosus, mixed connective tissue increase the risk of these complications include drinking
disease), Symptoms such as stiff neck, severe headache, excessive amounts of alcohol, increased age, smoking, poor
nausea, vomiting, fever, or changes in consciousness. health, H pylori infection, and taking certain medications
(e.g., warfarin, ASA, clopidogrel, prednisone, citalopram,
Bladder problems: This medication may cause bladder fluoxetine, paroxetine, sertraline). If you currently have
pain, painful or difficult urination, or increased frequency of ulcers in the stomach or intestines that are bleeding, or have
urination. an inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis) ,
Blood clotting: This medication may reduce the ability of
the blood to clot. If you are taking anticoagulants (e.g., Pregnancy: This medication should not be used during the
warfarin, heparin) or have hemophilia or other blood third trimester (last 3 months) of pregnancy. This
disorders (e.g., low platelets), discuss with your doctor how medication should not be used during the first and second
this medication may affect your medical condition, how your trimester (first 6 months) of pregnancy unless the benefits

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outweigh the risks. This medication may reduce your ability Renal
to become pregnant.
All NSAIDs can alter renal function by inhibiting COX-1
Breast-feeding: You should not use this medication if you (which regulates renal hemodynamics and glomerular
are breast- feeding. filtration) and/or COX-2 (which mediates salt and water
excretion) expressed in the kidneys. Uncommon, but
Adverse drug reactions of NSAIDS concerning, renal syndromes caused by nonselective NSAIDs
ADRs associated with NSAIDs primarily manifest in include sodium retention, peripheral edema, increased BP
gastrointestinal (GI), cardiovascular (CV), and renal sites. and weight, congestive heart failure (rare), hyperkalemia,
and acute renal failure. Risk factors include preexisting
GI effects severe hepatic or renal dysfunction, nephrotic syndrome
GI complications are well-recognized risks of NSAIDs as a with high-level proteinuria, older age, diabetes,
class and vary by the respective NSAID used as well as by hypertension, and congestive heart failure24. Furthermore,
dose14. Like Aspirin increases bleeding risk, even at low individuals experiencing renal stress (e.g., dehydration) from
cardioprotective doses. In terms of non-selective NSAIDs, a exercise in hot environments may be at a small increased
meta-analysis of data from three retrospective case-control risk for acute renal failure with ibuprofen25. NSAIDs may
studies found that ibuprofen had the lowest odds ratio (OR) lessen response to diuretics and worsen renal insufficiency
for development of GI bleeding versus diclofenac, naproxen, associated with use of angiotensin-converting enzyme
piroxicam, and indomethacin, but that the OR increases with inhibitors (ACEIs) and angiotensin II receptor blockers
dose level for each agent15,16. Ibuprofen was noted to (ARBs). However, a study of OTC analgesics in elderly
produce significantly fewer overall GI AEs vs acetaminophen. patients with diuretic-treated hypertension and mild renal
In this study, a significant AE was defined as any event that insufficiency found no significant impact of ibuprofen on
was serious, severe, or moderate; necessitated a second creatinine clearance nor on blood urea nitrogen, serum
physician consultation; led to treatment discontinuation; or creatinine, sodium, or potassium levels. Aldosterone
was of missing intensity. The Paracetamol, Aspirin, and antagonists (e.g., Spiranolactone) are associated with an
Ibuprofen New Tolerability (PAIN) study (N=8,677) assessed increased risk of GI bleeding and possibly impaired healing
the frequency of significant adverse events (AEs) associated of gastric or duodenal erosions 26,27. Thus, risk of GI bleeding
with OTC analgesic dosing in patients with acute pain. in patients taking these agents may be further increased
when NSAIDs are used concomitantly. Patients treated long
In this study, a significant AE was defined as any event that term with aldosterone antagonists should be informed of the
was serious, severe, or moderate; necessitated a second risk of upper GI bleeding and perhaps warned of the risk of
physician consultation; led to treatment discontinuation; or using OTC NSAIDs long term. It found that prescription of
was of missing intensity. The PAIN study demonstrated that ibuprofen and its administration decreased clearance of
OTC ibuprofen (≤1,200 mg/d) was similar to acetaminophen furosemide and increased urine sodium excretion. Topical
(≤3,000 mg/d) in terms of the incidence of significant AEs diclofenac had no effect on furosemide pharmacokinetics or
(13.7% vs 14.5%, respectively), but that statistically pharmacodynamics, and oral diclofenac compared with
significantly fewer such events occurred with ibuprofen in furosemide alone decreased urine output, but neither
comparison with aspirin during 1–7 days of treatment17. As formulation was associated with alterations in BP.
expected, rates of GI AEs were significantly lower in patients
receiving OTC doses of ibuprofen versus aspirin (4.0% vs Anti-thrombotics
7.1%; P<0.001), and interestingly, ibuprofen was noted to NSAIDs are not prone to a direct pharmacodynamic
produce significantly fewer overall GI AEs vs acetaminophen interaction with anticoagulants such as warfarin; however,
(5.3%; P=0.025). The PAIN study also identified numerous concurrent use of NSAIDs and anti-thrombotics may further
factors associated with increased risk of AEs, including increase the likelihood of GI bleeding. Metabolism of S-
female sex, older age, height ≤160 cm, use of the analgesic for warfarin, the most clinically relevant warfarin isomer, occurs
musculoskeletal pain (vs menstrual cramps, sore throat, via [Link] and other NSAIDs are also substrates
toothache, or fever), concomitant use of prohibited of CYP2C9and may thus increase anticoagulant activity by
medications, and increasing number of concomitant delaying S-warfarin metabolism. Therefore, it may be
medications18. Concomitant medications also influence the prudent to avoid prescription-strength NSAIDs in patients
risk of GI events among NSAID users. The risk of upper GI receiving warfarin28. In contrast, one of the metabolites of
events is increased when non-aspirin NSAIDs are combined acetaminophen (N-acetyl-para-benzoquinone-imine)
with aspirin, but this increase in risk may be ameliorated interferes with enzymes involved in the vitamin K cycle,
when NSAIDs are used concurrently with ulcer-healing drugs which ultimately can lead to reduction in synthesis of
(i.e., proton pump inhibitors)19. clotting factors and excessive anticoagulation29. Even with
CV risk short-term use, acetaminophen given concurrently with
anticoagulants may increase international normalized ratio
All non-aspirin NSAIDs may be associated with a potential (INR), implying an increase in bleeding risk and
increase in CV thrombotic risk. The risk of heart attack or necessitating close INR monitoring and possible warfarin
stroke may increase if you use more than directed or for dosage adjustments30. Aspirin Co-administration of aspirin
longer than directed 20,21. Hence there is no period of latency and most NSAIDs (other than diclofenac and ketorolac) can
for CV thrombotic risk, and therefore, patients should take lead to pharmacodynamic DDIs resulting from competition
the lowest dose of NSAIDs for the shortest period of time for access to the acetylation site of platelet-expressed COX-1.
possible. There are few data on actual CV risk with NSAID NSAID-driven reversible, transient inhibition of platelet
use at OTC doses, but risk is likely to be small, especially in aggregation blocks aspirin’s irreversible inhibition, thereby
younger patients who have few CV risk factors. It has been potentially allowing clot formation. This NSAID-driven effect
hypothesized that the increase in CV risk among NSAID users on aspirin is of particular concern in individuals at high CV
stems from increased blood pressure (BP) due to COX-2 risk who take low-dose aspirin daily to reduce the risk of a
inhibition in the kidneys – an effect that has not been thrombotic event. Ibuprofen should be avoided in patients
observed with OTC doses 22,23. with known or suspected aspirin-sensitive asthma. Patients
should be counseled to limit their use of OTC NSAIDs and to

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avoid acetaminophen while on anticoagulant therapy, the Corticosteroids

former because of the increased risk of GI bleeding with
Combined use of oral corticosteroids and NSAIDs may
NSAIDs, however small, and the latter because of the direct
increase the potential for serious GI toxicity. On further
interaction that would increase the risk of all-site bleeding31.
analysis, this increased risk was attributed to a 4.4-fold
Anti-depressants increased risk for peptic ulcer disease in individuals who had
also taken NSAIDs (any type or dosage) compared with no
Anti-depressants are psychiatric medications used to
elevated risk when NSAID users were excluded. although no
alleviate mood and anxiety disorders. Some antidepressants
specific studies have identified a clear risk for increased GI
may be associated with an increased risk for bleeding, which
bleeding when OTC NSAIDs are co-administered with oral
may be additively enhanced by co-administration of NSAIDs.
corticosteroids, it may be prudent for health care providers
Selective serotonin reuptake inhibitors (SSRIs) increase
to prescribe COX-2-specific NSAIDs or counsel patients to
bleeding risk by inhibiting platelet adhesion and
avoid OTC NSAIDs to reduce the potential risk for GI
function. Co-administration of NSAIDs in patients taking
bleeding42.
SSRIs can substantially increase the risk of bleeding32.
Several mechanisms may account for the interaction Drug interaction of NSAIDs
between SSRIs and NSAIDs: 1) Both classes inhibit platelet
aggregation and function but via different mechanisms;33. 2) NSAIDs are one of the most common causes of adverse drug
A pharmacokinetic interaction in which some SSRIs inhibit reactions. As patient age and the number of medications
CYP2C9, an enzyme responsible for the metabolism of some increase, NSAIDs in the elderly should be prescribed with
NSAIDs (e.g., ibuprofen and diclofenac); 34, or 3) Independent caution. NSAIDs concomitantly used with specific medication
effects in which SSRIs increase symptoms and bleeding via can alter the risk of gastrointestinal ulceration and/or
an independent mechanism without any direct bleeding. These drugs include selective serotonin reuptake
pharmacokinetic interaction (e.g., by increasing gastric acid inhibitors (SSRIs), corticosteroids, digitalis glycosides,
secretion). Tricyclic anti-depressants (TCAs) do not diuretics, beta blockers, calcium antagonists, angiotensin
substantially inhibit CYP2C9. In the Dutch cohort study, in converting enzyme, warfarin, clopidogrel, aspirin, and other
contrast to the tenfold increase in risk when NSAIDs are anti-coagulants. Some specific NSAIDs were found to reduce
added to SSRIs, patients receiving TCAs plus an NSAID renal clearance of Methotrexate, a commonly used
experienced a more modest increase in GI events34. medication for rheumatoid arthritis43.

Anti-rheumatics/chemotherapy Conclusion
Methotrexate is an anti-metabolite used at high doses as a Knowing about the mechanism of action, current guidelines,
chemotherapeutic and at low doses for treatment of adverse drug reaction, and the pleiotropic effects of common
psoriasis and RA 35. Several NSAIDs, including prescription drugs is important. NSAIDs are one of the most commonly
ibuprofen and naproxen, have been found to reduce renal prescribed drugs in the elderly. These medications should be
clearance of Methotrexate36, which could lead to toxicity prescribed for the shortest duration possible in the lowest
(e.g., renal failure or pancytopenia), at least when effective dose, and with careful surveillance to monitor GI,
Methotrexate is used at high doses. A single-case report renal, and cardiovascular toxicity. This is especially true for
speculated that daily use of an OTC ibuprofen product for 4 elderly patients who are very susceptible to the side effect
weeks reduced Methotrexate excretion. Resulting profiles of NSAIDs. There is some evidence to support the
Methotrexate accumulation caused bone marrow depletion, role of NSAIDs in dementia prevention, improve muscle
which may have contributed to Pneumocystis performance, improve urinary incontinence, and decrease
carinii pneumonia in a patient with Crohn’s disease37,38. the risk of some specific cancers.
Given that renal effects have also been reported with
Acknowledgement
prescription ibuprofen monotherapy39. Patients taking high-
dose Methotrexate should avoid NSAID use, even at OTC We wish to thank the management of School of Pharmacy,
doses. Additionally, caution should be exercised when Anurag Group of Institutions, Venkatapur, Ghatkesar,
NSAIDs are used in patients receiving low-dose Telangana, India for providing constant encouragement,
Methotrexate. No other reports of clinically relevant DDIs praiseworthy inspiration, facilities and support.
resulting in ADRs in individuals receiving concomitant
NSAIDs and chemotherapeutics or rheumatologic therapies Authors Contribution
were identified35. All the authors contributed equally.
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