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Nonsteroidal anti-inflammatory drugs (NSAIDs)

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications used to relieve pain, fever and inflammation and they include a large group of anti-inflammatory agents that work by inhibiting the production of prostaglandins. Nonsteroidal anti-inflammatory drugs (NSAIDs) also represent diverse group of drug with analgesic property and most frequently prescribed drug globally. They represent the first  choice  of  drug  with  well demonstrated  efficiency  for  the  pain  management  primarily  musculoskeletal  disorder  and osteoarthritis to treat mild to moderate pain. Although its serious toxicity related to Gastro intestinal tract its choice in this category of its choice (Gul and Ayub, 2014).

There is overwhelming evidence linking chronic nonselective NSAID (including aspirin) use to a variety of Gastrointestinal (GI) tract injuries. Age is a significant risk factor for NSAID-induced GI events; indeed, patients above 75 years of age carry the highest risk and are similar in this respect to patients with a history of peptic ulcer (Beradi and Welage, 2005)

People desire to take responsibility for their own health care management. Many do so via  self‑medication. Self‑medication is defined as the use of over‑the‑counter (OTC) drugs without consulting a professional health care practitioner. Self‑medication involves acquiring medication without  a prescription, resubmitting an old prescription to  procure medication, sharing medications with others, or utilizing a medication that is already available in the residence. Several governmental organizations developed policies to encourage self‑care for minor  illnesses, reclassifying many drugs as nonprescription  medications instead of prescription‑only medications,  allowing the drugs to be administered by patients  without a prescription. (Saeed et al, 2015) and could also be described as Medication  that  is  taken  on patient’s own initiative or on advice of a pharmacist or lay  person(Neha et al, 2013)

The terms ‘misuse’ and ‘abuse’ are often used interchangeably, but they have precise meanings in this context. Misuse is defined as using an OTC product for a legitimate medical reason but in higher doses or for a longer period than recommended. Abuse is the nonmedical use of OTC drugs(Gul and Ayub, 2015)


Aspirin and NSAIDs have a storied history in the treatment of pain and rheumatic diseases. In the 4th century B.C., Hippocrates detailed the use of powder made from the bark and leaves of the willow tree (Salixspp.) for  headache, pain, and fever. Ancient Egyptians and Assyrians also used a willow extract to relieve the pain and erythema of inflamed  joints( Apebum, 2002)

In 1828, Johann Buchner at the University of Munich extracted and purified salicin from willow, and three decades  later, Charles Gerhardt succeeded in synthesizing a  “buffered” form of salicylate to reduce dyspepsia, acetylsalicylic acid. This synthetic compound, containing no willow derivatives, was marketed by Felix Hoffmann of the Bayer company in 1899 as aspirin. The U.S. Food and Drug Administration (FDA) approved aspirin for  the primary and secondary prevention of cardiovascular  disease, and the secondary prevention of stroke and  transient ischemic attacks, in 1988.

Additional NSAIDs were developed, such as phenylbutazone in 1949, indomethacin in 1963, and ibuprofen in 1969; however, the mechanism of action of these NSAIDs was unknown. In 1972, John R. Vane demonstrated that aspirin blocks the synthesis of a proinflammatory cytokine, prostaglandin E, for which he was granted the Nobel Prize in 1982 (Vane, 1971)

Prostaglandin synthase (COX), the enzyme inhibited by aspirin, which  converts arachidonic acid to prostaglandins, was discovered in 1989, and was found to have two isoforms, COX-1 and COX-2; this discovery paved the way for  the development of COX-2 selective inhibitors, which were hypothesized and later proven to have reduced GI toxicity.Babberdia,1999, Goldstain, 2001) .The first COX-2 selective inhibitor, celecoxib  (Celebrex), approved by the FDA in 1998 based upon  the results of five clinical trials involving more than  5000 patients with degenerative or rheumatoid arthritis, showed comparable analgesia and efficacy to nonselective NSAIDs and placebo with fewer clinical and endoscopic gastroduodenal ulcers.(Emery, 1999; silverstainn et al, 2000;Denson et al 1999; and Bonberdier et al 2000)

Two other COX-2 selective inhibitors, valdecoxib and rofecoxib, were subsequently approved; however, in the wake of concerns  of an increased risk of thromboembolic events, and with valdecoxib an additional risk of Stevens–Johnson syndrome, both were withdrawn from the U.S. market in 2005(Bresalier et al, 2005;  Solomon et al 2005). Celecoxib remains available for the treatment of pain associated with degenerative joint disease  and rheumatoid arthritis, but as of April 2005 carries a “black box” warning alerting consumers to the increased cardiovascular risk associated with this medication.

Over the last few years, professional organizations, including the American College of Rheumatology, the American Pain Society (Emery et al 1999) , and the European League Against Rheumatism (Silverstein et al, 2000), have published treatment guidelines to assist clinicians in achieving effective pain management. Safety is a core concern in all these guidelines, especially for chronic conditions, such as OA, that require long-term treatment. Hence, there is a consensus among recommendations that paracetamol (acetaminophen) should be the first-line analgesic agent due to its favorable side effect and safety profile, despite several meta-analyses having shown that it is less effective in pain relief than anti-inflammatory drugs (Scarpignato et al, 2015).

Concerns have been raised regarding the safety of nonsteroidal antiinflammatory drugs (NSAIDs), which havebeen linked to increased cardiovascular morbidity. This association was first established in large clinical trials investigating the effect of selective cyclooxygenase-2 (COX-2) inhibitors on preventing gastrointestinal ulcers and gastrointestinal polyps. Later, these results have been confirmed in several large-scale observational studies(FitzGerald, 2003).

Pharmacists are usually the custodian of drugs and are charged with the responsibilities of delivering safe and efficacious medicines to the public (Owusu-Ansah, 2009). In developing countries, traders perceive drugs as items of trade. In Nigeria, a country where the ratio of pharmacist to non-pharmacist in an urban environment and commercial centre, like Lagos is approximately 1:3, NSAIDs are sold or ingested without the required level of caution. These unregistered drug outlets, usually manned by traders, are located virtually in every street of urban centers in Nigeria.

Evaluation of drug use revealed that there was a great deal of drug misuse ranging from sub – therapeutic dosing, wrong indication and irrational combination of drugs, even in high doses (Awofisayo et al, 2008)


One of the conditions that necessitate the use of NSAIDs is pain. Pain is an unpleasant, subjective sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.

Greater understanding of pain mechanisms and growing appreciation for pain control have, however, caused rheumatologists to consider new approaches in pain management.. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Both selective and nonselective cyclooxygenase (COX) inhibitors have antipyretic, anti-inflammatory and analgesic effects and are widely used in treating many painful conditions, including rheumatic diseases. NSAIDs are effective and widely available in over-the-counter formulations and in prescription products. Examples include ibuprofen, naproxen, diclofenac, and celecoxib. NSAIDs are frequently used without considering the relative contraindications since most NSAIDs are sold over the counter. Conventional NSAIDs are associated with gastrointestinal (GI) side effects. Estimates of the number of deaths from NSAID-related gastrointestinal bleeding vary widely and figures of approx. 3500 to 16.500 per year are quoted for the US in a recent FDA report. Both conventional NSAIDs and COX-2 inhibitors are associated with increased cardiovascular risk. NSAIDs may increase blood pressure, particularly in hypertensive patients. Of all NSAIDs, naproxen seems to pose the least cardiovascular risk, although naproxen is associated with the same risk for myocardial infarction as other NSAIDs. Contrary to some clinical assumptions, gastrointestinal risk is present at first dose with a non-selective NSAID, and co-therapy with a proton pump inhibitor (PPI) does not guarantee complete protection(Well et al, 2006)

Pain could be classified into two main groups: NOCICEPTIVE PAIN and NEUROPATHIC PAIN


Nociceptive (acute) pain is either somatic (arising from skin, bone, joint, muscle, or connective tissue) or visceral (arising from internal organs such as the large intestine or pancreas).

Stimulation of free nerve endings known as nociceptors is the first step leading to the sensation of pain. These receptors are found in both somatic and visceral structures and are activated by mechanical, thermal, and chemical impulses. Release of bradykinins, K+, prostaglandins, histamine, leukotrienes, serotonin, and substance P may sensitize and/or activate nociceptors. Receptor activation leads to action potentials that are transmitted along afferent nerve fibers to the spinal cord.

Action potentials continue from the site of noxious stimuli to the dorsal horn of the spinal cord and then ascend to higher centers. The thalamus acts as a relay station and passes the impulses to central structures where pain is processed further.

The body modulates pain through several processes. The endogenous opiate system consists of neurotransmitters (e.g., enkephalins, dynorphins, and beta-endorphins) and receptors that are found throughout the central nervous system (CNS). Endogenous opioids bind to opioid receptors and inhibit the transmission of pain impulses.

The CNS also contains a descending system for control of pain transmission. This system originates in the brain and can inhibit synaptic pain transmission at the dorsal horn. Important neurotransmitters here include endogenous opioids, serotonin, norepinephrine, gama-aminobutyric acid (GABA), and neurotensin.


Neuropathic (chronic) pain is sustained by abnormal processing of sensory input by the peripheral or central nervous system. There are a large number of neuropathic pain syndromes that are often difficult to treat (e.g., low back pain, diabetic neuropathy, postherpetic neuralgia, cancer-related pain, spinal cord injury). Nerve damage or persistent stimulation may cause pain circuits to produce spontaneous nerve stimulation, autonomic neuronal pain stimulation, and a progressive increase in discharge of dorsal horn neurons.

The inflammatory process is the response to an injurious stimulus. It can be evoked by a wide variety of noxious agents (e.g., infections, antibodies, or physical injuries). The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury; in some situations and diseases, the inflammatory response may be exaggerated and sustained without apparent benefit and even with severe adverse consequences. No matter what the initiating stimulus, the classic inflammatory response includes calor (warmth), dolor (pain), rubor (redness), and tumor (swelling).

Inflammatory responses occur in three distinct temporal phases, each apparently mediated by different mechanisms:

(1)  An acute phase characterized by transient local vasodilation and increased capillary permeability;

 (2)  A delayed, subacute phase characterized by infiltration of leukocytes and phagocytic cells; and

(3)  A chronic proliferative phase, in which tissue degeneration and fibrosis occur.

Many mechanisms are involved in the promotion and resolution of the inflammatory process. Although earlier studies emphasized the promotion of migration of cells out of the microvasculature, recent work has focused on adhesive interactions, including the E-, P-, and L-selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and leukocyte integrins, in the adhesion of leukocytes and platelets to endothelium at sites of inflammation.
Activated endothelial cells play a key role in “targeting” circulating cells to inflammatory sites. Expression of the adhesion molecules varies among cell types involved in the inflammatory response. Cell adhesion occurs by recognition of cell-surface glycoproteins and carbohydrates on circulating cells due to the augmented expression of adhesion molecules on resident cells. Thus, endothelial activation results in leukocyte adhesion as the leukocytes recognize newly expressed L-selectin and P-selectin; other important interactions include those of endothelial-expressed E-selectin with sialylated Lewis X and other glycoproteins on the leukocyte surface and endothelial ICAM-1 with leukocyte integrins. It has been proposed that some, but not all, NSAIDs may interfere with adhesion by inhibiting expression or activity of certain of these cell-adhesion molecules . Novel classes of antiinflammatory drugs directed against cell-adhesion molecules are under active development but have not yet entered the clinical arena.
In addition to the cell-adhesion molecules outlined above, the recruitment of inflammatory cells to sites of injury involves the concerted interactions of several types of soluble mediators. These include the complement factor C5a, platelet-activating factor, and the eicosanoid LTB4. All can act as chemotactic agonists. Several cytokines also play essential roles in orchestrating the inflammatory process, especially interleukin-1 (IL-1) and tumor necrosis factor (TNF) . IL-1 and TNF are considered principal mediators of the biological responses to bacterial lipopolysaccharide (LPS, also called endotoxin). They are secreted by monocytes and macrophages, adipocytes, and other cells. Working in concert with each other and various cytokines and growth factors (including IL-8 and granulocyte-macrophage colony-stimulating factor, they induce gene expression and protein synthesis in a variety of cells to mediate and promote inflammation.
IL-1 comprises two distinct polypeptides (IL-1a and IL-1b) that bind to the same cell-surface receptors and produce similar biological responses. Plasma IL-1 levels are increased in patients with active inflammation. IL-1 can bind to two types of receptors, an 80-kd IL-1 receptor type 1 and a 68-kd IL-1 receptor type 2, which are present on different cell types.
TNF, originally termed “cachectin” because of its ability to produce a wasting syndrome, is composed of two closely related proteins: mature TNF (TNF-a) and lymphotoxin (TNF-b), both of which are recognized by the same cell-surface receptors. There are two types of TNF receptors, a 75-kd type 1 receptor and a 55-kd type 2 receptor. IL-1 and TNF produce many of the same proinflammatory responses.

A naturally occurring IL-1 receptor antagonist (IL-1ra), competes with IL-1 for receptor binding, blocks IL-1 activity in vitro and in vivo, and in experimental animals can prevent death induced by administration of bacteria or LPS. IL-1ra often is found in high levels in patients with various infections or inflammatory conditions. Thus, the balance between IL-1 and IL-1ra may contribute to the extent of an inflammatory response. Preliminary studies suggest that the administration of IL-1ra (designated anakinra)¾by blocking IL-1 action on its receptor¾may be beneficial in rheumatoid arthritis and other inflammatory conditions(Louie et al., 2003; Olson and Stein, 2004).  

Other cytokines and growth factors [e.g., IL-2, IL-6, IL-8, and granulocyte/macrophage colony stimulating factor (GM-CSF)] contribute to manifestations of the inflammatory response. The concentrations of many of these factors are increased in the synovia of patients with inflammatory arthritis. Certain relevant peptides, such as substance P, which promotes firing of pain fibers, also are elevated and act in concert with cytokines at the site of inflammation. Other cytokines and growth factors counter the effects and initiate resolution of inflammation. These include transforming growth factor-b1 (TGF-b1), which increases extracellular matrix formation and acts as an immunosuppressant, IL-10, which decreases cytokine and prostaglandin E2 formation by inhibiting monocytes, and interferon gamma, IFN-g, which possesses myelosuppressive activity and inhibits collagen synthesis and collagenase production by macrophages.
Histamine was one of the first identified mediators of the inflammatory process. Although several H1 histamine-receptor antagonists are available, they are useful only for the treatment of vascular events in the early transient phase of inflammation. Bradykinin and 5-hydroxytryptamine (serotonin, 5-HT) also may play a role in mediating inflammation, but their antagonists ameliorate only certain types of inflammatory response. Leukotriene (LT)-receptor antagonists (montelukast and zafirlukast) exert antiinflammatory actions and have been approved for the treatment of asthma. Another lipid autacoid, platelet-activating factor (PAF), has been implicated as an important mediator of inflammation; however, inhibitors of PAF synthesis and PAF-receptor antagonists have proven disappointing in the treatment of inflammation.
Intradermal, intravenous, or intra-arterial injections of small amounts of prostaglandins mimic many components of inflammation. Administration of prostaglandin E2 (PGE2) or prostacyclin (PGI2) causes erythema and an increase in local blood flow. Such effects may persist for up to 10 hours with PGE2 and include the capacity to counteract the vasoconstrictor effects of substances such as norepinephrine and angiotensin II, properties not generally shared by other inflammatory mediators. In contrast to their long-lasting effects on cutaneous vessels and superficial veins, prostaglandin-induced vasodilation in other vascular beds vanishes within a few minutes.
Although PGE1 and PGE2 (but not PGF2a) cause edema when injected into the hind paw of rats, it is not clear if they can increase vascular permeability in the postcapillary and collecting venules without the participation of other inflammatory mediators (e.g., bradykinin, histamine, and leukotriene C4 [LTC4]). Furthermore, PGE1 is not produced in significant quantities in humans in vivo, except under rare circumstances such as essential fatty acid deficiency. Unlike LTs, prostaglandins are unlikely to be involved in chemotactic responses, even though they may promote the migration of leukocytes into an inflamed area by increasing blood flow.
Rheumatoid Arthritis. Although the detailed pathogenesis of rheumatoid arthritis is largely unknown, it appears to be an autoimmune disease driven primarily by activated T cells, giving rise to T cell-derived cytokines, such as IL-1 and TNF-a. Activation of B cells and the humoral response also are evident, although most of the antibodies generated are IgGs of unknown specificity, apparently elicited by polyclonal activation of B cells rather than from a response to a specific antigen.
Many cytokines, including IL-1 and TNF-a, have been found in the rheumatoid synovium. Glucocorticoids interfere with the synthesis and actions of cytokines, such as IL-1 or TNF-a . Although some of the actions of these cytokines are accompanied by the release of prostaglandins and thromboxane A2 (TXA2), COX inhibitors appear to block only their pyrogenic effects. In addition, many of the actions of the prostaglandins are inhibitory to the immune response, including suppression of the function of helper T cells and B cells and inhibition of the production of IL-1. Thus, it has been suggested that COX-independent effects may contribute to the efficacy of NSAIDs in this setting. Besides an impact on adhesive interactions, salicylate and certain NSAIDs can directly inhibit the activation and function of neutrophils, perhaps by blockade of integrin-mediated neutrophil responses by inhibiting downstream Erk signaling.

The availability of a wide variety of drugs coupled with easy access and lack of effective regulatory control has led to problems associated with drug use like self-medication, drug misuse and drug abuse (Amoako et al 2003). Self medication: defined as the act of taking medicines or medical devices especially designed and labeled for use in the treatment of common health problems without the authority or prescription of a physician(Lawan et al, 2013). is the recurrent use of illegal drugs, or the misuse of prescription or over-the-counter drugs with negative consequences. Hence, drug misuse is an aspect of drug abuse. This practice cuts across all age groups, gender, educational backgrounds, marital status, employment and occupation. Pattern of drug misuse varies from place to place and it is known to be affected by socio-economic factors (Kehinde and Ogunnowo, 2013).

Self-medication is the act of taking medicines or medical devices especially designed and labeled for use in the treatment of common health problems without the authority or prescription of a physician and it is one of the rapidly growing areas of concern to medical professionals, government and the general public (Lawan et al, 2013).

There is overwhelming evidence linking chronic nonselective NSAID (including aspirin) use to a variety of Gastrointestinal (GI) tract injuries. Age is a significant risk factor for NSAID-induced GI events; indeed, patients above 75 years of age carry the highest risk and are similar in this respect to patients with a history of peptic ulcer (Berardi and Welage, 2005).

NSAIDs rank second to aminoglycosides as the most common cause of drug induced renal failure (ARF) and also known to cause acute interstitial nephritis with haematuria, proteinuria and flank pain (Welton, 1999).

In a study carried out in Ghana, about 40% of prescribed analgesics were NSAIDs and diclofenac was the most widely prescribed (Owusu-Ansah, 2009).

Aspirin remains the most commonly prescribed NSAIDs in cardiovascular diseases like hypertension and ischemic heart disease where it is used as antiplatelet agent(Aguw and Adibe, 2012).

Exposure of pregnant women to any type of NSAIDs during early pregnancy predispose them to spontaneous abortion (Li et al, 2003)

A high proportion of chronic urticarial patients experience symptom aggravation when exposed to aspirin and NSAIDs known as Aspirin-exacerbated cutaneous disease (Sánchez-Borges, 2013)


Salicylic acid and salicylates, obtained from natural sources, have long been used as medicaments. Salicylic acid was chemically synthesized in 1860 and was used as an antiseptic, an antipyretic, and an antirheumatic. Almost 40 years later, aspirin was developed as a more palatable form of salicylate. Soon after, other drugs having similar actions to aspirin were discovered, and the group was termed the “aspirin-like drugs” (also now termed the nonsteroidal anti-inflammatory drugs [NSAIDs]). Twenty-five years ago, it was proposed that the mechanism of action of NSAIDs was through their inhibition of prostaglandin biosynthesis. Since then, there has been general acceptance of the concept that these drugs work by inhibition of the enzyme cyclo-oxygenase (COX), which we now know to have at least two distinct isoforms: the constitutive isoform, COX-1, and the inducible isoform, COX-2. COX-1 has clear physiologic functions. Its activation leads, for instance, to the production of prostacyclin, which when released by the endothelium is antithrombogenic and when released by the gastric mucosa is cytoprotective. COX-2, discovered 6 years ago, is induced by inflammatory stimuli and cytokines in migratory and other cells. It is therefore attractive to suggest that the anti-inflammatory actions of NSAIDs are due to inhibition of COX-2, whereas the unwanted side-effects, such as irritation of the stomach lining, are due to inhibition of COX-1. Drugs that have the highest COX-2 activity and a more favorable COX-2: COX-1 activity ratio will have a potent anti-inflammatory activity with fewer side-effects than drugs with a less favorable COX-2.(Vane and  Botting, 1998)

All NSAIDs, including the subclass of selective COX-2 inhibitors, are antiinflammatory, analgesic, and antipyretic. NSAIDs are a chemically heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and adverse effects. Aspirin also inhibits the COX enzymes but in a manner molecularly distinct from the competitive, reversible, active site inhibitors and is often distinguished from the NSAIDs (Brunton et al, 2008).

Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting cyclooxygenase activity. This is an important distinction from all the NSAIDs because the duration of aspirin’s effects is related to the turnover rate of cyclooxygenases in different target tissues. The duration of effect of nonaspirin NSAIDs, which competitively inhibit the active sites of the COX enzymes, relates more directly to the time course of drug disposition. The importance of enzyme turnover in relief from aspirin action is most notable in platelets, which, being anucleate, have a markedly limited capacity for protein synthesis. Thus, the consequences of inhibition of platelet COX-1 (COX-2 is expressed only in megakaryocytes) last for the lifetime of the platelet. Inhibition of platelet COX-1-dependent TXA2 formation therefore is cumulative with repeated doses of aspirin (at least as low as 30 mg/day) and takes roughly 8 to 12 days¾the platelet turnover time to recover once therapy has been stopped(Brunton et al, 2008).


SALICYLATE Aspirin2-3hrs , 80-90%Antiplatelet -40-80mg/day Pain /fever 325-650mg/4-6hPermanent COX-1 inhibition
Diflunisal2-3h,  99%250-500mg/8-12hCompetitive COX inhibitor
ACETIC ACID DERIVATIVES Indomethacin1-2h; 90%25mg 2-3 times/day; 75-100mg at nightSide effects in 3-50% including frontal head ache, neutropenia, thrombocytopenia. Up to 20% will discontinue and 20% suffer GI side effects
Sulindac7h, 18h for metabolite; 30%150-200mg twice /day20% suffer GI side effects, 10% CNS side sffects
Ethodolac1h, 99%200-400mg 3-4 times/dayEfficacy similar to Aspirin, 25% GI side effects
Femanates (N-phenylanthranilates) Mefenamic acid2-4h; greater than 90%500mg load, then 250mg/6hPossible central action
Meclofenamate0.5-2h;99%50-100mg 4-6 times/day, max 400mg/dayEfficacy similar to Aspirin, 25% experience GI side effects
Flufenamic acid Tolmetin 5h; 99%   400–600 mg 3 times/dayFood delay absorption.GI side effect in remarkable, 5-10% discontinue
Ketorolac (pyrrolizinecarboxylate)  4-6h; 90%IM route 10 mg/4–6 h (not to exceed parenterally ; >65years: 10 mg/4–6 hCommonly given IM. Potent analgesic with poor antiimflammatory
Diclofenac  (phenylacetate derivative)  2-3h; 99%50mg three times daily or 75mg twice dailyMore potent, 20% develop side effects, 2% discontinue, 15% develop elevated liver enzymes
Proprionic acid derivatives Ibuprofen2-4h; 99%Analgesic: 200-400mg/4-6h Anti-inflammatory:300mg/6-8h or 400-800mg 3-4 times/day10-15% discontinue due to adverse effects
Naproxen14;99%, less in elderly250mg f0ur times a day or 500mg twice a dayUsually better tolerated variably prolonged half life
Fenoprofen2h; 99%200mg 4-6times /day or 5mg/kg in inflammatory condition.15% experience side effects, few discontinue
Ketoprofen2h;98%Analgesic: 25mg 3-4 times/day Antiimflammatory: 50-75mg 3-4 times /day30% develop side effects usually GI
Enolic acid derivatives Piroxicam45-50h; 99%20mg/dayMay inhibit activation of neutrophils
Meloxicam15-20h; 99%7.5-15mg/daySome COX-2 selectivity especially at a lower dose
Nabumetone  (naphthyl  Alkanone)  24h;99%500-1000mg 1-2 times dailyShow some COX-2 selectivity
COX-2 selective inhibitors Celecoxib( Diaryl substituted pyrazone; sulphonamide derivative)6-12; 97%100mg 1-2 times dailyCoadministration with inhibitors of CYP2C9 or substrate of CYP2D6 should be done with caution
Valdecoxib     7-8h; 98%Analgesic: 20mg twice daily Primary dysmenorrhea: 10mg once daily 



Inhibition of Prostaglandin Biosynthesis by NSAIDs. The principal therapeutic effects of NSAIDs derive from their ability to inhibit prostaglandin production. The first enzyme in the prostaglandin synthetic pathway is prostaglandin G/H synthase, also known as cyclooxygenase or COX. This enzyme converts arachidonic acid (AA) to the unstable intermediates PGG2 and PGH2 and leads to the production of thromboxane A2 (TXA2) and a variety of prostaglandins.
Therapeutic doses of aspirin and other NSAIDs reduce prostaglandin biosynthesis and there is a reasonably good correlation between the potency of these drugs as cyclooxygenase inhibitors and their antiinflammatory activity. Further support linking cyclooxygenase inhibition to antiinflammatory activity is the high degree of stereoselectivity among several pairs of enantiomers of a-methyl arylacetic acids for inhibition of cyclooxygenase and suppression of inflammation; in each instance the d or (+) isomer is more potent in inhibiting cyclooxygenase and suppressing inflammation. G&G
There are two forms of cyclooxygenase, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 is a primarily constitutive isoform found in most normal cells and tissues, while cytokines and inflammatory mediators that accompany inflammation induce COX-2 production (Seibert et al., 1997. However, COX-2 also is constitutively expressed in certain areas of kidney and brain (Breder et al., 1995) and is induced in endothelial cells by laminar shear forces (Topper et al., 1996). Importantly, COX-1, but not COX-2, is expressed as the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation. Inhibition of COX-1 at this site is thought to account largely for the gastric adverse events that complicate therapy with tNSAIDs, thus providing the rationale for the development of NSAIDs specific for inhibition of COX-2 (FitzGerald and Patrono, 2001).
Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting cyclooxygenase activity. This is an important distinction from all the NSAIDs because the duration of aspirin’s effects is related to the turnover rate of cyclooxygenases in different target tissues. The duration of effect of nonaspirin NSAIDs, which competitively inhibit the active sites of the COX enzymes, relates more directly to the time course of drug disposition. The importance of enzyme turnover in relief from aspirin action is most notable in platelets, which, being anucleate, have a markedly limited capacity for protein synthesis. Thus, the consequences of inhibition of platelet COX-1 (COX-2 is expressed only in megakaryocytes) last for the lifetime of the platelet. Inhibition of platelet COX-1-dependent TXA2 formation therefore is cumulative with repeated doses of aspirin (at least as low as 30 mg/day) and takes roughly 8 to 12 days three quarter of the platelet turnover time three quarter to recover once therapy has been stopped.
COXs are configured such that the active site is accessed by the AA substrate via a hydrophobic channel. Aspirin acetylates serine 530 of COX-1, located high up in the hydrophobic channel. Interposition of the bulky acetyl residue prevents the binding of AA to the active site of the enzyme and thus impedes the ability of the enzyme to make prostaglandins. Aspirin acetylates a homologous serine at position 516 in COX-2. Although covalent modification of COX-2 by aspirin also blocks the cyclooxygenase activity of this isoform, an interesting property not shared by COX-1 is that acetylated COX-2 synthesizes 15(R)-hydroxyeicosatetraenoic acid [15(R)-HETE]. This may be metabolized, at least in vitro, by 5-lipoxygenase to yield 15-epilipoxin A4, which has potent antiinflammatory properties . Due to these features, repeated doses of aspirin that acutely do not completely inhibit platelet COX-1-derived TXA2 can exert a cumulative effect with complete blockade. This has been shown in randomized trials for doses as low as 30 mg per day. However, most of the clinical trials demonstrating cardioprotection from low-dose aspirin have used doses in the range of 75 to 81 mg/day.
The unique sensitivity of platelets to inhibition by such low doses of aspirin is related to their presystemic inhibition in the portal circulation before aspirin is deacetylated to salicylate on first pass through the liver (Pederson and FitzGerald, 1984). In contrast to aspirin, salicylic acid has no acetylating capacity. It is a weak, reversible competitive inhibitor of cyclooxygenase.
The vast majority of NSAIDs listed are organic acids, and in contrast to aspirin, act as reversible, competitive inhibitors of cyclooxygenase activity. Even the nonacidic parent drug nabumetone is converted to an active acetic acid derivative in vivo. As organic acids, the compounds generally are well absorbed orally, highly bound to plasma proteins, and excreted either by glomerular filtration or by tubular secretion. They also accumulate in sites of inflammation, potentially confounding the relationship between plasma concentrations and duration of drug effect. The NSAIDs include those with shorter (less than 6 hours) or longer (greater than 10 hours) half-lives.
Most NSAIDs inhibit both COX-1 and COX-2 with little selectivity, although some, conventionally thought of as NSAIDs  diclofenac, meloxicam, and nimesulide¾exhibit selectivity for COX-2 that is close to that of celecoxib in vitro. Indeed, meloxicam achieved approval in some countries as a selective inhibitor of COX-2. The hypothesis that the antiinflammatory effects of NSAIDs would be accompanied by a lower ulcerogenic potential propelled efforts to design drugs with greater selectivity for COX-2 versus COX-1 (FitzGerald and Patrono, 2001). These efforts led to the approval and marketing of rofecoxib, celecoxib, and valdecoxib as selective COX-2 inhibitors, known as the coxibs, and the development of others (e.g.,  etoricoxib and lumiracoxib). Based on whole blood assays, several previously marketed NSAIDs also have selectivity ratios comparable to those of the least-selective of the novel COX-2 inhibitors, celecoxib. These include meloxicam, nimesulide, and diclofenac (Warner et al., 1999; FitzGerald and Patrono, 2001).

Observational studies suggest that acetaminophen, which is a very weak antiinflammatory agent at the typical daily dose of 1000 mg, is associated with a reduced incidence of gastrointestinal adverse effects compared to tNSAIDs. At this dose, acetaminophen inhibits both cyclooxygenases by about 50%. The ability of acetaminophen to inhibit the enzyme is conditioned by the peroxide tone of the immediate environment (Boutaud et al., 2002). This may partly explain the poor antiinflammatory activity of acetaminophen, since sites of inflammation usually contain increased concentrations of leukocyte-generated peroxides.

NSAIDs find their chief clinical application as antiinflammatory agents in the treatment of musculoskeletal disorders, such as rheumatoid arthritis and osteoarthritis. In general, NSAIDs provide only symptomatic relief from pain and inflammation associated with the disease, do not arrest the progression of pathological injury to tissue, and are not considered to be “disease-modifying” anti-rheumatic drugs.


 NSAIDs usually are classified as mild analgesics. However, consideration of the type of pain, as well as its intensity, is important in the assessment of analgesic efficacy. NSAIDs are particularly effective when inflammation has caused sensitization of pain receptors to normally painless mechanical or chemical stimuli. Pain that accompanies inflammation and tissue injury probably results from local stimulation of pain fibers and enhanced pain sensitivity (hyperalgesia), in part a consequence of increased excitability of central neurons in the spinal cord.

Bradykinin, released from plasma kininogen, and cytokines, such as TNFa, IL-1, and IL-8, appear to be particularly important in eliciting the pain of inflammation. These agents liberate prostaglandins and probably other mediators that promote hyperalgesia. Neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), also may be involved in eliciting pain.
 In general, NSAIDs do not affect either hyperalgesia or pain caused by the direct action of prostaglandins, consistent with the notion that the analgesic effects of these agents are due to inhibition of prostaglandin synthesis. However, relief of pain by these compounds may occur via mechanisms other than inhibition of prostaglandin synthesis, including antinociceptive effects at peripheral or central neurons (Burke et al, 2008)

When employed as analgesics, these drugs usually are effective only against pain of low-to-moderate intensity, such as dental pain. Although their maximal efficacy is generally much less than the opioids, NSAIDs lack the unwanted adverse effects of opiates in the CNS, including respiratory depression and the development of physical dependence. NSAIDs do not change the perception of sensory modalities other than pain. Chronic postoperative pain or pain arising from inflammation is controlled particularly well by NSAIDs, whereas pain arising from the hollow viscera usually is not relieved. An exception to this is menstrual pain. The release of prostaglandins by the endometrium during menstruation may cause severe cramps and other symptoms of primary dysmenorrhea; treatment of this condition with NSAIDs has met with considerable success (Marjoribanks et al., 2003).


 Regulation of body temperature requires a delicate balance between the production and loss of heat; the hypothalamus regulates the set point at which body temperature is maintained. This set point is elevated in fever, and NSAIDs promote its return to normal. These drugs do not influence body temperature when it is elevated by factors such as exercise or in response to ambient temperature.
Fever may reflect infection or result from tissue damage, inflammation, graft rejection, or malignancy. These conditions all enhance formation of cytokines such as IL-1b, IL-6, interferons, and TNFa. The cytokines increase synthesis of PGE2 in circumventricular organs in and adjacent to the preoptic hypothalamic area; PGE2, in turn, increases cyclic AMP and triggers the hypothalamus to elevate body temperature by promoting an increase in heat generation and a decrease in heat loss. Aspirin and NSAIDs suppress this response by inhibiting PGE2 synthesis. Prostaglandins, especially PGE2, acting via its EP3 receptor, can produce fever when infused into the cerebral ventricles or when injected into the hypothalamus. As with pain, NSAIDs do not inhibit the fever caused by directly administered prostaglandins; rather they inhibit fever caused by agents that enhance the synthesis of IL-1 and other cytokines, which presumably cause fever, at least in part, by inducing the endogenous synthesis of prostaglandins.

NSAIDs reduce fever in most situations, but not the circadian variation in temperature or the rise in response to exercise or increased ambient temperature. Comparative analysis of the impact of NSAIDs and selective COX-2 inhibitors suggests that COX-2 is the dominant source of prostaglandins that mediate the rise in temperature evoked by bacterial LPS administration (McAdam et al., 1999). Debilitating disease may not respond adequately to full therapeutic doses of NSAIDs and may require aggressive therapy with second-line agents.

    Prostaglandins also have been implicated in the maintenance of patency of the ductus arteriosus, and indomethacin and other tNSAIDs have been used in neonates to close the inappropriately patent ductus. Both COX-1 and COX-2 appear to participate in maintaining patency of the ductus arteriosus in fetal lambs (Clyman et al., 1999), while in mice COX-2 appears to play the dominant role . It is not known which isoform(s) is involved in maintaining patency of the fetal ductus in utero in humans.


Systemic mastocytosis is a condition in which there are excessive mast cells in the bone marrow, reticuloendothelial system, gastrointestinal system, bones, and skin. In patients with systemic mastocytosis, prostaglandin D2, released from mast cells in large amounts, has been found to be the major mediator of severe episodes of vasodilation and hypotension; this PGD2 effect is resistant to antihistamines. The addition of aspirin or ketoprofen has provided relief (Worobec, 2000). However, aspirin and NSAIDs can cause degranulation of mast cells, so blockade with H1 and H2 histamine receptor antagonists should be established before NSAIDs are initiated.

5. BARTER’S SYNDROME. Bartter’s syndrome includes a series of rare disorders (1-0.1/100,000) characterized by hypokalemic, hypochloremic metabolic alkalosis with normal blood pressure and hyperplasia of the juxtaglomerular apparatus. Fatigue, muscle weakness, diarrhea, and dehydration are the main symptoms. Distinct variants are caused by mutations in a Na+:K+:2Cl cotransporter, an apical ATP-regulated K+ channel, a basolateral Cl channel, a protein (barttin) involved in cotransporter trafficking, and the extracellular calcium-sensing receptor. Renal COX-2 is induced and biosynthesis of PGE2 is increased. Treatment with indomethacin, combined with potassium repletion and spironolactone, is associated with improvement in the biochemical derangements and symptoms. Selective COX-2 inhibitors also have been used (Guay-Woodford, 1998).

6. Cancer Chemoprevention. Chemoprevention of cancer is an area where the potential use of aspirin and/or NSAIDs is under active investigation. Epidemiological studies suggested that frequent use of aspirin is associated with as much as a 50% decrease in the risk of colon cancer (Kune et al., 1998) and similar observations have been made with other cancers (Jacobs et al., 2004). NSAIDs have been used in patients with familial adenomatous polyposis (FAP), an inherited disorder characterized by multiple adenomatous colon polyps developing during adolescence and the inevitable occurrence of colon cancer by the sixth decade.


 Large doses of niacin (nicotinic acid) effectively lower serum cholesterol levels, reduce LDL, and raise HDL. However, niacin is tolerated poorly because it induces intense flushing. This flushing is mediated by a release of prostaglandin D2 from the skin, which can be inhibited by treatment with aspirin (Jungnickel et al., 1997) and would be susceptible to inhibition of PGD synthesis or antagonism of its DP receptors.


 Age generally is correlated with an increased probability of developing serious adverse reactions to NSAIDs, and caution is warranted in choosing a lower starting dose for elderly patients.

Gastrointestinal. The most common symptoms associated with these drugs are gastrointestinal, including anorexia, nausea, dyspepsia, abdominal pain, and diarrhea. These symptoms may be related to the induction of gastric or intestinal ulcers, which is estimated to occur in 15% to 30% of regular users. Ulceration may range from small superficial erosions to full-thickness perforation of the muscularis mucosa. There may be single or multiple ulcers, and ulceration can be accompanied by gradual blood loss leading to anemia or by life-threatening hemorrhage. The risk is further increased in those with Helicobacter pylori infection, heavy alcohol consumption, or other risk factors for mucosal injury, including the concurrent use of glucocorticoids. Although there is a perception that  NSAIDs vary considerably in their tendency to cause such erosions and ulcers, this is based on overview analyses of small and heterogeneous studies, often at single doses of individual  NSAIDs. Large-scale comparative studies of  NSAIDs have not been performed, and there is no reliable information on which to assess the comparative likelihood of GI ulceration on antiinflammatory doses of aspirin  versus  NSAIDs. Thus, most information is derived from the use of surrogate markers or from epidemiological datasets and suggests that the relative risk for serious adverse gastrointestinal events is elevated about threefold in NSAID users compared to nonusers. Epidemiological studies suggest that combining low-dose aspirin (for cardioprotection) with other NSAIDs synergistically increases the likelihood of gastrointestinal adverse events.
All of the selective COX-2 inhibitors have been shown to be less prone than equally efficacious doses of tNSAIDs to induce endoscopically visualized gastric ulcers (Deeks et al., 2002), and this has provided the basis of FDA approval of valdecoxib and celecoxib. To date, three comparative studies of clinical outcome have been published, two of which reported a significant difference in serious gastrointestinal events. The VIGOR study showed that important gastrointestinal events¾mainly bleeds¾were reduced from 4% to 2% in subjects treated with rofecoxib (now withdrawn from the market worldwide), and the TARGET trial (which actually was two distinct comparative studies with naproxen and ibuprofen, respectively) showed a reduction in ulcer complications in patients taking lumiracoxib (Schnitzer et al., 2004). In contrast, adverse events with celecoxib were not significantly decreased in the CLASS study . While the outcome of the VIGOR study was consistent with the hypothesis that COX-2-selective inhibitors are associated with a decreased incidence of gastrointestinal adverse events, the results were tempered by a fivefold increase in the incidence of myocardial infarction, probably reflecting a cardiovascular hazard in predisposed individuals treated with selective COX-2 inhibitors together with a modest cardioprotective effect of naproxen.
Gastric damage by NSAIDs can be brought about by at least two distinct mechanisms. Inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective prostaglandins, especially PGI2 and PGE2. These eicosanoids inhibit acid secretion by the stomach, enhance mucosal blood flow, and promote the secretion of cytoprotective mucus in the intestine. Inhibition of PGI2 and PGE2 synthesis may render the stomach more susceptible to damage and can occur with oral, parenteral, or transdermal administration of aspirin or NSAIDs. Another mechanism by which NSAIDs or aspirin may cause ulceration is by local irritation from contact of orally administered drug with the gastric mucosa. Local irritation allows backdiffusion of acid into the gastric mucosa and induces tissue damage. It also is possible that enhanced generation of lipoxygenase products (e.g., LTs) contributes to ulcerogenicity in patients treated with NSAIDs.
Coadministration of the PGE1 analog misoprostol or proton pump inhibitors (PPIs), which now are available over the counter in the United States, in conjunction with NSAIDs can be beneficial in the prevention of duodenal and gastric ulceration While a combination of aspirin with a selective COX-2 inhibitor will undermine its distinction from a NSAID with respect to serious GI complications, we do not know if the combination retains an advantage over aspirin plus a NSAID.

Cardiovascular. Given their relatively short half-lives, tNSAIDs, unlike aspirin, are not thought to afford cardioprotection, and most epidemiological overviews are consistent with this likelihood An exception in some individuals may be naproxen. Although there is considerable variation, a small study suggests that platelet inhibition might be anticipated throughout the dosing interval in some but not all individuals on naproxen Epidemiological evidence of cardioprotection is less impressive; it suggests about a 10% reduction in myocardial infarction, compared to 20% to 25% with low-dose aspirin. This would fit with heterogeneity of response to naproxen. Reliance on prescription databases may have constrained the ability of this approach to address the question with precision. Controlled evaluation of naproxen in cardioprotection has not been performed, and naproxen should not be used as a substitute for aspirin for this purpose. Several groups have attached nitric oxide-donating moieties to NSAIDs and to aspirin in the hope of reducing the incidence of adverse events. It seems likely that benefit may be attained by abrogation of the inhibition of angiogenesis by tNSAIDs during ulcer healing in rodents.
Selective inhibitors of COX-2 depress PGI2 formation by endothelial cells without concomitant inhibition of platelet thromboxane. Experiments in mice suggest that PGI2 restrains the cardiovascular effects of TXA2, affording a mechanism by which selective inhibitors might increase the risk of thrombosis. This mechanism should pertain to individuals otherwise at risk of thrombosis, such as those with rheumatoid arthritis, as the relative risk of myocardial infarction is increased in these patients compared to patients with osteoarthritis or no arthritis. The incidence of myocardial infarction and stroke has diverged in such at-risk patients when COX-2 inhibitors are compared with NSAIDs

Blood Pressure, Renal, and Renovascular Adverse Events.  NSAIDs and COX-2 inhibitors have been associated with renal and renovascular adverse events NSAIDs have little effect on renal function or blood pressure in normal human subjects. However, in patients with congestive heart failure, hepatic cirrhosis, chronic kidney disease, hypovolemia, and other states of activation of the sympathoadrenal or renin-angiotensin systems, prostaglandin formation becomes crucial in model systems and in humans. NSAIDs are associated with loss of the prostaglandin-induced inhibition of both the reabsorption of Cl and the action of antidiuretic hormone, leading to the retention of salt and water. Experiments in mice that attribute the generation of vasodilator prostaglandins (PGE2 and PGI2) to COX-2 raise the likelihood that the incidence of hypertensive complications (either new onset or worsened control) induced by NSAIDs in patients may correlate with the degree of inhibition of COX-2 in the kidney and the selectivity with which it is attained . Deletion of receptors for both PGI2 and PGE2 elevate blood pressure in mice, mechanistically integrating hypertension with a predisposition to thrombosis. Although this hypothesis has never been addressed directly, epidemiological studies suggest hypertensive complications occur more commonly in patients treated with coxibs than with NSAIDs.
NSAIDs promote reabsorption of K+ as a result of decreased availability of Na+ at distal tubular sites and suppression of the prostaglandin-induced secretion of renin. The latter effect may account in part for the usefulness of NSAIDs in the treatment of Bartter’s syndrome.
Analgesic Nephropathy. Analgesic nephropathy is a condition of slowly progressive renal failure, decreased concentrating capacity of the renal tubule, and sterile pyuria. Risk factors are the chronic use of high doses of combinations of NSAIDs and frequent urinary tract infections. If recognized early, discontinuation of NSAIDs permits recovery of renal function((Burke et al, 2008)

Pregnancy and Lactation. In the hours before parturition, there is induction of myometrial COX-2 expression, and levels of prostaglandin E2 and F2a increase markedly in the myometrium during labor . Prolongation of gestation by NSAIDs has been demonstrated in model systems and in humans. Some NSAIDs, particularly indomethacin, have been used off-label to terminate preterm labor. However, this use is associated with closure of the ductus arteriosus and impaired fetal circulation in utero, particularly in fetuses older than 32 weeks’ gestation. COX-2-selective inhibitors have been used as tocolytic agents; this use has been associated with stenosis of the ductus arteriosus and oligohydramnios. Finally, the use of NSAIDs and aspirin late in pregnancy may increase the risk of postpartum hemorrhage. Therefore pregnancy, especially close to term, is a relative contraindication to the use of all NSAIDs, and their use must be weighed against potential fetal risk, even in cases of premature labor, and especially in cases of pregnancy-induced hypertension, where they have been used with questionable effect


Two types of hypersensitivities experienced in NSAIDs use are Cutaneous Hypersensitivity and nonallergic anaphylaxis.The cutaneous pattern of NSAID-induced crossreactions includes cross-reacting urticaria and angioedema in patients with or without chronic idiopathic urticarial. The mechanisms are not completely understood, but in patients with CIU, COX-1 inhibition has beendemonstrated.

Nonallergic Anaphylaxis, Previously known as anaphylactoid or pseudoallergic reaction, it is observed in cross-reactive patients and presumably mediated by inhibition of COX-1(Mario, 2008)

Certain individuals display hypersensitivity to aspirin and NSAIDs, as manifested by symptoms that range from vasomotor rhinitis with profuse watery secretions, angioedema, generalized urticaria, and bronchial asthma to laryngeal edema, bronchoconstriction, flushing, hypotension, and shock. Aspirin intolerance is a contraindication to therapy with any other NSAID because cross-sensitivity can provoke a life-threatening reaction reminiscent of anaphylactic shock. Despite the resemblance to anaphylaxis, this reaction does not appear to be immunological in nature.
Although less common in children, this syndrome may occur in 10% to 25% of patients with asthma, nasal polyps, or chronic urticaria, and in 1% of apparently healthy individuals. It is provoked by even low doses (<80 mg) of aspirin and apparently involves COX inhibition. Cross-sensitivity extends to other salicylates, structurally dissimilar NSAIDs, and rarely acetaminophen (see below). Treatment of aspirin hypersensitivity is similar to that of other severe hypersensitivity reactions, with support of vital organ function and administration of epinephrine. Aspirin hypersensitivity is associated with an increase in biosynthesis of LTs, perhaps reflecting diversion of AA to lipoxygenase metabolism. Indeed, results in a small number of patients suggest that blockade of 5-lipoxygenase with the drug zileuton (no longer marketed in the United States) or use of the leukotriene receptor antagonists may ameliorate the symptoms and signs of aspirin intolerance, albeit incompletely.
Aspirin Resistance. All forms of treatment failure with aspirin have been collectively called “aspirin resistance.” Although this has attracted much attention, there is little information concerning the prevalence of a stable, aspirin-specific resistance or the precise mechanisms that might convey this “resistance.” Genetic variants of COX-1 that cosegregate with resistance have been described, but the relation to clinical outcome is not clear.


  Concomitant NSAIDs and Low-Dose Aspirin. Many patients combine either NSAIDs or COX-2 inhibitors with “cardioprotective” low-dose aspirin. Epidemiological studies suggest that this combination therapy increases significantly the likelihood of gastrointestinal adverse events over either class of NSAID alone.

Prior occupancy of the active site of platelet COX-1 by the commonly consumed tNSAID ibuprofen impedes access of aspirin to its target Ser 529 and prevents irreversible inhibition of platelet inhibition. Epidemiological studies have provided conflicting data as to whether this adversely impacts clinical outcomes, but they generally are constrained by the use of prescription databases to examine an interaction between two drug groups commonly obtained without prescription. Evidence in support of this interaction has been observed in cEomparing ibuprofen-treated patients with and without aspirin in two coxib outcome studies (CLASS and TARGET), but the trials were not powered to address this question definitively. In theory, this interaction should not occur with selective COX-2 inhibitors, because mature human platelets lack COX-2.
Other Drug Interactions. Angiotensin-converting enzyme (ACE) inhibitors act, at least partly, by preventing the breakdown of kinins that stimulate prostaglandin production. Thus, it is logical that NSAIDs might attenuate the effectiveness of ACE inhibitors by blocking the production of vasodilator and natriuretic prostaglandins. Due to hyperkalemia, the combination of NSAIDs and ACE inhibitors also can produce marked bradycardia leading to syncope, especially in the elderly and in patients with hypertension, diabetes mellitus, or ischemic heart disease. NSAIDs may increase the frequency or severity of gastrointestinal ulceration when combined with corticosteroids and augment the risk of bleeding in patients receiving warfarin. Many NSAIDs are highly bound to plasma proteins and thus may displace other drugs from their binding sites. Such interactions can occur in patients given salicylates or other NSAIDs together with warfarin, sulfonylurea hypoglycemic agents, or methotrexate; the dosage of such agents may require adjustment to prevent toxicity. The problem with warfarin is accentuated, both because almost all NSAIDs suppress normal platelet function and because some NSAIDs also increase warfarin levels by interfering with its metabolism; thus, concurrent administration should be avoided.

Pharmacokinetics and Pharmacodynamics. Most of the NSAIDs are rapidly and completely absorbed from the gastrointestinal tract, with peak concentrations occurring within 1 to 4 hours. Aspirin begins to acetylate platelets within minutes of reaching the presystemic circulation. The presence of food tends to delay absorption without affecting peak concentration. Most NSAIDs are extensively protein-bound (95% to 99%) and undergo hepatic metabolism and renal excretion. In general, NSAIDs are not recommended in the setting of advanced hepatic or renal disease due to their adverse pharmacodynamic effects. Many NSAIDs metabolized by hepatic CYPs are subject to circadian variation in their metabolic disposition; however, the implications of this observation are not clear.


NSAIDs are among the most commonly prescribed categories of drugs worldwide in the treatment of pain and inflammation in many conditions as over the counter drugs. Each day it is estimated that 30 million people would wide get benefit from their antimflammatory and analgesic effects (Chowdhury et al, 2012)

NSAID guidelines have been established to increase physician awareness of the complications associated with NSAID use; however, some physicians either do not recognize or do not adhere to such guidelines. A recent survey of physicians identified six major barriers that affected their use of established NSAID guidelines. The barriers mentioned were as follows: lack of familiarity with the guidelines, perceived limited validity of the guidelines, limited applicability of the guidelines to specific patient populations, clinical inertia, anecdotal experiences, and clinical heuristics. The lack of familiarity was attributed to the overwhelming number of published medical guidelines and difficulties in keeping up to date with new recommendations. In support of this, a search of the literature identified more than 20 different guidelines that mention NSAIDs and the elderly in addition to other highly acclaimed medication risk factor guidelines or tools ( Tailor et at, 2012).

Prescribers need to be aware of the possibility of overdosing on NSAIDs that might result from prescribing and/or taking OTC medications that contain the same active NSAID ingredient. A meta-analysis of data from case-control studies revealed that the odds ratio (reference point is nonuse of NSAIDs) for experiencing a serious GI complication was 4.9 in patients taking a single NSAID, 10.7 in patients taking two, and 60.0 in patients taking three NSAIDs simultaneously (Lewis et al, 2002). Combination of certain medications or herbal additives with prescribed or OTC NSAIDs may intensify or mask the side effects associated with NSAIDs; for example, corticosteroids (Tulner et al, 2008), ginkgo biloba( Abebe, 2002), warfarin ( Cheetham, 2009), and alcohol ( kauman, 1999) can increase the severity of gastrointestinal bleeding or peptic ulcers.


Self-medication can be defined as the use of drugs to treat self-diagnosed disorders or symptoms, or the intermittent or continued use of a prescribed drug for chronic or recurrent disease or symptoms (Donkor et al, 2012).

It has also been defined as the act of taking medicines or medical devices especially designed and labeled for use in the treatment of common health problems without the authority or prescription of a physician. It is one of the rapidly growing areas of concern to medical professionals, government and the general public. Self-medication may initially result in reduction of distress but in the long-run however, it can cause many serious problems. Symptoms may rebound, resulting in stronger desires to take more drugs (Lawan et al, 2013).

Self-medication is a common practice all over the world (Abasiubong et al, 2012). In  the  face  of  current  global  economic  downturn,  a  large  number  of  countries  are  facing  serious health challenges, with people finding it difficult to meet their health needs. In developed countries, self-medication is not uncommon, but the practice is guided because people are enlightened and could derive adequate information from various sources. Consequently, it is often regarded as consumers’ luxury and very attractive. Evidence suggests that many people involved in self-medication tend to acquire knowledge of the practice from relatives, neighbours, medicine dealers, and sometimes media.  The  situation  in  developing  countries  is  frightening,  where there  is  poor  medical  services  and  lack  of  professional  control  of  pharmaceutical  products.  This therefore forces people to self-medicate and various forms of substances and herbs are often used for different medical complaints(Abasiubong et al, 2012).

Other patient  factors  that might limit the effectiveness of pain treatment or predispose to greater risk of adverse effects are barriers to patient education regarding the proper use of medication, failure of the drug to properly and safely alleviate the pain, economic factors( cheaper NSAIDs are less safe), misperception about the safety of Over The Counter( OTC) medications  regarding risk of overdosing, drug-drug interaction and chronic use and limited awareness about the NSAIDs sources whether prescription or OTC (Tailor et al, 2012).

 Before taking any type of medication, patients should be fully aware of the risks involved; however, data suggest that current patient education on NSAIDs, in particular side effects and how to manage them, is not adequate (Schmitt et al, 2011)

In addition to being ill-informed on the side effects of taking a single NSAID, patients are also unaware of the consequences of taking multiple NSAIDs or taking NSAIDs for long periods of time. Some of the reasons for taking multiple doses of NSAIDs include seeking more or faster relief, experiencing no relief with the recommended dose, or a result of doctor’s suggestion (Cham et al, 2002).

Expanding the role of pharmacists is supported by evidence‐based outcomes and existing

innovative models. The benefits translate into improved consumer outcomes that support

many tenets of health reform ‐ enhanced access and quality of care, cost‐effectiveness and

patient safety. The Report is framed around four focus points that clearly articulate and present

objective data that support the need for innovative practice models that include pharmacists as

essential health care providers.  

Based on current practice models, perceptions of pharmacists’ roles, specifically as a health

professional exclusively associated with drug product and delivery, should now include many

additional patient care, primary care, and public health services. It is essential to note that

pharmacists currently provide multiple levels of direct and indirect patient care services in a

variety of practice settings. Management of disease through medication use ‐ inclusive of

Collaborative Drug Therapy Management (CDTM), Comprehensive Medication Management

(CMM) or Medication Therapy Management (MTM), health promotion, patient safety, disease

prevention, care coordination, follow‐up care and other primary patient care services ‐ are

performed by pharmacists in a similar manner as other health care providers. The rationale for

this practice model is the fact that once a diagnosis is made, patient care services rely on

pharmacologic interventions as the major form of therapy. Data clearly suggest that

medications are currently the cornerstone of chronic disease therapy, yet our health care

system continues to fragment care and ‘reward’ reactive health care delivery models( Giberson et al, 2011)

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent diverse group of drug with analgesic property and most frequently prescribed drug  globally. This  is  first  choice  of  drug  with  well  demonstrated  efficiency  for  the  pain  management  primarily  musculoskeletal  disorder  and  osteoarthritis to treat mild to moderate pain. Although its serious toxicity related to GIT limits its expediency.”Big evil” have tendency to just cure pain relieving symptom not disease. In this  study  we  aimed  to  determine  the  prescribing  practice  of  multiple  NSAIDs  in  Pakistan  by  healthcare practitioner and their attitude towards patient life safety and what consequences are  responsible  for  irrational  practice  of  these  most  common  OTC  drug.  For the purpose of these evaluation descriptive studies was conducted based on prescription reading and case histories of more than 200 patients to rule out prescribing habit of physicians. Prescription collected were mostly from emergency (80%)  and  general  physicians  (20%).  Nearly  everyone  patient  came  with  intense  pain  related  with  muscular  and  arthritis  pain.  About 69% patients were being prescribed by double NSAIDs in which acetaminophen ratio was mostly high with Diclofenac sodium (ratio  of  60:35).  Single  practice  of  NSAIDs  has  reported  just  25%  but  more  than  prescription containing multiple NSAIDs 6%.  Traditional NSAIDs prescribed more frequently compared to selective NSAIDs by physician which makes patients susceptible to GIT associated toxicity.  For  the  prophylaxis  of  NSAIDs  associated  GIT  bleeding  only   15%  patients  were co prescribe by H 2  receptor blocker primarily ranitidine (15%) and PPis (7%) and other (2%).

After careful consideration about prescribing habit of NSAIDs by physician we conclude that  the  irrational  practices  prevalence  have  been  rising  dangerously  which  needs  careful  consideration by health authorities.(Gul S and Ayub M, 2014) Current guidelines on NSAID use have been developed by rheumatologists, gastroenterologists, cardiologists [ or multidisciplinary teams of experts. Rheumatologists were first concerned with safety, thus recommending paracetamol (acetaminophen) as a first-line analgesic. Gastroenterologists dealt mainly with GI risk factors and gastroprotection, emphasizing how misused and underused it is, while cardiologists were worried about CV safety and suggested naproxen use in patients with CV risk factors. Some multidisciplinary consensus papers discussed both Gastrointestinal and Cardiovascular risks and put forward evidence-based proposals on how to balance the benefits and risks of anti-inflammatory therapy. Despite this, some important issues have been left unsettled, partly because sufficient evidence was not available at the time of guideline drafting. Besides efficacy and safety, costs will also influence therapeutic choices. However, together with medication costs, the economic burden on the healthcare system of NSAID-induced GI or CV events should be taken into Account (Scarpignatoet al, 2015)

Pharmacists have unique, comprehensive knowledge about the safe and effective use of medications and about the adverse effects of their inappropriate use. The provision of pharmaceutical care to individual patients involves pharmacists assessing the appropriateness of pharmacotherapy, counseling, and monitoring medication-use outcomes.

Health-system pharmacists have responsibilities for ensuring a safe and effective medication-use system, including legal and organizational responsibilities for medication distribution and control across the continuum of practice settings within health care organizations. With this combination of knowledge and organizational responsibilities, pharmacists are prepared to serve in leadership and service roles in substance abuse prevention and education and assist in a variety of patient care, employee health, and community activities.

A study carried out among 120 patients who attended the rheumatology clinic Hospital, Raja Permaisuri Bainun, Malaysia showed that NSAIDs were prescribed for almost all arthritic patients either in regular or pro re nata basis irrespective of the rheumatological diagnosis. In that survey, rheumatoid arthritis patients receiving NSAIDs outnumbered other rheumatic disorders compared to the study conducted by Wynne and Long where NSAIDs were mostly prescribed for osteoarthritis followed by rheumatoid arthritis and other disorders(Wyne and Long, 2006). The difference obtained appeared to be attributed to the number of Rheumatoid arthritis patients most commonly seen at the rheumatology clinic, whereas more of Osteoarthritis patients were treated by orthopedic surgeons.

The choice of NSAIDs prescribed is individualized and varies in different practices.Drug availability, cost, familiarity and tolerability are among many factors which play an important role in the treatment strategy for rheumatic diseases. In this study most of the older NSAIDs (indomethacin, diclofenac sodium, ibuprofen, naproxen, meloxicam) and newer COX-2 inhibitors (celecoxib, etoricoxib) were readily available. The duration of NSAIDs usage and the quantity needed to be taken varied from patient to patient (Sulaiman et al, 2012).


The use of NSAIDs accounts for an estimated 76 000 hospitalizations and 7600 deaths in the United States( Fries, 1992) and 3897 hospitalizations and 365 deaths in Canada (IMSC, 1997)every year. These hospitalizations and deaths are majorly due to ulcer and gastrointestinal bleeding related to NSAID use. Irrational prescribing has further complicated the adverse effects from the use of NSAIDs.

Asides gastrointestinal toxicity, renal failure has been recently known to be a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic – the so-called “triple whammy” effect.Liver problems are also possible with the long term use of NSAIDs (Awodele  et al, 2015).


 Self-medication is widespread all over the world and occurs in both urban(Pandy et al, 2013) and rural population(Bello and Bello, 2013).Pharmacies and patient medicine stores are visible in both urban and rural settlements in the study area suggest access of people to various types of drugs. These medications may be acquired with or without recommendation from qualified medical practitioners. The potential of NSAIDs to cause significant unwanted effects for users especially when taken in high doses and for prolonged duration, necessitates this study. The new trend in pharmacy practice entails appropriate guide in medication use (Isetts and McGann, 2012)


The general objective of this study was To evaluate rationale use of NSAID in Ilorin metropolis

The specific objectives of this study include to:

  1.  Assess the level of prevalence and pattern of misuse of NSAIDS  among the residents of Ilorin
  2. Describe the Prescribing pattern of NSAIDs among prescribers in the University of Ilorin Teaching Hospital.
  3. Assess the Dispensing pattern of NSAIDs among the Community Pharmacists in Ilorin metropolis
  4.    Determine factors that influence misuse of NSAIDs among the residents.