Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. The term "non-steroidal" is used to distinguish these drugs from steroids, which (amongst a broad range of other effects) have a similar eicosanoid depressing anti-inflammatory action. NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs). The most prominent members of this group of drugs are aspirin and ibuprofen. Paracetamol, or acetaminophen, has little anti-inflammatory activity, and is not an NSAID.
Beginning in 1829, with the isolation of salicylic acid from the folk remedy willow bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Part of the popularity of NSAIDs is that, unlike opioids, they do not produce sedation, respiratory depression, or addiction. NSAIDs, however, are not without their own problems (see below). Certain NSAIDs have become accepted as relatively safe, resulting in the rescheduling of these agents, e.g. ibuprofen, to allow availability over-the-counter.
Mode of action
Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase - they inhibit both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyses the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation.
This mechanism of action was elucidated by John Vane, who later received a Nobel Prize for his work.
COX-1 is also found in the stomach lining, but the prostaglandins here serve a protective role, preventing the stomach mucosa from being eroded by its own acid. When COX-1 inhibitors lower stomach prostaglandin levels, their protective effects are lost, and ulcers of the stomach or duodenum and internal bleeding can result.
Examples of NSAIDs
NSAIDs can be broadly classified based on their chemical structure. NSAIDs within a group will tend to have similar characteristics and tolerability. There is little difference in clinical efficacy between the NSAIDs when used at equivalent doses. Rather, differences between compounds tended to be with regards to dosing regimens (related to half-life), route of administration, and tolerability profile. Some more common examples are given below.
Paracetamol (acetaminophen), owing to its inhibitory action on cyclooxygenase, is sometimes grouped together with the NSAIDs. Paracetamol, however, does not have any significant anti-inflammatory properties and is not a true NSAID. Though it has not been clearly elucidated, it is suspected that this lack of anti-inflammatory action may be due to the paracetamol inhibiting cyclooxygenase predominantly in the central nervous system. There is also some speculation that paracetamol acts through inhibition of the recently discovered COX-3 isoform (see below).
2-arylpropionic acids (profens)
N-arylanthranilic acids (fenamic acids)
Uses of NSAIDs
NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease.
NSAIDs are generally indicated for the symptomatic relief of the following conditions. (Rossi, 2004)
Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation; an indication useful in the management of arterial thrombosis and prevention of adverse cardiovascular events.
In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States. (Green, 2001). With the aging of the Baby Boomer generation and the associated rise in the incidence of osteoarthritis and other such conditions for which NSAIDs are indicated, the use of NSAIDs may increase further still.
The widespread use of NSAIDs has meant that the adverse effects of these relatively safe drugs have become increasingly prevalent. The two main adverse drug reactions (ADRs) associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents.
These effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10-20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits. (Green, 2001)
The main ADRs associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT - the acidic molecules directly irritate the gastric mucosa; and inhibition of COX-1 reduces the levels of protective prostaglandins.
Common gastrointestinal ADRs include: (Rossi, 2004)
Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed.
There are also some differences in the propensity of individual agents to cause gastrointestinal ADRs. Ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to have lower rates. (Rossi, 2004)
Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations which are claimed to reduce the incidence of gastrointestinal ADRs. Similarly, there is a belief that rectal formulations may reduce gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration. (Rossi, 2004)
Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhoea). While these techniques may be effective, they prove to be expensive for maintenance therapy.
NSAIDs are also associated with a relatively high incidence of renal ADRs. The mechanism of these renal ADRs is probably due to changes in renal haemodynamics (bloodflow), ordinarily mediated by prostaglandins, which are affected by NSAIDs.
Common ADRs associated with altered renal function include: (Rossi, 2004)
These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect. (Thomas, 2000)
In rarer instances NSAIDs may also cause more severe renal conditions. (Rossi, 2004)
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. (Moore, 2002) It is somewhat ironic that these antiinflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac and benzydamine .
Benoxaprofen , since withdrawn due to its hepatotoxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. Whilst ibuprofen is somewhat of an exception, having weak absorption, it has been reported to be a weak photosensitising agent.
Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness. (Rossi, 2004)
Uncommon ADRs include: heart failure, hyperkalaemia, confusion, bronchospasm, rash. (Rossi, 2004)
The COX-2 paradigm
The discovery of the existence of COX-2 in 1991 by Daniel L. Simmons at Brigham Young University in Provo, Utah raised the hope of developing an effective NSAID without the gastric problems characteristic of these agents so far. It was thought that selective inhibition of COX-2 would result in antiinflammatory action without disrupting gastroprotective prostaglandins.
The relatively selective COX-2 oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.
Issues with COX-2 inhibitors
While it was hoped that this COX-2 selectivity would reduce gastrointestinal adverse drug reactions (ADRs) there is little conclusive evidence that this is true. The original study touted by Searle (now part of Pfizer), showing a reduced rate of ADRs for celecoxib, was later revealed to be based on preliminary data - the final data showed no significant difference in ADRs when compared with diclofenac.
Rofecoxib however, which has since been withdrawn, had been shown to produce significantly fewer gastrointestinal ADRs compared to naproxen. (Bombardier et al 2003). This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs - a statistically insignificant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a relative risk of cardiovascular events of 1.97 versus placebo - a result which resulted in the worldwide withdrawal of rofecoxib in October 2004.
Simmons also recently co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to acetaminophen (paracetamol), arguably the most widely used analgesic drug in the world. (Chandrasekharan et al 2002). The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
The clinical ramifications and knowledge of COX isozymes are therefore rapidly expanding and could perhaps offer significant hope for future treatments of pain, inflammation and fever.
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- Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002;99:13926-31. PMID 12242329.
- Green GA. Understanding NSAIDS: from aspirin to COX-2. Clin Cornerstone 2002;3:50-59. PMID 11464731.
- Moore DE. Drug-induced cutaneous photosensitivity. Drug Safety 2002;25:345-72. PMID 12020173.
- Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
- Thomas MC. Diuretics, ACE inhibitors and NSAIDs - the triple whammy. Med J Aust 2000;172:184-185. PMID 10772593.
Last updated: 05-21-2005 02:18:05