This is the main article on NSAIDs. Several more specific or detailed others are indexed at non-steroidal anti-inflammatory drugs.
Non-steroidal anti-inflammatory drugs (NSAIDS) helped start the science of pharmacology and the commerical pharmacology industry with the patenting of aspirin by Bayer in 1899. This is still a very active area of research with a Nobel prize as recently as 1982 and new drugs of the class still being launched and developed. Extracts of 'Salix alba', the White Willow of the English and European river bank and other willows have been used to treat rheumatism and inflammation from before recorded history in several cultures. The key first records are Hippocrates in the 5th century BC and in the context of Western Medicine the report in 1763 of Reverend Edward Stone, that willow extract reduced fever. Such extracts contain Salicylic acid which is therefore the prototype NSAID. It was first purified in 1828 but Meadowsweet (Filipendula ulmaria) provided a more convenient plant source and it was this German work from 1839 onwards that motivated Charles Gerhardt to make acetosalicylic anhydride in 1853, a product that worked, but which was not exploited commercially. This French work lapsed and it was Felix Hoffmann, in 1897 who synthesised 2-(acetyloxy)benzoic acid (Acetylsalicylic acid, ASA, Aspirin etc, etc) using Arthur Eichengrün's process while both worked for Bayer. Bayer's product became a run away commercial success.
One of the most expensive drug class failures in history was initiated by rofecoxib, the first to the market of a new class of NSAIDs, the Cyclo-oxygenase (COX) 2 inhibitors (coxibs). This drug was withdrawn in 2004 when studies revealed conclusively a relatively high incidence of cardiovascular side-effects in long term use. There was a marked impact on the share prices of a number of pharmaceutical companies as the COX 2 inhibitors had been promoted on their safety profile compared to traditional NSAIDs. This had resulted in marked commercial success with annual sales of several billion US dollars. The importance of NSAIDs in medicine is likely to ensure that the COX 2 inhibitors evolve as a therapeutic option.
The in vivo chemistry is relatively well understood. They are structural analogues of the natural substrates of COX. Interestingly salicylic acid acts as a natural plant hormone.
Mechanism of action
Main article cyclo-oxygenase
NSAIDs suppress the production of prostaglandins and thromboxanes through inhibition of cyclo-oxygenase (COX). In man three cyclo-oxygenases have been characterised. NSAIDs reversibly (or in the case of aspirin irreversibly) inhibit COX 1 and COX 2 with varying specifity and activity for the two enzymes. COX 3 seems to be specifically inhibited by paracetamol (acetaminophen) which is not an NSAID as such inhibition is not anti-inflammatory. Of course other NSAIDs might also reversibly inhibit COX 3.
Pharmacokinetics and Pharmacodynamics
These vary markedly between the drugs. Ibuprofen is a weak COX 1 predominant reversible inhibitor with a short half life. Rofecoxib is a strong COX 2 predominant reversible inhibitor with a long half life. Piroxicam is a strong COX 1 inhibitor with a long half life.
Clinical Differences between the Drugs
There is level 1a evidence for no important differences in efficacy between different NSAIDs in treating the symptoms of musculoskeletal disorders. Isolated drugs have evidence for specific indications such as indometacin is likely to be beneficial compared to ibuprofen in treating patent ductus arteriosus in preterm and/or low birth weight infants.
Ibuprofen is a drug of choice. Aspirin is contra-indicated in children because of the risk of Reye's syndrome. Despite its wide use there is only low quality evidence for paracetamol in this indication.
Ibuprofen is a drug of choice. Aspirin is contra-indicated in children because of the risk of Reye's syndrome. It is suspected that other NSAIDs attain any greater benefit in providing analgesia in specific situations by their COX 1 actions. NSAIDs alone, or combined with opioids, are beneficial for short-term treatment of cancer pain. Bone cancer pain responds well to NSAIDs such as diclofenac, and the severe pain of gout is rapidly relieved by agents such as indomethacin or naproxen. Parenteral NSAIDs such as ketorolac are used in perioperative analgesia and parenteral ketoprofen is a drug of choice for renal colic as NSAIDs are overall beneficial compared to opiates. There is level 1a evidence that there is no clinical difference between single oral doses of diclofenac 50 mg and ibuprofen 400 mg in relieving post operative pain.
Numerous clinical trials have established that NSAIDs are first line agents in treating the symptoms of conditions such as Rheumatoid arthritis and crystal arthropathy. Both COX 1 and COX 2 inhibitors are effective. Individual patients will often respond to one NSAID better than another, presumably because of the wide variations between the drugs and their pharmacodynamics in individuals. Interestingly in rheumatoid arthritis paracetamol and NSAID remain of unknown effectiveness in providing the best long term tradeoff of pain control verus safety. Patients tend to prefer NSAIDs if tolerated. It is known that COX 2 inhibitors are unlikely to be benefical compared to traditional NSAIDs in RA.
Stronger NSAIDs such as indometacin are the most effective. Except for recently licensed NSAIDs for this indication there is only low quality evidence but they are likely to be beneficial Aspirin is contraindicated as it blocks renal urate excretion.
While numerous trials have established NSAID efficiency in short term use is beneficial(this can be regarded as the standard to which they are licensed) long term use and use in elderly and those with relative contra-indications it is definitely a trade off between benefits and harms. In osteoarthritis with moderate-to-severe levels of pain, NSAIDs appear to be beneficial compared to paracetamol. In long term use over a year oral ibuprofen appears to have no advantage over topical ibuprofen and most patients seem to self select the later safer option if given the choice.
Soft Tissue Injury
Despite the wide use of these drugs the clinical trial evidence shows little or no benefit over paracetamol. An example is shoulder injury where oral or topical use is of unknown effectiveness. Interestingly Cochrane suggests that a widely studied drug piroxicam is worse in some soft tissue injury situations than paracetamol although it is better than placebo.
While there is little high quality clinical evidence NSAIDs have been used widely and relatively safely in this indication. Animal models suggest bone healing is impaired by COX 2 inhibition, but the situation in man is unclear. The current deprecation of COX 2 inhibitors in clinical practice is likely to leave this issue unresolved.
Aspirin is an irreversible inhibitor of COX 1 through acetylation and is beneficial at low dose. It modifies thromboxane production, thus inactivating platelet aggregation, which can prevent myocardial infarction and stroke. Not unexpectedly some studies have suggested ibuprofen might partially prevent aspirin's cardioprotective properties by partial antagonism and the combination of aspirin with other NSAIDs may not be as effective as aspirin alone. Cardiovascular safety concerns over COX 2 inhibitors exist and presently patients with high risk of ischaemic heart disease and cerebrovascular disease should not be treated with COX 2 inhibitors. The lack of any significant COX 1 activity in COX 2 inhibitors offers a reasonable mechanism for this. There is evidence that naproxen is more cardio-protective than diclofenac, but COX 1 inhibitors have been relatively poorly studied. Large epidemiological studies suggest high dose use of conventional NSAIDs are associated with increased risk of cardiac events in those with ischaemic heart disease, but except for diclofenac this risk is not as great as with COX 2 inhibitors and is minimal at low doses of conventional NSAIDs.
Combination of another NSAID and aspirin
Unhappily it appears that combining low dose aspirin and some NSAIDs does in real life lead to loss of effectiveness of low dose aspirin. This issue which has been known on theoretical grounds since the early 1980's was subject to an FDA warning on combining ibuprofen and aspirin in 2006 but more evidence has accumulated since. In a 27-month period, 72% of a cohort of stroke patients on aspirin who also took either ibuprofen or naproxen had a recurrent ischaemic episode. The same paper confirmed a significant reduction in the magnitude and duration of aspirin's inhibitory effect on platelet aggregation when ibuprofen was given. Further ibuprofen, indomethacin, naproxen, and tiaprofenic acid all block the antiplatelet effect of aspirin, although diclofenac, rofecoxib sulindac and celecoxib appear not to.
This issue is potentially important because many doctors and patients are likely to be unaware of an evidence base that has steadily accumulated and there can be good clinical reasons why the combination might be considered.
Apoptosis induction in malignacy due perhaps to up-regulation of the p75(NTR) tumor suppressor gene due to a mechanism certainly independent of COX activity, has been described with a number of NSAIDS, with ibuprofen and R-flurbiprofen having the most favorable characteristics, although aspirin and celecoxib act at lowest dose which is more interesting for derivative drug development 
There is evidence for neuroprotection (other than ischaemic stroke) in Alzheimer's disease and Parkinson's disease. Presently there is no role using NSAIDs in primary protection in either of these conditions as net benefit has not been demonstrated and indeed it was FDA analysis of data from trials looking at the secondary neuroprotective potential of a COX2 inhibitor rofecoxib that finally brought the suspected ischaemic heart disease risk to the fore.
Gastric mucosal damage
Numerous clinical and in vitro studies have shown differences between the drugs. This is not as simple as a COX 1 action, as it has been known since the 1980s that prolonged COX 2 inhibition might impair gastric mucosa repair. In short term use specific COX 2 inhibitors produce less gastric mucosal damage compared to NSAIDs with predominant COX 1 action. Therapeutic bleeding risk does not correlate well with short term mucosal damage surrogates and this has lead to heavy promotion that may have misrepresented the situation with regard to toxic morbidity and mortality.
Renal toxicityThey are all potentially toxic to the kidney. The potential for acute renal failure when given to patients on ACE and angiotension 2 inhibitors is often over looked, as is the patient's baseline renal function.
Aggravation of heart failure (causing oedema or pulmonary oedema) due to the inhibition of renal prostaglandins is a potential problem with all NSAIDs but the COX 2 inhibitors are specifically contraindicated. There is also increased mortality in chronic heart failure use with diclofenac and coxibs having more increased risk than naproxen. As mentioned earlier the increased mortality from ischaemic heart disease that lead to the withdrawal from market of several coxibs has been well studied and appears to follow a similar pattern in terms of risk of individual drugs epidemiologically to that of heart failure risk.
Several NSAIDs have been withdrawn or had their indications restricted because of enhanced drug specific toxicity. Some have caused a skin reactions(Valdecoxib-now withdrawn) and Fenbufen. Tiaprofenic Acid can cause severe cystitis. Azapropazone-now discontinued, had the highest incidence of gastro-intestinal bleeding but was effective in gout. Asthma can be aggravated by all NSAIDs, but particular care needs to be taken with aspirin in hyperallergic asthmatics.
As expected by their mechanism of action they may impair ovulation and implantation of the embryo.
- Upper gastro-intestinal. All NSAIDs are associated with serious gastrointestinal side effects. For non-selective NSAIDs these were most common with azapropazone and least common with Ibuprofen. Selective cyclo-oxygenase-2 inhibitors are associated with a lower risk of gastrointestinal side effects
- Renal failure (especially in combination with diuretics and drugs acting on angiotensin system)
- Fluid retention
- Cardiovascular events. This may be related to degree of cyclo-oxygenase-2 inhibition
- In chronic heart failure all NSAIDS have a dose-dependent increase in risk of death and increased risk of hospitalization with some such as diclofenac and coxibs having higher hazard ratios
List of NSAID side-effects - many rare
Some NSAIDs are more likely to cause these side-effects than others but they all appear to be class side-effects
- Hypersensitivity reactions
- Nervous system
- ↑ Wikipedia on Aspirin
- ↑ The Macdonald Encyclopaedia of Medicinal Plants Roberto Chief English Translation 1984
- ↑ Chandrasekharan, N.V., Dai, H., Roos, K.L.T. et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proceedings of the National Academy of Sciences of the United States of America 99(21):13926-31, (2002).
- ↑ Hashkes PJ, Tauber T, Somekh E, Brik R, Barash J, Mukamel M, et al. Naproxen as an alternative to aspirin for the treatment of arthritis of rheumatic fever: a randomized trial. The Journal of pediatrics. 2003;143:399-401.
- ↑ Clinical Evidence on non-steroidal anti-inflammatory drugs (oral) in osteoarthritis: Web publication date: 01 October 2003 (based on November 2002 search)
- ↑ Underwood M, Ashby D, Cross P, Hennessy E, Letley L, Martin J, Mt-Isa S, Parsons S, Vickers M, Whyte K. Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study. BMJ (Clinical research ed.). 2008 Jan 19; 336(7636):138-42.(Link to article – subscription may be required.)
- ↑ Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. 1994;308(6921):81-106. Erratum in: BMJ 1994;308(6943):1540.
- ↑ Gislason GH, Jacobsen S, Rasmussen JN, Rasmussen S, Buch P, Friberg J, Schramm TK, Abildstrom SZ, Køber L, Madsen M, Torp-Pedersen C Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction Circulation 2006;doi:10.1161/CIRCULATIONAHA.106.616219 accessed 20.06.06
- ↑ Rao GH, Johnson GG, Reddy KR, White JG. Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. Arteriosclerosis (Dallas, Tex.). 1983 Jul-Aug; 3(4):383-8.
- ↑ Gengo FM, Rubin L, Robson M, Rainka M, Gengo MF, Mager DE, Bates V. Effects of ibuprofen on the magnitude and duration of aspirin's inhibition of platelet aggregation: clinical consequences in stroke prophylaxis. Journal of clinical pharmacology. 2008 Jan; 48(1):117-22.(Link to article – subscription may be required.)
- ↑ Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. The New England journal of medicine. 2001 Dec 20; 345(25):1809-17.(Link to article – subscription may be required.)
- ↑ Gladding PA, Webster MW, Farrell HB, Zeng IS, Park R, Ruijne N. The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers. The American journal of cardiology. 2008 Apr 1; 101(7):1060-3.(Link to article – subscription may be required.)
- ↑ Andrews P, Zhao X, Allen J, Li F, Chang M. A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro. . 2007 Apr 20.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Quann EJ, Khwaja F, Zavitz KH, Djakiew D. The aryl propionic acid R-flurbiprofen selectively induces p75NTR-dependent decreased survival of prostate tumor cells. Cancer research. 2007 Apr 1; 67(7):3254-62.(Link to article – subscription may be required.)
- ↑ Imbimbo BP. An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease. Expert opinion on investigational drugs. 2009 Aug; 18(8):1147-68.(Link to article – subscription may be required.)
- ↑ Gagne JJ, Power MC. Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology. 2010 Mar 23; 74(12):995-1002.(Link to article – subscription may be required.)
- ↑ Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA : the journal of the American Medical Association. 2008 Apr 16; 299(15):1813-7.(Link to article – subscription may be required.)
- ↑ Gislason GH, Rasmussen JN, Abildstrom SZ, Schramm TK, Hansen ML, Fosbøl EL, Sørensen R, Folke F, Buch P, Gadsbøll N, Rasmussen S, Poulsen HE, Køber L, Madsen M, Torp-Pedersen C Increased Mortality and Cardiovascular Morbidity Associated With Use of Nonsteroidal Anti-inflammatory Drugs in Chronic Heart Failure Arch Intern Med. 2009;169(2):141-149