VOL: 99, ISSUE: 16, PAGE NO: 30
Carolyn Middleton, BSc, RGN, is clinical nurse specialist, Acute Pain Service, Nevill Hall Hospital, Gwent Healthcare NHS Trust
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used of all therapeutic agents, with an estimated 100 million people worldwide using them regularly (Berde and Sundel, 1998). They are particularly effective for postoperative pain and for pain associated with musculo-skeletal conditions such as rheumatoid arthritis or osteoarthritis. When summarising the results of a therapeutic trial of a drug, the term ‘number needed to be treated (NNT) to prevent one adverse outcome’ is used to indicate the benefit of an active treatment over a control.
The application of this method to test the efficacy of NSAIDs has shown that diclofenac 100mg has an NNT of 1.9 and ibuprofen 400 an NNT of 2.4 compared to morphine 10mg (intramuscular injection) which has an NNT of 2.9 (Bandolier, 2002).
Although NSAIDs are effective analgesics, they are not without significant adverse side-effects: this class of drug is responsible for considerable morbidity and mortality. Tenenbaum (in Jordan and White, 2001) suggests that up to 30 per cent of regular users experience adverse gastrointestinal side-effects. Also, figures released by the National Institute for Clinical Excellence (NICE, 2001) state that 2000 deaths occur in the UK each year related to NSAID usage.
How NSAIDs work
Following cell membrane damage, phospholipids are liberated into the body. One of these, phospholipase A2, is converted into arachidonic acid, which is acted upon by the enzyme cyclo-oxygenase (COX), producing prostaglandins, prostacyclin and thromboxanes.
NSAIDs are believed to exert their anti-inflammatory and analgesic actions by inhibiting the synthesis of the prostaglandins, which are responsible for inflammation and pain following tissue damage. NSAIDs inhibit action of the enzyme cyclo-oxygenase (COX), so reducing the production of prostaglandins (Fig 1). NSAIDs not only provide analgesia through this system but also produce adverse effects because the same physiological mechanisms are responsible for protective functions within the body (Fig 2).
COX-I and COX-II
COX-I: This is always active in the body synthesising prostaglandins. These have a variety of physiological purposes, all designed to maintain normal organ function; for example, protection of the gastrointestinal tract, renal homoeostasis and platelet aggregation.
COX-II: Until 1991 it was believed that the actions of prostaglandins, both at the site of tissue damage and those involved in homoeostasis, were inseparable and were all caused by the inhibition of cyclo-oxygenase. Then the COX-II isoform was identified.
The structure of both COX-I and COX-II are similar except that COX-II has an internal pocket that gives it a larger surface area and therefore an increased binding site. Research into COX-II mechanisms has led to drug developments, with COX-II selective inhibitors having the capability of blocking the COX-II isoform of the cyclo-oxygenase enzyme but largely sparing the COX-I isoform.
The COX-II enzyme, which is responsible for the bio-synthesis of COX-II inflammatory prostaglandins (Fig 2), is predominantly inducible (normally present at low levels but has the potential to be upregulated). Under normal basal conditions it is virtually undetectable in most tissues, but injury or inflammatory stimulus can increase both peripheral and central levels of the enzyme by up to twenty-fold (Bandolier, 2000).
Rofecoxib and celecoxib are classified as COX-II-specific agents because of their higher COX-II selectivity compared to traditional NSAIDs such as diclofenac or ibuprofen.
Meloxicam was marketed before the COX-II gene was identified but has been found to have a high selectivity for COX-II compared to traditional NSAIDs, as does etodolac. However, these two particular drugs are not COX-II specific in the same way as rofecoxib or celecoxib, but are said to be COX-II selective.
Adverse effects of NSAIDs
Prostaglandins in the gastric mucosa help to maintain mucosal blood flow and barrier function. By inhibiting COX-I, NSAIDs reduce the ability of the stomach to protect itself from its acid contents,resulting in increased acid secretion. This can potentially cause erosion, ulceration, blood loss and ultimately perforation. Gastric protective agents are therefore often co-prescribed with NSAIDs with the aim of reducing the associated adverse effects of these drugs on the gastrointestinal system.
Approximately 34 per cent of patients who take NSAIDs regularly also take protective agents such as proton pump inhibitors (NICE, 2001).
Renal prostaglandins, mainly PGE2, are involved in mediating blood flow and also in sodium and water re-absorption within the kidneys. Inhibition by NSAIDs can lead to toxicity, particularly in dehydrated patients. NSAIDs (including COX-II inhibitors) can reduce renal blood flow, glomerular filtration rates and urine production. In extreme cases, increased plasma volume can induce congestive cardiac failure, with pulmonary oedema and breathlessness.
Thromboxanes promote clotting by causing platelets to aggregate and blood vessels to constrict. Prostacyclin inhibits the action of platelets, dilates blood vessels and causes fibrinolysis.
Because NSAIDs inhibit the production of thromboxanes responsible for platelet aggregation and the initiation of clotting (see Fig 1), COX-I inhibition reduces platelet aggregation and increases bleeding time. This has the potential to produce haemorrhagic complications, particularly if given to patients before surgery. In high doses, NSAIDs also inhibit the production of prostacyclin, which is responsible for vasodilation and clot limitation (Jordan and White, 2001).
Following trauma or an inflammatory stimulus causing cell membrane damage, prostaglandins (E2) are released which synthesise nociceptors (pain receptors). This stimulation increases COX-I enzyme levels up to four-fold (Bandolier, 2000). Traditional or conventional NSAIDs such as diclofenac or ibuprofen inhibit both COX-I and COX-II enzymes.
Efficacy of COX-I and COX-II inhibitors in clinical practice
Bandolier (2000) suggests that information on the efficacy of COX-1 and COX-2 inhibitors is somewhat limited. However, several studies have found that COX-II inhibitors have an equivalent efficacy to traditional NSAIDs in terms of peak visual analogue scale scores (NICE, 2001; Berde and Sundel, 1998). NICE (2001) suggests that in the absence of evidence of significant differences in anti-inflammatory efficacy between the COX-II and traditional NSAIDs, the avoidance of serious adverse effects becomes the most relevant factor when prescribing.
The therapeutic activity of NSAIDs is thought to be primarily due to the inhibition of COX-II, whereas the toxicity results from inhibition of COX-I. In theory, therefore, drugs that can inhibit COX-II but not COX-I promise to provide an analgesic effect with a reduction of the organ toxicities associated with COX-I inhibitors.
Although there is some increased evidence for adverse effects by NSAIDs on the gastrointestinal system compared to placebo, with COX-II inhibitors it is significantly less than with traditional NSAIDs (NICE, 2001; Reuben and Connelly, 2000). The Celecoxib Long-term Arthritis Safety Study (CLASS) investigated 8,059 patients with either osteoarthritis or rheumatoid arthritis randomised to take celecoxib, ibuprofen or diclofenac over a 12-month period. The trial initially demonstrated favourable results, showing that at six months there were fewer reported gastrointestinal complications with celecoxib than with diclofenac or ibuprofen. However, much controversy surrounds the study because the publication of the less favourable 12-month outcomes did not demonstrate a reduction in adverse gastrointestinal events with the COX-II inhibitor. A possible explanation could be that co-administration of aspirin was allowed during the trial (CLASS Advisory Committee, 2001).
A significant implication for practice derived from the CLASS study is that patients receiving aspirin as a prophylactic measure against adverse vascular events (thrombotic cerebrovascular or cardiovascular disease) will probably not derive any gastrointestinal safety advantage from COX-II selective inhibitors. Clearly, further research is required.
The evidence for improved renal safety of COX-II inhibitors compared to traditional NSAIDs is weaker than the evidence for increased gastrointestinal safety. COX-II enzymes are found in the kidneys and are inhibited by both COX-I and COX-II inhibitors.
Studies of platelet aggregation suggest that COX-II inhibitors produce less or no inhibition of platelet function compared to traditional NSAIDs (Reuben and Connelly, 2000; Berde and Sundel, 1998).
Some uncertainty over the use of COX-II selective inhibitors in patients with cardiovascular disease has arisen. The Vioxx Gastro-intestinal Outcomes Research (VIGOR) multi-centred, double blind, randomised study involving 8,076 patients, compared rofecoxib 50mg/day with naproxen 1000mg/day. The results showed an increased number of myocardial infarctions in the patients randomised to the rofecoxib group (0.4 per cent in the rofecoxib group compared to 0.1 per cent in the naproxen group) (Mukherjee et al, 2001). It is important to note that for this trial the use of low dose aspirin as a prophylactic measure was not permitted whereas patients who took part in the CLASS study were allowed to take up to 325mg per day of aspirin. The CLASS study demonstrated no difference in the cardiovascular event rates for COX-I or COX-II inhibitors (Mukherjee et al, 2001).
The issue of potential increased risk of cardiovascular mortality with rofecoxib remains unresolved and further research is recommended. NICE (2001) suggests that this information should be taken into account when prescribing selective COX-II inhibitors for patients with cardio-vascular disease.
Cost is also an issue that needs some consideration. The newer COX-II agents are more expensive than traditional NSAID drugs, and NICE (2001) has estimated that changing all high-risk patients (see Table 1) from COX-I to COX-II inhibitors would cost the NHS £25 million.
NICE (2001) suggests that COX-II inhibitors are not recommended for routine use but should be used instead of traditional NSAIDs for high-risk patients (Table 1).
Long-term use of NSAIDs should be avoided where possible. Where there is a demonstrable clinical need for prolonged use, physicians and patients should remain alert for signs of ulceration and bleeding. Also, regular assessment should be made regarding the appropriateness of continued usage.