Non-Steroidal Anti-Inflammatory Drugs

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Chapter: Pharmacovigilance: Gastrointestinal ADRs

When grouped by category, NSAIDs are the most commonly prescribed of all drugs.


NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

When grouped by category, NSAIDs are the most commonly prescribed of all drugs. More than 20 million prescriptions per year are written in the United Kingdom alone (Langman, 1988). In the United States, 2–3 million patients take daily NSAIDs and worldwide, it has been estimated that over 30 million people take NSAIDs each day (Gibson, 1988). The use of NSAIDs has been rising steadily since the 1970s, particularly amongst the elderly (Walt et al., 1986). Approximately 50% of all NSAID prescriptions are for persons over 60 years old (Langman, 1988; Fries et al., 1990).

Although NSAIDs reduce pain and inflammation and improve quality of life for patients with inflam-matory disorders, it is widely recognised that such benefit is achieved at the risk of gastrointestinal injury. In the upper gastrointestinal tract, this may range from clinically insignificant blood loss and minor erosive changes to deep ulceration with the asso-ciated risk of haemorrhage or perforation. Adverse effects of NSAIDs are also recognised in the small and large intestine and range from asymptomatic enteropathy to severe complications such as ulcer-ation, bleeding, perforation and stricture (Bjarnason et al., 1993; Aabakken, 1999; Faucheron, 1999).

UPPER GASTROINTESTINAL LESIONS

The annual incidence of upper gastrointestinal bleed-ing associated with the use of NSAIDs has been reported to be from 50 to 150 cases per 100 000 (Gilbert, 1990; Laporte et al., 1991) with chronic NSAID users experiencing a 1%–4% annual inci-dence of gastroduodenal perforation, ulcer or bleeding (Singh, 1998). In the United States, gastrointestinal injury induced by NSAIDs is responsible for an esti-mated 107 000 hospitalised patients and 16 500 deaths annually (Singh, 1998; Wolfe, Lichtenstein and Singh, 1999). Estimates for the United Kingdom suggest that some 12 000 emergency upper gastrointestinal admis-sions (including over 2200 deaths) per annum are because of NSAID use (Blower et al., 1997).

Studies of the prevalence of peptic ulceration in arthritic patients receiving NSAIDs have been reviewed (McCarthy, 1989). Crude prevalence rates of gastric and duodenal ulcer were 13% and 11%, respectively. Similar findings were reported from an endoscopic screening study of over 1800 rheumatoid or osteoarthritic patients (Geis et al., 1991). Gastric ulcers were present in 14.8% of patients and duodenal ulcers in 10.2%.

Many investigators have addressed the question of the relative gastrointestinal toxicities of NSAIDs. Most assessments of relative toxicity have been derived from case–control studies. Despite the diffi-culties in the interpretation of these data, such as NSAIDs being used in different populations for diverse indications and at a range of doses, some clear differences have been found. In general, studies have shown that the risk of adverse upper gastrointesti-nal effects is lowest with ibuprofen and diclofenac. Piroxicam and azapropazone have consistently been associated with a high risk of upper gastrointesti-nal toxicity (Committee on Safety of Medicines, 1986; Somerville, Faulkener and Langman, 1986; Carson et al., 1987a; Rossi, Hsu and Faich, 1987; Gabriel, Jaakkimainen and Bombardier, 1991; Grif-fin et al., 1991; Laporte et al., 1991; Henry, Dobson and Turner, 1993; Kaufman et al., 1993; Savage et al., 1993; Garcia-Rodriguez and Jick, 1994; Langman et al., 1994).

These studies and others have been included in a meta-analysis to examine the relative risks of serious gastrointestinal complications reported with NSAIDs (Henry et al., 1996). This showed that there are wide differences between individual NSAIDs in the risk of inducing gastrointestinal bleeding and ulcer perfora-tion. Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Ranked highest for risk was tolmetin, piroxicam and ketoprofen, with the greatest risk being with azapropazone.

A meta-analysis of studies has also shown that long-term therapy with aspirin is associated with a significant increase in the incidence of gastrointestinal haemorrhage (Derry and Loke, 2000). This occurred in 2.4% of patients taking aspirin compared with 1.42% taking placebo. Furthermore, it was shown that neither reducing the dose nor using modified release preparations reduced the incidence of gastrointestinal haemorrhage.

The risk of developing peptic ulcer disease and complications exists for the duration of NSAID treat-ment. However, the risk may be greatest in the first month of taking NSAIDs (Gabriel, Jaakkimainen and Bombardier, 1991; Griffin et al., 1991; Henry, Dobson and Turner, 1993). Griffin et al. (1991) reported that persons with a shorter duration of exposure to NSAIDs had an increased risk for the development of peptic ulcer disease. The relative risk was 7.2 for those with a total duration of use of no more than 30 days, significantly greater than the relative risks of 3.7 and 3.9 for persons with 31–90 days and more than 90 days of use, respectively.

Meta-analysis of studies resulted in similar findings (Gabriel, Jaakkimainen and Bombardier, 1991). The highest measures of risk for adverse gastrointestinal events related to NSAID use were obtained from stud-ies in which the duration of NSAID consumption was less than 1 month.

Higher doses of NSAIDs increase the risk of gastro-duodenal ulceration and upper gastrointestinal compli-cations (Carson et al., 1987b; Gabriel, Jaakkimainen and Bombardier, 1991; Griffin et al., 1991; Henry, Dobson and Turner, 1993; Garcia-Rodriguez and Jick, 1994; Langman et al., 1994). The relative risk of developing peptic ulcer disease as a function of the dose of NSAID was investigated in a nested case– control study of 1400 patients over 65 years old enrolled in a Medicaid programme in the United States (Griffin et al., 1991). Patients had been hospi-talised for confirmed peptic ulcer, and relative risks were compared with over 7000 controls. For users of NSAIDs, the risk increased with increasing dose, from a relative risk of 2.8 for the lowest to a relative risk of 8.0 for the highest dose category.

Similar findings were reported from a study in the United Kingdom (Langman et al., 1994). The previous use of NSAIDs in 1144 patients aged 60 years or older and admitted to hospital with peptic ulcer bleeding was compared with matched hospi-tal and community controls. Among subjects who took a non-aspirin NSAID during the previous month, the risk of ulcer complications increased with dose. Non-steroidal anti-inflammatory drug users with a prior history of gastrointestinal disease are more likely to experience adverse gastrointestinal events when taking NSAIDs (Gabriel, Jaakkimainen and Bombardier, 1991; Garcia-Rodriguez and Jick, 1994; Weil et al., 2000). Patients with a past history of peptic ulcer disease who are receiving NSAIDs are at a three-to four-fold higher risk of another episode of upper gastrointestinal bleeding than are NSAID users with no past history of ulcer (Garcia-Rodriguez and Jick, 1994; Weil et al., 2000).

Elderly women are often believed to be at a partic-ular risk of NSAID-associated peptic ulcer complica-tions. Whilst elderly patients are at a greater risk than younger patients (Garcia-Rodriguez and Jick, 1994), the effect of gender is less clear. Findings from stud-ies have been inconsistent and whilst some investiga-tors report that the risk for a serious gastrointestinal event appears approximately equal amongst men and women, others suggest that women may be at a some-what greater risk (Griffin et al., 1991; Henry, Dobson and Turner, 1993; Neutel, Maxwell and Appel, 2000).

The combined use of NSAIDs and corticosteroids is associated with approximately two to three times the risk of gastrointestinal toxicity than is the use of NSAIDs alone (Carson et al., 1987a; Gabriel, Jaakki-mainen and Bombardier, 1991; Piper et al., 1991; Garcia-Rodriguez and Jick, 1994; Weil et al., 2000).

Concomitant treatment with NSAIDs and corticos-teroids increased the risk of hospitalisation due to gastroduodenal events in elderly patients (Piper et al., 1991). Relative risk of hospitalisation was 1.1 with corticosteroids alone and 4.1 with NSAIDs alone but was increased 15-fold when both were combined. It should be noted that peptic ulcer is a rare complication of corticosteroid therapy alone (Conn and Poynard, 1994). The concurrent use of selective serotonin re-uptake inhibitors with NSAIDs has also been shown to potentiate the risk of upper gastrointestinal bleed-ing (de Abajo, Garcia-Rodriguez and Montero, 1999) as has the concomitant use of NSAIDs and anticoag-ulants (Shorr et al., 1993; Weil et al., 2000).

Non-steroidal anti-inflammatory drugs are effective in the management of inflammatory disease because they inhibit cyclooxygenase (COX) and hence inhibit the production of prostaglandins (Vane, 1971). Two COX isoforms exist, namely COX-1 and COX-2. Prostaglandins protect the upper gastrointestinal mucosa from damage and are a product of the activity of COX-1, a constitutive isoform. COX-2, however, is an enzyme that is induced to generate other prostaglandins that mediate pain and inflamma-tion. The beneficial therapeutic effects of the non-selective NSAIDs are hence attributable to inhibition of the COX-2 enzyme, whereas the toxic effects on the upper gastrointestinal tract are a result of COX-1 inhibition (Vane and Botting, 1998).

The development of COX-2 selective NSAIDs (Jackson and Hawkey, 2000), such as celecoxib (Clemett and Goa, 2000) and rofecoxib (Hawkey et al., 2001), promises to reduce the gastrointestinal problems of patients needing anti-inflammatory drug therapy. Studies suggest that in osteoarthritis and in rheumatoid arthritis, COX-2 inhibitors have similar efficacy to conventional NSAIDs in relieving pain and improving functional status but are associated with a lower incidence of upper gastrointestinal perforations, ulcers and bleeding (Clemett and Goa, 2000; Hawkey et al., 2001).

INTESTINAL LESIONS

In the small intestine, NSAIDs may cause a low-grade enteropathy (increased intestinal permeability and low-grade inflammation with blood and protein loss), strictures, bleeding, lesions and perforation (Bjarnason et al., 1993; Aabakken, 1999).

An estimate of the prevalence of NSAID-induced lesions in the small intestine is available from a prospective autopsy study involving over 700 subjects (Allison et al., 1992). Non-specific small intesti-nal ulceration was found in 8.4% of 249 users of NSAIDs compared with 0.6% of 464 non-users. The prevalence of non-specific ulceration was higher in long-term users of NSAIDs (13.5%) compared with short-term users (6.3%). Three patients (4.1%) in the long-term NSAID group died as a direct conse-quence of peritonitis from perforated, non-specific small intestinal ulcers.

The ingestion of NSAIDs has also been asso-ciated with colonic ulcers, large intestinal perfo-ration and bleeding, complications of diverticular disease (perforation, fistulae and bleeding) and relapse of inflammatory bowel disease (Bjarnason et al. 1993; Faucheron, 1999). In addition, in the 1990s, there have been an increasing number of anecdo-tal reports of NSAID-associated colonic strictures or NSAID-induced colonic diaphragm disease in patients receiving diclofenac, indomethacin, sulindac, phenylbutazone, ibuprofen and etodolac (Eis et al., 1997; Ribeiro et al., 1998; Faucheron, 1999; Wein-stock, Hammond and Brandwin, 1999; Smith and Pineau, 2000).

In the large intestine NSAIDs, in particular, the fenamates (mefenamic and flufenamic acid) may cause colitis. This may range from proctitis to pancoli-tis, although most histological reports are of mild non-specific colitis. Non-steroidal anti-inflammatory drugs have also been implicated in causing eosinophilic, pseudomembranous and collagenous colitis.

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