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Drug-induced gastrointestinal disorders
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Drug-induced gastrointestinal disorders
principally by inhibiting prostaglandin synthesis. In other cases, impairment of defence mechanisms is less direct; for example, there is a greater incidence of Salmonella and Campylobacter enteritis with proton pump inhibitors because the main physiological role of stomach acid is to sterilize ingested food before passage to the intestine.1 Direct injury to the GI tract – examples include oesophageal damage by potassium preparations, gastroduodenal ulcers caused by cytotoxic drugs, and the ulceration and colitis associated with NSAIDs independent of prostaglandin inhibition. Changes in colonic bacterial flora – widespread use of antibiotics, particularly cephalosporins, is associated with an increased incidence of Clostridium difficile infection and pseudomembranous colitis. However, there may be overlap between the groups (e.g. aspirin exhibits topical toxicity and inhibits prostaglandin-dependent mucosal defences).
Paul Fortun Christopher J Hawkey
Abstract Adverse drug effects on the gastrointestinal (GI) tract can occur as a predictable result of a drug’s mode of action, by direct injury, through compromising GI defences, or as a consequence of changes in colonic bacterial flora. Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonest cause of gastroduodenal injury due to inhibition of prostaglandin synthesis, and increase the risk of serious GI complications between 2.5- to 5- fold. There is considerable variation in risk across the recommended dose ranges for individual NSAIDs. Low doses of aspirin are associated with an increased risk of upper GI haemorrhage. COX-2 inhibitors largely spare the GI mucosa from injury, unless they are co-administered with aspirin when the GI safety benefits are abrogated. As the small intestine becomes more accessible to imaging modalities such as capsule endoscopy, small bowel enteropathy is suggested by hypoalbuminaemia and iron deficiency. Druginduced colitis is an important problem, with antibiotics the commonest drug cause. Drugs can also exacerbate pre-existing inflammatory bowel disease. Strategies to minimize the adverse GI effects of drugs include giving the lowest dose of NSAID for the shortest time, selective COX-2 inhibitors for high GI/low cardiovascular risk patients, and upper GI mucosal protection by co-prescription of NSAIDs with proton pump inhibitors.
Oesophageal disease Heartburn Drugs commonly associated with heartburn and/or oesophageal injury are listed in Table 1. Drugs that relax the lower oesophageal sphincter are particularly likely to cause problems because of the increased acid exposure of the oesophagus (often without mucosal injury). Patients should be managed by drug withdrawal when possible, though a few may require acid suppression. Endoscopy is not usually required if the onset is clearly related to the drug and the condition settles on drug cessation. Candida oesophagitis is a common cause of dyspepsia (heartburn) or odynophagia (painful swallowing) in patients taking corticosteroids, antibiotics, and those on immunosuppressive drugs. The characteristic change on endoscopy is the formation of discrete white plaques.
Keywords adverse events; drugs; gastrointestinal injury; large bowel; NSAIDs; small intestine
Mucosal injury and strictures Tetracyclines, potassium chloride, certain bisphosphonates and quinidine are recognized as toxic to the oesophageal mucosa.
Almost any drug can affect the gastrointestinal (GI) tract. It has been estimated that 40% of adverse drug reactions affect the GI tract, and 4% of admissions to hospital are caused by drug-induced disorders. This contribution highlights drug-induced GI disorders that are common, important or often missed. It is useful to consider drug effects on the GI tract in the four categories below. Consequences of pharmacological mode of action – adverse drug effects can occur as a predictable result of a drug’s mode of action. Thus, anticholinergic agents (e.g. antidepressants) reduce oesophageal sphincter pressure, resulting in reflux and heartburn; they also reduce colonic transit, resulting in constipation. Impairment of GI defences – the best-known examples are non-steroidal anti-inflammatory drugs (NSAIDs), which act
Common drug causes of oesophageal problems Relax lower oesophageal sphincter causing heartburn • Anticholinergic agents (e.g. procyclidine, trihexyphenidyl) • Tricyclic antidepressants • Calcium channel blockers • Nitrates • Phenothiazines Direct mucosal injury • Tetracyclines • Bisphosphonates Associated with strictures • Potassium chloride1 • Quinidine1 • NSAIDs
Paul Fortun MRCP is Lecturer in Gastroenterology at University Hospital, Nottingham, UK. Competing interests: none declared.
1Particularly
Christopher J Hawkey DM FRCP is Professor of Gastroenterology at the University Hospital, Nottingham, UK. Competing interests: none declared.
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slow-release preparations.
Table 1
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However, presentation may vary with different drugs. NSAIDs and tetracyclines are a relatively common cause of erosive or pill oesophagitis; potassium chloride and quinidine are more strongly associated with stricture, often in the mid-oesophagus. These problems are more common in elderly patients, particularly those with pre-existing oesophageal disease or massive left atrial enlargement, and are more likely to occur when patients swallow their pills in a reclining position. Sustained-release preparations of potassium and quinidine are particularly likely to cause problems. There is an association between bisphosphonates and reversible oesophagitis, but the risk is low if the medication is administered correctly (i.e. in an upright position).2
gastrointestinal problems about once every 50–100 patient-years. In the UK, it is likely that at least 2000 patients per year die as a result of NSAID use (due to GI complications).9 Risk factors Patient-associated risk factors – concomitant risk factors are age, previous gastrointestinal bleeding, and patients who are also on anticoagulants, and to a lesser extent corticosteroids.3,10–13 Drug-related risk factors – the main drug-related risk factors are dose, choice of NSAID, co-prescription of corticosteroids and co-prescription of warfarin. The risk of ulcer complications increases with dose. A meta-analysis by Lewis et al found significant differences in the odds ratio for upper gastrointestinal bleeding, with an increased risk from the safest (ibuprofen, odds ratio 1.7) to ketoprofen (34.9).14 In addition, there was an up to 8-fold variation in risk across the recommended dose ranges for each drug. Indomethacin <1200 mg/day was no more harmful than paracetamol, but at doses >1800 mg/day had an odds ratio of 4.6. As a general rule, the GI toxicity of NSAIDs correlates with the degree of anti-inflammatory activity, so that those with high analgesic/low anti-inflammatory activity (e.g. ibuprofen) are less ulcerogenic than those with relatively high anti-inflammatory: analgesic properties (e.g. piroxicam).15 The GI risks with aspirin are becoming a major cause of ulcer complications as its use becomes more widespread. Furthermore, the combination of NSAIDs and aspirin has a multiplicative rather than a simple additive effect on risk. Even the low doses of aspirin widely used to prevent cardiovascular events are associated with an increased risk of upper GI haemorrhage, with a daily dose of 75 mg having an odds ratio of around 2, and a daily dose of 300 mg an odds ratio of almost 4.16
Dyspepsia and gastroduodenal ulcers NSAIDs About one-third of patients taking NSAIDs experience dyspepsia. In most cases, this occurs in the absence of ulceration. Some studies suggest that NSAID-induced dyspepsia is particularly common in patients infected with Helicobacter pylori. NSAIDs are the commonest cause of gastric and duodenal ulcers (Figure 1). Studies in which patients taking NSAIDs have undergone endoscopy regardless of symptoms have shown a high incidence of ulceration (about 20%). It seems likely, however, that some of these ulcers are relatively trivial or transient, or are superficial erosions mistakenly classified as ulcers. NSAIDs cause ulcers due to inhibition of prostaglandin synthesis. Diagnostic problems: many NSAID-associated ulcers are silent, and NSAIDs often cause dyspepsia without ulceration. Dyspepsia is thus a poor guide when deciding whether to perform endoscopy. Estimation of risk: The use of traditional NSAIDs increases the risk of serious GI complications between 2.5 and 5-fold.3–5 Recent studies have shown that the cumulative incidence of upper GI complications is between 0.92% and 1.4% after 12 months of NSAID use.6–8 With the increasing use of aspirin (particularly in low doses for cardiovascular prophylaxis), this drug is now associated with as many ulcer bleeds as all other NSAIDs together. Overall, patients taking NSAIDs probably undergo hospitalization for
Cyclo-oxygenase (COX)-2 inhibitors Selective COX-2 inhibitors were heralded as a ‘safer aspirin’ because they carried the anti-inflammatory benefits of COX-2 inhibition whilst retaining the gastroprotective benefits of COX- 1. An outcome study of 8000 patients (VIGOR) showed that use of the COX-2 selective inhibitor rofecoxib was associated with 50% fewer complicated ulcers than a traditional NSAID.17 Another large outcome study, Celecoxib Long-term Arthritis Safety Study (CLASS), however, found no significant reduction in symptomatic upper GI ulcers and ulcer complications.6 The likely explanation is that gastroprotection with COX-2 inhibition was lost in patients taking concomitant low-dose aspirin. H. pylori – the interaction between H. pylori and NSAIDs is controversial. H pylori appears to increase the risk of ulcers in NSAID users, and vice versa.18,19 One study has shown that eradication of H. pylori before NSAID use reduces the risk of ulcers and ulcer complications.20 Another has shown that eradication alone makes no difference to the outcome in patients already established on NSAIDs.21 Other studies have shown that continuing H. pylori infection is associated with better rather than worse outcomes when acid-suppressing drugs are used.22 Prophylaxis (see Table 2) Patients with one or more risk factors for NSAID associated ulcers should be prescribed preventive treatment, although this is often neglected.
Figure 1 An NSAID-induced gastric ulcer with active bleeding. Courtesy of Clinical gastroenterology and hepatology, Mosby, 2005.2
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Nausea and vomiting
NSAID recommendations post rofecoxib Risk
No/low NSAID gastrointestinal risk
No cardiovascular Traditional NSAID risk (no aspirin)
Cardiovascular risk (consider aspirin)
Traditional NSAID2 plus PPI if gastrointestinal risk warrants gastroprotection Consider nonNSAID therapy
Nausea and vomiting are common adverse drug reactions that may occur in the context of gut damage, including ulceration, or pharmacologically. The more common drug causes are listed in Table 3. Many drugs (e.g. levodopa, opiates, cisplatin, digoxin) induce symptoms by directly stimulating the chemoreceptor trigger zone in the area postrema (located on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle). Chemotherapeutic agents probably cause nausea and vomiting by stimulating serotonin release from entero-chromaffin cells within the gut, which activates the vagus. Drugs such as potassium chloride, iron preparations and NSAIDs probably act via direct gastric irritation. In a few patients, these symptoms are accompanied by gastric or duodenal ulceration. Dopamine receptors in the area postrema are the target for anti-emetic drugs like chlorpromazine, haloperidol, domperidone and metoclopramide. Nausea is a challenging symptom to investigate and no drug should be judged blameless until the effect of stopping it has been assessed. Use of several drugs at one time, particularly in elderly patients, can cause nausea, and it is important to simplify drug regimens in such patients.
NSAID gastrointestinal risk
Traditional NSAID + PPI or Coxib + PPI1 (if necessary) Consider non-NSAID therapy A gastroprotective agent must be added if a traditional NSAID2 is prescribed Consider non-NSAID therapy
Adapted from Chan FKL, Graham D. Aliment Pharmacol Ther 2004; 19: 1051–61.25
Table 2
Pancreatitis
• Use of alternative analgesia, not NSAID. • When possible, ibuprofen, 1200 mg or less/24 hours, should be used in preference to other NSAIDs because it is safer. • Many patients are given H2-receptor antagonists to protect them against NSAID damage, but there is good evidence to suggest that only duodenal ulcer is prevented at normal dose. • Proton pump inhibitors (PPIs) have been shown to prevent aspirin and NSAID induced injury. Misoprostol is as effective as PPIs but poorly tolerated.23 • Use of COX-2 inhibitors may also reduce the risk for GI events, although this benefit is negated in patients who also take aspirin, and COX-2 inhibitors (and probably non-selective NSAIDs) are associated with increased cardiovascular adverse events.24
Alcohol is a common cause of pancreatitis. Other drug-related causes are uncommon, but the main culprits are: • diuretics (thiazides, furosemide) • sulphonamides • azathioprine • 6-mercaptopurine • corticosteroids • L-asparaginase (about 7% of recipients).
Constipation Antimuscarinic drugs and opiates are the main causes of druginduced constipation (Table 4). Reduced bowel frequency also
Management: NSAID ulcers have been shown to heal with all standard anti-ulcer drug regimens. Healing is faster if the NSAID is stopped. Comparative studies show that omeprazole, 20 mg daily, achieves faster healing in gastric and duodenal ulcers than ranitidine, 150 mg bd, or misoprostol, 200 μg qds.26
Common drug causes of nausea and vomiting Locally irritant • Potassium chloride • Iron preparations • NSAIDs • Theophyllines • Azathioprine (?mechanism) • Metronidazole
Other causes It should be remembered that dyspepsia occurs with the non-aspirin salicylates (e.g. mesalazine) used in inflammatory bowel disease. For most drugs, the precise mechanism by which dyspepsia arises is unknown, though there are a few exceptions (e.g. erythromycin, which causes epigastric pain and general cramp as a consequence of its motilin receptor agonist prokinetic activity). Drugs such as reserpine, cytotoxic agents, oral gold and pivampicillin have been associated with peptic ulceration, though the evidence for the association is often informal. Recently, calcium channel antagonists have been implicated in peptic ulcer bleeding. Corticosteroids – it now seems likely that corticosteroids do not increase the risk of ulceration, except in patients taking NSAIDs.
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Act via the CNS • Levodopa • Bromocriptine • Opiates • Digoxin • Chemotherapeutic agents (e.g. cisplatin, mustine, dacarbazine, cyclophosphamide) Table 3
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pseudo- membranous colitis in hospitalized patients – there is evidence to implicate indiscriminate use of cephalosporins) • β-blockers, which act by antagonizing antiperistaltic adrenergic stimulation • bile acids, which have a direct irritant action in the colon • misoprostol, which stimulates intestinal secretion and motility. Other causes include the following. • Magnesium-containing antacids (available over the counter), in a recent study they accounted for 4% of patients referred for evaluation of diarrhoea. Generally, this was not detected in the initial history. • Deliberate use of laxatives should always be considered in patients with diarrhoea, particularly when potassium is low. • All salicylates can cause diarrhoea, but it is particularly likely with olsalazine, which has been shown to stimulate small intestinal secretion. • Azathioprine can occasionally cause diarrhoea, sometimes in the context of toxic shock-like syndrome. This may cause diagnostic confusion when the drug is used for inflammatory bowel disease. • It is increasingly recognized that drugs that suppress acid production (H2-antagonists and PPIs) predispose to enteric superinfection.
Common drug causes of constipation and diarrhoea Constipation • Antimuscarinic drugs (e.g. atropine, phenothiazines, tricyclic antidepressants) • Opiates • Mebeverine • Peppermint oil • Aluminium-containing antacids • Sucralfate • Gaviscon • Iron • Laxatives (chronic) Diarrhoea • β-blockers • Misoprostol • Antibiotics • Magnesium-containing antacids • Olsalazine • Mefenamic acid • Iron • Laxatives (acute) • Metformin • Angiotension-converting enzyme inhibitors • Statins
Malabsorption Many drugs (e.g. colchicine, methotrexate, laxatives) can cause malabsorption, though this is usually of little clinical significance. Sulfasalazine and phenytoin commonly cause folate malabsorption.
Table 4
occurs with 5-HT antidepressants (e.g. fluoxetine) and locally acting antispasmodics (e.g. mebeverine, peppermint oil). Codeine-containing analgesics are available over the counter, and some patients establish a self-defeating cycle, using them for constipation-induced abdominal pain. Aluminium-containing antacids, sucralfate and Gaviscon (GlaxoSmithKline) also commonly constipate, as does iron (though this can also cause diarrhoea). Drug-induced megacolon from enteric neurotoxicity caused by vincristine or (possibly) laxatives is an uncommon but important cause of drug-induced constipation. Although fibre (dietary and prescribed) is used to treat constipation, it can cause pain, bloating and occasionally impaction if excessive amounts are ingested unaccompanied by adequate volumes of liquid.
Small intestinal injury
Anthranoid laxatives (e.g. senna) are widely used laxatives of natural origin which pass unabsorbed to the large bowel, where they are metabolized to aglycones. These aglycones exert their laxative effect by damaging epithelial cells, which leads directly and indirectly to changes in absorption, secretion and motility. Damaged epithelial cells can be found as apoptotic bodies in the pigmented colonic mucosa, characteristic for pseudomelanosis coli.
The small intestine may be a more common site for NSAID toxicity than the well recognized effects on the stomach and duodenum, although these effects may be more occult, and usually arise only after chronic (e.g. 6 months) use. An estimated 70% of NSAID users demonstrate intestinal inflammation when indirectly measured, for example by scintigraphy.27 Small bowel enteropathy, a combination of increased intestinal permeability and mild mucosal inflammation, is suggested by hypoalbuminaemia and iron deficiency. Studies of longterm NSAID users suggest 60–70% have an asymptomatic enteropathy.27,28 Until recently, most indications of small ulceration have come indirectly, or from surgical or indeed post-mortem specimens. A large autopsy study revealed small bowel ulcers in 8.4% of patients who had been taking NSAIDs compared to 0.6% of patients who had not been taking NSAIDs.29 With the advent of capsule endoscopy the small bowel can now be directly visualized, and initial studies suggest a higher rate of small bowel lesions seen at capsule endoscopy in NSAID users (76%) compared to healthy volunteers (11%)(Figure 2).30
Diarrhoea
Colitis
Drug-induced diarrhoea (Table 4) is common. The main causes are: • antibiotics, which disturb the colonic flora and tend to select C. difficile (responsible for a growing epidemic of
The most common drug-related causes of colitis are shown in Table 5. Mefenamic acid directly damages epithelial cells; clinical presentation ranges from simple reversible secretory diarrhoea
Melanosis coli
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Figure 3 Appearance of pseudomembrane in sigmoid colon after broad spectrum antibiotics (cephalosporin), with proven Clostridium difficile toxin on stool testing. Courtesy of Clinical gastroenterology and hepatology, Mosby, 2005.2
Figure 2 Typical small bowel erosions in the terminal ileum in a healthy volunteer taking NSAIDs, with red halo due to hyperaemia and pale centre.
that NSAIDs cause lower gastrointestinal tract problems, including erosions, ulcers and strictures. Presentations include blood and protein loss, perforation and obstruction.
to colitis. Other NSAIDs seldom cause diarrhoea and none has been conclusively shown to be a primary cause of colitis, though they may provoke relapse. The rare condition, collagenous colitis, may be associated with NSAID use, but this may be a consequence rather than a cause because patients with collagenous colitis exhibit a greater incidence of arthritis, which may require NSAID administration. Antibiotics commonly cause loose stools or diarrhoea, and patients may present with severe pseudo-membranous colitis (see Figure 3) as a result of C. difficile selection.
Minimizing the adverse gastrointestinal effects of drugs • Drugs can get stuck in the oesophagus, particularly when in gelatine capsules; they should be taken with plenty of fluid. • NSAID-associated gastroduodenal toxicity varies with drug and dose; the best action is to stop the NSAID whenever possible, minimize the dose and/or use ibuprofen, ≤1200 mg daily, or a COX-2 inhibitor. • NICE recommends that COX-2 inhibitors be reserved for patients at ‘high risk’ of GI side-effects; an alternative might be to use COX-2 inhibitors in ‘average-risk’ patients and consider NSAIDs plus a PPI, or even coxib plus a PPI in high-risk patients, based on individual circumstances.32 • Avoiding slow-release preparations may reduce small and large bowel problems associated with NSAIDs and iron preparations. • In patients with inflammatory bowel disease, the possibility of drug-induced diarrhoea caused by olsalazine or azathioprine, and disease relapse caused by paracetamol or NSAIDs, requires careful consideration. • Diarrhoea caused by β-blockers is common and often not appreciated by prescribers. • Prescribers of H2-antagonists and proton pump inhibitors should be aware of the possibility of enteric infections. ◆
Exacerbation of ulcerative colitis There is evidence that analgesic drugs (NSAIDs and paracetamol) provoke relapse of colitis in some patients. COX-2 drugs have also been implicated in the exacerbation of Inflammatory bowel disease.31 The mechanism is unknown. It is increasingly recognized
Drugs that cause colitis Antibiotics Amoxicillin Ampicillin Clindomycin Erythromycin Cephalosporins Drugs causing ischaemic colitis Oral contraceptive pill Chemotherapeutic agents – 5-fluorouracil, cisplatin Danazol Vasopressin Clindamycin Miscellaneous NSAIDs Methyldopa Penicillamine Gold (oral)
References 1 Neal KR, Scott HM, Slack RC, et al. Omeprazole as a risk factor for campylobacter gastroenteritis: case-control study. BMJ 1996; 312: 414–15. 2 Cryer B, Bauer DC. Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence? Mayo Clin Proc 2002; 77: 1031–43. 3 Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/ perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000; 160: 2093–99.
Table 5
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4 Derry S. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000; 321: 1183–7. 5 Garcia Rodriguez LA, Hernandez-Diaz S, De Abajo J. Association between aspirin and upper gastrointestinal complications: systematic review of epidemilogic studies. Br J Clin Pharmacol 2001; 52: 563–71. 6 Silverstein FE, Goldstein JL, Simon LS, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–55. 7 Bombardier C, Reicin A, Shapiro D, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343: 1520–8. 8 Schnitzer TJ, Mysler E, Hochberg MC, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004; 364: 665–74. 9 Blower AL, Brooks A, Fenn GC, et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283–91. 10 Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 2002; 123: 1006–12. 11 Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal antiinflammatory drugs. A meta-analysis. Arch Intern Med 1991; 115: 787–96. 12 Shorr RI, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for haemorrhagic peptic ulcer disease. Arch Intern Med 1993; 153: 1665–70. 13 Mellemkjaer L, Sorensen HT, Thomassen L, et al. Upper gastrointestinal bleeding among users of NSAIDs: a population-based cohort study in Denmark. Br J Clin Pharmacol 2002; 53: 173–81. 14 Lewis SC, Laporte J, Matthews JN, Rawlins MD, Wiholm B. Doseresponse relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Br J Clin Pharmacol 2002; 54: 320. 15 Graham DY. Nonsteroidal anti-inflammatory drugs, helicobacter pylori, and ulcers: where we stand. Am J Gastroenterol 1996; 91: 2080–6. 16 Tashima K, Fujita A, Umeda M, Takeuchi K. Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats. Life Sci 2000; 67: 1639–52. 17 Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343: 1520–8. 18 Santucci L, Forucci S, Patoia L, Dimatteo FM, Brunori PM, Morelli A. Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens. Dig Dis Sci 1995; 40: 2074–80. 19 Huang J-Q, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002; 359: 14–22.
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20 Chan FK, Sung JJ, Chung SC, et al. Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997; 350: 975–79. 21 Hawkey C, Tulassay Z, Szczepanski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Lancet 1998; 352: 1016–21. 22 Bianchi Porro G, Parente F, Imbesi V, Montrone F, Caruso I. Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users. Response to omeprazole dual therapy. Gut 1996; 39: 22–26. 23 Graham DY, Agrawal NM, Campbell DR, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebocontrolled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162: 169–75. 24 Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102. 25 Chan FK, Graham DY. Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complications–review and recommendations based on risk assessment. Aliment Pharmacol Ther 2004; 19: 1051–61. 26 Yeomans N. New data on healing of nonsteroidal anti-inflammatory drug-associated ulcers and erosions. Omeprazole NSAID Steering Committee. Am J Med 1998; 104: 79S–80S. 27 Bjarnason I, Hayllar J, MacPherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104: 1832–47. 28 Bjarnason I, Smith T, Prouse P, Williams P, Smethurst P. NSAID drug induced inflammation in humans. Gastroenterology 1987; 93: 480–89. 29 Allison MC, Howatson AG, Torance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992; 327: 749–54. 30 Gomez-Rodriguez B, Romero-Vasquez J, et al. NSAIDs erosive enteropathy assessed by capsule endoscopy. Gastroenterology 2004; 126: A96. 31 Matuk R, Crawford J, Abreu MT, Targan SR, Vasilauskas EA, Papadakis KA. The spectrum of gastrointestinal toxicity and effect on disease activity of selective cyclo-oxygenase-2 inhibitors in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004; 10: 352–56. 32 National Institute for Health and Clinical Excellence. Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for OA and RA. Technology Appraisal Guidance No. 27, 2001.
Further reading Fortun PJ, Hawkey CJ. Non-steroidal anti-inflammatory drugs and the small intestine. Curr Opin Gastroenterol 2005; 21: 169–75. Gilman AG, Roll TW, Nies AS, et al. The pharmacological basis of therapeutics. New York: McGraw-Hill, 1992. Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers (Cochrane Review). Cochrane Database Syst Rev 2002; (Issue 4).
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principally by inhibiting prostaglandin synthesis. In other cases, impairment of defence mechanisms is less direct; for example, there is a greater incidence of Salmonella and Campylobacter enteritis with proton pump inhibitors because the main physiological role of stomach acid is to sterilize ingested food before passage to the intestine.1 Direct injury to the GI tract – examples include oesophageal damage by potassium preparations, gastroduodenal ulcers caused by cytotoxic drugs, and the ulceration and colitis associated with NSAIDs independent of prostaglandin inhibition. Changes in colonic bacterial flora – widespread use of antibiotics, particularly cephalosporins, is associated with an increased incidence of Clostridium difficile infection and pseudomembranous colitis. However, there may be overlap between the groups (e.g. aspirin exhibits topical toxicity and inhibits prostaglandin-dependent mucosal defences).
Paul Fortun Christopher J Hawkey
Abstract Adverse drug effects on the gastrointestinal (GI) tract can occur as a predictable result of a drug’s mode of action, by direct injury, through compromising GI defences, or as a consequence of changes in colonic bacterial flora. Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonest cause of gastroduodenal injury due to inhibition of prostaglandin synthesis, and increase the risk of serious GI complications between 2.5- to 5- fold. There is considerable variation in risk across the recommended dose ranges for individual NSAIDs. Low doses of aspirin are associated with an increased risk of upper GI haemorrhage. COX-2 inhibitors largely spare the GI mucosa from injury, unless they are co-administered with aspirin when the GI safety benefits are abrogated. As the small intestine becomes more accessible to imaging modalities such as capsule endoscopy, small bowel enteropathy is suggested by hypoalbuminaemia and iron deficiency. Druginduced colitis is an important problem, with antibiotics the commonest drug cause. Drugs can also exacerbate pre-existing inflammatory bowel disease. Strategies to minimize the adverse GI effects of drugs include giving the lowest dose of NSAID for the shortest time, selective COX-2 inhibitors for high GI/low cardiovascular risk patients, and upper GI mucosal protection by co-prescription of NSAIDs with proton pump inhibitors.
Oesophageal disease Heartburn Drugs commonly associated with heartburn and/or oesophageal injury are listed in Table 1. Drugs that relax the lower oesophageal sphincter are particularly likely to cause problems because of the increased acid exposure of the oesophagus (often without mucosal injury). Patients should be managed by drug withdrawal when possible, though a few may require acid suppression. Endoscopy is not usually required if the onset is clearly related to the drug and the condition settles on drug cessation. Candida oesophagitis is a common cause of dyspepsia (heartburn) or odynophagia (painful swallowing) in patients taking corticosteroids, antibiotics, and those on immunosuppressive drugs. The characteristic change on endoscopy is the formation of discrete white plaques.
Keywords adverse events; drugs; gastrointestinal injury; large bowel; NSAIDs; small intestine
Mucosal injury and strictures Tetracyclines, potassium chloride, certain bisphosphonates and quinidine are recognized as toxic to the oesophageal mucosa.
Almost any drug can affect the gastrointestinal (GI) tract. It has been estimated that 40% of adverse drug reactions affect the GI tract, and 4% of admissions to hospital are caused by drug-induced disorders. This contribution highlights drug-induced GI disorders that are common, important or often missed. It is useful to consider drug effects on the GI tract in the four categories below. Consequences of pharmacological mode of action – adverse drug effects can occur as a predictable result of a drug’s mode of action. Thus, anticholinergic agents (e.g. antidepressants) reduce oesophageal sphincter pressure, resulting in reflux and heartburn; they also reduce colonic transit, resulting in constipation. Impairment of GI defences – the best-known examples are non-steroidal anti-inflammatory drugs (NSAIDs), which act
Common drug causes of oesophageal problems Relax lower oesophageal sphincter causing heartburn • Anticholinergic agents (e.g. procyclidine, trihexyphenidyl) • Tricyclic antidepressants • Calcium channel blockers • Nitrates • Phenothiazines Direct mucosal injury • Tetracyclines • Bisphosphonates Associated with strictures • Potassium chloride1 • Quinidine1 • NSAIDs
Paul Fortun MRCP is Lecturer in Gastroenterology at University Hospital, Nottingham, UK. Competing interests: none declared.
1Particularly
Christopher J Hawkey DM FRCP is Professor of Gastroenterology at the University Hospital, Nottingham, UK. Competing interests: none declared.
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slow-release preparations.
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However, presentation may vary with different drugs. NSAIDs and tetracyclines are a relatively common cause of erosive or pill oesophagitis; potassium chloride and quinidine are more strongly associated with stricture, often in the mid-oesophagus. These problems are more common in elderly patients, particularly those with pre-existing oesophageal disease or massive left atrial enlargement, and are more likely to occur when patients swallow their pills in a reclining position. Sustained-release preparations of potassium and quinidine are particularly likely to cause problems. There is an association between bisphosphonates and reversible oesophagitis, but the risk is low if the medication is administered correctly (i.e. in an upright position).2
gastrointestinal problems about once every 50–100 patient-years. In the UK, it is likely that at least 2000 patients per year die as a result of NSAID use (due to GI complications).9 Risk factors Patient-associated risk factors – concomitant risk factors are age, previous gastrointestinal bleeding, and patients who are also on anticoagulants, and to a lesser extent corticosteroids.3,10–13 Drug-related risk factors – the main drug-related risk factors are dose, choice of NSAID, co-prescription of corticosteroids and co-prescription of warfarin. The risk of ulcer complications increases with dose. A meta-analysis by Lewis et al found significant differences in the odds ratio for upper gastrointestinal bleeding, with an increased risk from the safest (ibuprofen, odds ratio 1.7) to ketoprofen (34.9).14 In addition, there was an up to 8-fold variation in risk across the recommended dose ranges for each drug. Indomethacin <1200 mg/day was no more harmful than paracetamol, but at doses >1800 mg/day had an odds ratio of 4.6. As a general rule, the GI toxicity of NSAIDs correlates with the degree of anti-inflammatory activity, so that those with high analgesic/low anti-inflammatory activity (e.g. ibuprofen) are less ulcerogenic than those with relatively high anti-inflammatory: analgesic properties (e.g. piroxicam).15 The GI risks with aspirin are becoming a major cause of ulcer complications as its use becomes more widespread. Furthermore, the combination of NSAIDs and aspirin has a multiplicative rather than a simple additive effect on risk. Even the low doses of aspirin widely used to prevent cardiovascular events are associated with an increased risk of upper GI haemorrhage, with a daily dose of 75 mg having an odds ratio of around 2, and a daily dose of 300 mg an odds ratio of almost 4.16
Dyspepsia and gastroduodenal ulcers NSAIDs About one-third of patients taking NSAIDs experience dyspepsia. In most cases, this occurs in the absence of ulceration. Some studies suggest that NSAID-induced dyspepsia is particularly common in patients infected with Helicobacter pylori. NSAIDs are the commonest cause of gastric and duodenal ulcers (Figure 1). Studies in which patients taking NSAIDs have undergone endoscopy regardless of symptoms have shown a high incidence of ulceration (about 20%). It seems likely, however, that some of these ulcers are relatively trivial or transient, or are superficial erosions mistakenly classified as ulcers. NSAIDs cause ulcers due to inhibition of prostaglandin synthesis. Diagnostic problems: many NSAID-associated ulcers are silent, and NSAIDs often cause dyspepsia without ulceration. Dyspepsia is thus a poor guide when deciding whether to perform endoscopy. Estimation of risk: The use of traditional NSAIDs increases the risk of serious GI complications between 2.5 and 5-fold.3–5 Recent studies have shown that the cumulative incidence of upper GI complications is between 0.92% and 1.4% after 12 months of NSAID use.6–8 With the increasing use of aspirin (particularly in low doses for cardiovascular prophylaxis), this drug is now associated with as many ulcer bleeds as all other NSAIDs together. Overall, patients taking NSAIDs probably undergo hospitalization for
Cyclo-oxygenase (COX)-2 inhibitors Selective COX-2 inhibitors were heralded as a ‘safer aspirin’ because they carried the anti-inflammatory benefits of COX-2 inhibition whilst retaining the gastroprotective benefits of COX- 1. An outcome study of 8000 patients (VIGOR) showed that use of the COX-2 selective inhibitor rofecoxib was associated with 50% fewer complicated ulcers than a traditional NSAID.17 Another large outcome study, Celecoxib Long-term Arthritis Safety Study (CLASS), however, found no significant reduction in symptomatic upper GI ulcers and ulcer complications.6 The likely explanation is that gastroprotection with COX-2 inhibition was lost in patients taking concomitant low-dose aspirin. H. pylori – the interaction between H. pylori and NSAIDs is controversial. H pylori appears to increase the risk of ulcers in NSAID users, and vice versa.18,19 One study has shown that eradication of H. pylori before NSAID use reduces the risk of ulcers and ulcer complications.20 Another has shown that eradication alone makes no difference to the outcome in patients already established on NSAIDs.21 Other studies have shown that continuing H. pylori infection is associated with better rather than worse outcomes when acid-suppressing drugs are used.22 Prophylaxis (see Table 2) Patients with one or more risk factors for NSAID associated ulcers should be prescribed preventive treatment, although this is often neglected.
Figure 1 An NSAID-induced gastric ulcer with active bleeding. Courtesy of Clinical gastroenterology and hepatology, Mosby, 2005.2
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Nausea and vomiting
NSAID recommendations post rofecoxib Risk
No/low NSAID gastrointestinal risk
No cardiovascular Traditional NSAID risk (no aspirin)
Cardiovascular risk (consider aspirin)
Traditional NSAID2 plus PPI if gastrointestinal risk warrants gastroprotection Consider nonNSAID therapy
Nausea and vomiting are common adverse drug reactions that may occur in the context of gut damage, including ulceration, or pharmacologically. The more common drug causes are listed in Table 3. Many drugs (e.g. levodopa, opiates, cisplatin, digoxin) induce symptoms by directly stimulating the chemoreceptor trigger zone in the area postrema (located on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle). Chemotherapeutic agents probably cause nausea and vomiting by stimulating serotonin release from entero-chromaffin cells within the gut, which activates the vagus. Drugs such as potassium chloride, iron preparations and NSAIDs probably act via direct gastric irritation. In a few patients, these symptoms are accompanied by gastric or duodenal ulceration. Dopamine receptors in the area postrema are the target for anti-emetic drugs like chlorpromazine, haloperidol, domperidone and metoclopramide. Nausea is a challenging symptom to investigate and no drug should be judged blameless until the effect of stopping it has been assessed. Use of several drugs at one time, particularly in elderly patients, can cause nausea, and it is important to simplify drug regimens in such patients.
NSAID gastrointestinal risk
Traditional NSAID + PPI or Coxib + PPI1 (if necessary) Consider non-NSAID therapy A gastroprotective agent must be added if a traditional NSAID2 is prescribed Consider non-NSAID therapy
Adapted from Chan FKL, Graham D. Aliment Pharmacol Ther 2004; 19: 1051–61.25
Table 2
Pancreatitis
• Use of alternative analgesia, not NSAID. • When possible, ibuprofen, 1200 mg or less/24 hours, should be used in preference to other NSAIDs because it is safer. • Many patients are given H2-receptor antagonists to protect them against NSAID damage, but there is good evidence to suggest that only duodenal ulcer is prevented at normal dose. • Proton pump inhibitors (PPIs) have been shown to prevent aspirin and NSAID induced injury. Misoprostol is as effective as PPIs but poorly tolerated.23 • Use of COX-2 inhibitors may also reduce the risk for GI events, although this benefit is negated in patients who also take aspirin, and COX-2 inhibitors (and probably non-selective NSAIDs) are associated with increased cardiovascular adverse events.24
Alcohol is a common cause of pancreatitis. Other drug-related causes are uncommon, but the main culprits are: • diuretics (thiazides, furosemide) • sulphonamides • azathioprine • 6-mercaptopurine • corticosteroids • L-asparaginase (about 7% of recipients).
Constipation Antimuscarinic drugs and opiates are the main causes of druginduced constipation (Table 4). Reduced bowel frequency also
Management: NSAID ulcers have been shown to heal with all standard anti-ulcer drug regimens. Healing is faster if the NSAID is stopped. Comparative studies show that omeprazole, 20 mg daily, achieves faster healing in gastric and duodenal ulcers than ranitidine, 150 mg bd, or misoprostol, 200 μg qds.26
Common drug causes of nausea and vomiting Locally irritant • Potassium chloride • Iron preparations • NSAIDs • Theophyllines • Azathioprine (?mechanism) • Metronidazole
Other causes It should be remembered that dyspepsia occurs with the non-aspirin salicylates (e.g. mesalazine) used in inflammatory bowel disease. For most drugs, the precise mechanism by which dyspepsia arises is unknown, though there are a few exceptions (e.g. erythromycin, which causes epigastric pain and general cramp as a consequence of its motilin receptor agonist prokinetic activity). Drugs such as reserpine, cytotoxic agents, oral gold and pivampicillin have been associated with peptic ulceration, though the evidence for the association is often informal. Recently, calcium channel antagonists have been implicated in peptic ulcer bleeding. Corticosteroids – it now seems likely that corticosteroids do not increase the risk of ulceration, except in patients taking NSAIDs.
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Act via the CNS • Levodopa • Bromocriptine • Opiates • Digoxin • Chemotherapeutic agents (e.g. cisplatin, mustine, dacarbazine, cyclophosphamide) Table 3
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pseudo- membranous colitis in hospitalized patients – there is evidence to implicate indiscriminate use of cephalosporins) • β-blockers, which act by antagonizing antiperistaltic adrenergic stimulation • bile acids, which have a direct irritant action in the colon • misoprostol, which stimulates intestinal secretion and motility. Other causes include the following. • Magnesium-containing antacids (available over the counter), in a recent study they accounted for 4% of patients referred for evaluation of diarrhoea. Generally, this was not detected in the initial history. • Deliberate use of laxatives should always be considered in patients with diarrhoea, particularly when potassium is low. • All salicylates can cause diarrhoea, but it is particularly likely with olsalazine, which has been shown to stimulate small intestinal secretion. • Azathioprine can occasionally cause diarrhoea, sometimes in the context of toxic shock-like syndrome. This may cause diagnostic confusion when the drug is used for inflammatory bowel disease. • It is increasingly recognized that drugs that suppress acid production (H2-antagonists and PPIs) predispose to enteric superinfection.
Common drug causes of constipation and diarrhoea Constipation • Antimuscarinic drugs (e.g. atropine, phenothiazines, tricyclic antidepressants) • Opiates • Mebeverine • Peppermint oil • Aluminium-containing antacids • Sucralfate • Gaviscon • Iron • Laxatives (chronic) Diarrhoea • β-blockers • Misoprostol • Antibiotics • Magnesium-containing antacids • Olsalazine • Mefenamic acid • Iron • Laxatives (acute) • Metformin • Angiotension-converting enzyme inhibitors • Statins
Malabsorption Many drugs (e.g. colchicine, methotrexate, laxatives) can cause malabsorption, though this is usually of little clinical significance. Sulfasalazine and phenytoin commonly cause folate malabsorption.
Table 4
occurs with 5-HT antidepressants (e.g. fluoxetine) and locally acting antispasmodics (e.g. mebeverine, peppermint oil). Codeine-containing analgesics are available over the counter, and some patients establish a self-defeating cycle, using them for constipation-induced abdominal pain. Aluminium-containing antacids, sucralfate and Gaviscon (GlaxoSmithKline) also commonly constipate, as does iron (though this can also cause diarrhoea). Drug-induced megacolon from enteric neurotoxicity caused by vincristine or (possibly) laxatives is an uncommon but important cause of drug-induced constipation. Although fibre (dietary and prescribed) is used to treat constipation, it can cause pain, bloating and occasionally impaction if excessive amounts are ingested unaccompanied by adequate volumes of liquid.
Small intestinal injury
Anthranoid laxatives (e.g. senna) are widely used laxatives of natural origin which pass unabsorbed to the large bowel, where they are metabolized to aglycones. These aglycones exert their laxative effect by damaging epithelial cells, which leads directly and indirectly to changes in absorption, secretion and motility. Damaged epithelial cells can be found as apoptotic bodies in the pigmented colonic mucosa, characteristic for pseudomelanosis coli.
The small intestine may be a more common site for NSAID toxicity than the well recognized effects on the stomach and duodenum, although these effects may be more occult, and usually arise only after chronic (e.g. 6 months) use. An estimated 70% of NSAID users demonstrate intestinal inflammation when indirectly measured, for example by scintigraphy.27 Small bowel enteropathy, a combination of increased intestinal permeability and mild mucosal inflammation, is suggested by hypoalbuminaemia and iron deficiency. Studies of longterm NSAID users suggest 60–70% have an asymptomatic enteropathy.27,28 Until recently, most indications of small ulceration have come indirectly, or from surgical or indeed post-mortem specimens. A large autopsy study revealed small bowel ulcers in 8.4% of patients who had been taking NSAIDs compared to 0.6% of patients who had not been taking NSAIDs.29 With the advent of capsule endoscopy the small bowel can now be directly visualized, and initial studies suggest a higher rate of small bowel lesions seen at capsule endoscopy in NSAID users (76%) compared to healthy volunteers (11%)(Figure 2).30
Diarrhoea
Colitis
Drug-induced diarrhoea (Table 4) is common. The main causes are: • antibiotics, which disturb the colonic flora and tend to select C. difficile (responsible for a growing epidemic of
The most common drug-related causes of colitis are shown in Table 5. Mefenamic acid directly damages epithelial cells; clinical presentation ranges from simple reversible secretory diarrhoea
Melanosis coli
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Figure 3 Appearance of pseudomembrane in sigmoid colon after broad spectrum antibiotics (cephalosporin), with proven Clostridium difficile toxin on stool testing. Courtesy of Clinical gastroenterology and hepatology, Mosby, 2005.2
Figure 2 Typical small bowel erosions in the terminal ileum in a healthy volunteer taking NSAIDs, with red halo due to hyperaemia and pale centre.
that NSAIDs cause lower gastrointestinal tract problems, including erosions, ulcers and strictures. Presentations include blood and protein loss, perforation and obstruction.
to colitis. Other NSAIDs seldom cause diarrhoea and none has been conclusively shown to be a primary cause of colitis, though they may provoke relapse. The rare condition, collagenous colitis, may be associated with NSAID use, but this may be a consequence rather than a cause because patients with collagenous colitis exhibit a greater incidence of arthritis, which may require NSAID administration. Antibiotics commonly cause loose stools or diarrhoea, and patients may present with severe pseudo-membranous colitis (see Figure 3) as a result of C. difficile selection.
Minimizing the adverse gastrointestinal effects of drugs • Drugs can get stuck in the oesophagus, particularly when in gelatine capsules; they should be taken with plenty of fluid. • NSAID-associated gastroduodenal toxicity varies with drug and dose; the best action is to stop the NSAID whenever possible, minimize the dose and/or use ibuprofen, ≤1200 mg daily, or a COX-2 inhibitor. • NICE recommends that COX-2 inhibitors be reserved for patients at ‘high risk’ of GI side-effects; an alternative might be to use COX-2 inhibitors in ‘average-risk’ patients and consider NSAIDs plus a PPI, or even coxib plus a PPI in high-risk patients, based on individual circumstances.32 • Avoiding slow-release preparations may reduce small and large bowel problems associated with NSAIDs and iron preparations. • In patients with inflammatory bowel disease, the possibility of drug-induced diarrhoea caused by olsalazine or azathioprine, and disease relapse caused by paracetamol or NSAIDs, requires careful consideration. • Diarrhoea caused by β-blockers is common and often not appreciated by prescribers. • Prescribers of H2-antagonists and proton pump inhibitors should be aware of the possibility of enteric infections. ◆
Exacerbation of ulcerative colitis There is evidence that analgesic drugs (NSAIDs and paracetamol) provoke relapse of colitis in some patients. COX-2 drugs have also been implicated in the exacerbation of Inflammatory bowel disease.31 The mechanism is unknown. It is increasingly recognized
Drugs that cause colitis Antibiotics Amoxicillin Ampicillin Clindomycin Erythromycin Cephalosporins Drugs causing ischaemic colitis Oral contraceptive pill Chemotherapeutic agents – 5-fluorouracil, cisplatin Danazol Vasopressin Clindamycin Miscellaneous NSAIDs Methyldopa Penicillamine Gold (oral)
References 1 Neal KR, Scott HM, Slack RC, et al. Omeprazole as a risk factor for campylobacter gastroenteritis: case-control study. BMJ 1996; 312: 414–15. 2 Cryer B, Bauer DC. Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence? Mayo Clin Proc 2002; 77: 1031–43. 3 Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/ perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000; 160: 2093–99.
Table 5
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4 Derry S. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000; 321: 1183–7. 5 Garcia Rodriguez LA, Hernandez-Diaz S, De Abajo J. Association between aspirin and upper gastrointestinal complications: systematic review of epidemilogic studies. Br J Clin Pharmacol 2001; 52: 563–71. 6 Silverstein FE, Goldstein JL, Simon LS, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–55. 7 Bombardier C, Reicin A, Shapiro D, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343: 1520–8. 8 Schnitzer TJ, Mysler E, Hochberg MC, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004; 364: 665–74. 9 Blower AL, Brooks A, Fenn GC, et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283–91. 10 Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 2002; 123: 1006–12. 11 Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal antiinflammatory drugs. A meta-analysis. Arch Intern Med 1991; 115: 787–96. 12 Shorr RI, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for haemorrhagic peptic ulcer disease. Arch Intern Med 1993; 153: 1665–70. 13 Mellemkjaer L, Sorensen HT, Thomassen L, et al. Upper gastrointestinal bleeding among users of NSAIDs: a population-based cohort study in Denmark. Br J Clin Pharmacol 2002; 53: 173–81. 14 Lewis SC, Laporte J, Matthews JN, Rawlins MD, Wiholm B. Doseresponse relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Br J Clin Pharmacol 2002; 54: 320. 15 Graham DY. Nonsteroidal anti-inflammatory drugs, helicobacter pylori, and ulcers: where we stand. Am J Gastroenterol 1996; 91: 2080–6. 16 Tashima K, Fujita A, Umeda M, Takeuchi K. Lack of gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in the stomach of diabetic rats. Life Sci 2000; 67: 1639–52. 17 Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343: 1520–8. 18 Santucci L, Forucci S, Patoia L, Dimatteo FM, Brunori PM, Morelli A. Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens. Dig Dis Sci 1995; 40: 2074–80. 19 Huang J-Q, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002; 359: 14–22.
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20 Chan FK, Sung JJ, Chung SC, et al. Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997; 350: 975–79. 21 Hawkey C, Tulassay Z, Szczepanski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Lancet 1998; 352: 1016–21. 22 Bianchi Porro G, Parente F, Imbesi V, Montrone F, Caruso I. Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users. Response to omeprazole dual therapy. Gut 1996; 39: 22–26. 23 Graham DY, Agrawal NM, Campbell DR, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebocontrolled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162: 169–75. 24 Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102. 25 Chan FK, Graham DY. Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complications–review and recommendations based on risk assessment. Aliment Pharmacol Ther 2004; 19: 1051–61. 26 Yeomans N. New data on healing of nonsteroidal anti-inflammatory drug-associated ulcers and erosions. Omeprazole NSAID Steering Committee. Am J Med 1998; 104: 79S–80S. 27 Bjarnason I, Hayllar J, MacPherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104: 1832–47. 28 Bjarnason I, Smith T, Prouse P, Williams P, Smethurst P. NSAID drug induced inflammation in humans. Gastroenterology 1987; 93: 480–89. 29 Allison MC, Howatson AG, Torance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992; 327: 749–54. 30 Gomez-Rodriguez B, Romero-Vasquez J, et al. NSAIDs erosive enteropathy assessed by capsule endoscopy. Gastroenterology 2004; 126: A96. 31 Matuk R, Crawford J, Abreu MT, Targan SR, Vasilauskas EA, Papadakis KA. The spectrum of gastrointestinal toxicity and effect on disease activity of selective cyclo-oxygenase-2 inhibitors in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004; 10: 352–56. 32 National Institute for Health and Clinical Excellence. Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for OA and RA. Technology Appraisal Guidance No. 27, 2001.
Further reading Fortun PJ, Hawkey CJ. Non-steroidal anti-inflammatory drugs and the small intestine. Curr Opin Gastroenterol 2005; 21: 169–75. Gilman AG, Roll TW, Nies AS, et al. The pharmacological basis of therapeutics. New York: McGraw-Hill, 1992. Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers (Cochrane Review). Cochrane Database Syst Rev 2002; (Issue 4).
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