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Web site: May 2001
Prescriber Update No.21:25-27
Dr Ruth Savage, Medical Assessor, CARM, Dunedin
Two recent reports to the Centre for Adverse Reactions Monitoring (CARM) are a reminder that non-steroidal anti-inflammatory agents (NSAIAs) can cause damage to the mucosa of the distal small intestine and large intestine, as well as their more commonly known effects on the stomach and duodenum. Damage to the intestinal mucosa can lead to ulceration, bleeding, perforation and obstruction with the formation of diaphragm strictures. Presenting symptoms are similar to those of many bowel disorders, and serious complications may occur unless the possibility of NSAIAs as a cause is recognised. Immediate investigation is recommended with referral to a specialist and discontinuation of all NSAIAs.
Low incidence may hinder recognition of NSAIAs
as cause
Recent cases of intestinal ulcers reported to CARM
Multiple diaphragm strictures pathognomonic of NSAIA-induced
damage
Blood loss, obstruction and anaemia are suggestive of small
intestine damage
Diarrhoea, anaemia and weight loss may indicate large
intestine damage
NSAIAs can complicate existing bowel disease
References
Minor damage from NSAIAs can occur to the mucosa of the distal small intestine and large intestine as well as the stomach and duodenum. This damage is common but more serious complications are thought to occur rarely. Gastroduodenal events causing hospitalisation are estimated to occur in between 1 in 500 and 1 in 50 patients taking NSAIAs for a year depending on predisposing factors.1 In comparison, haemorrhage and perforation in the more distal intestine has been estimated to occur in about 1 in 5000 NSAIA-users a year.2 This low incidence may contribute to the association not being recognised.
Case 1: A 39 year old woman had been taking slow-release ketoprofen for many years. She had recurrent episodes of intestinal obstruction and iron deficiency anaemia over a five year period. Laparotomy revealed multiple intestinal ulcers on the mucosal surface and diaphragm strictures.
Case 2: A 73 year old woman had taken slow-release diclofenac for several months for a shoulder injury. She had a massive gastrointestinal haemorrhage, and was found to have colonic and ileal ulcers. She recovered after withdrawal of diclofenac and blood transfusion.
As well as haemorrhage, ulceration and perforation, NSAIAs can cause obstruction due to the formation of diaphragm strictures. These are thin septate narrowings, usually of the small intestinal mucosa and are thought to arise from circumferential ulcers. Multiple diaphragm strictures are pathognomonic of NSAIA-induced intestinal damage.3
Case series and case reports have now described diaphragm strictures in the large intestine and most have been associated with slow-release or enteric-coated NSAIA preparations.4 Epidemiological studies are needed to confirm whether the risk to the large intestine is greater with altered release than with standard release NSAIA preparations.
Symptoms of complications due to mucosal damage can differ between the small and large intestine as described below.
Case 1 illustrates the diagnostic difficulty with intestinal lesions and this is particularly so for the small intestine. It is estimated that 20-65% of long-term NSAIA-users have NSAIA enteropathy, i.e. small bowel inflammation.3 This is usually asymptomatic but clinical problems can arise from associated complications. These include blood loss, protein loss, ulceration and obstruction due to diaphragm stricture formation.3
Iron deficiency anaemia in a patient taking NSAIAs with a normal endoscopy and colonoscopy may be due to blood loss from the small intestine. Intermittent postprandial colicky pain (subacute obstruction) often with a history of iron deficiency and hypoalbuminaemia is suggestive of diaphragm strictures in the small intestine. Radiological findings may resemble malignancy or Crohn's disease, or can be normal. Enteroscopy can be helpful but is not always available.3
Colonic ulceration, perforation and haemorrhage have been associated with NSAIAs in one epidemiological study2 and in many published case reports. NSAIA-induced diaphragm strictures are usually found in the ascending colon.5 Symptoms suggestive of ulceration and diaphragm strictures in the large intestine are chronic diarrhoea, iron deficiency anaemia and weight loss, rather than pain and subacute obstruction.6 Major haemorrhage may occur as in Case 2. Colonoscopy, rather than x-ray, will help to ensure the correct diagnosis. 6
NSAIAs may also cause relapse of Crohn's disease and ulcerative colitis, and diverticular perforation, fistulae and abscesses.3 Due to similar presentations, it may be difficult to distinguish between relapses and NSAIA-induced exacerbations.
Early referral to a specialist is recommended when NSAIA complications are suspected. All NSAIAs should be stopped while investigation is undertaken. Patients should also be asked about any other medicines they may be taking, especially as some NSAIAs can be purchased over-the-counter.